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    Clinical Trial Results:
    A Phase 3 Randomized, Placebo-controlled, Double-blind Study of Apalutamide Plus Androgen Deprivation Therapy (ADT) Versus ADT in Subjects with Metastatic Hormonesensitive Prostate Cancer (mHSPC)

    Summary
    EudraCT number
    2015-000735-32
    Trial protocol
    SE   GB   HU   DE   ES   CZ   PL   RO   IT  
    Global end of trial date

    Results information
    Results version number
    v1(current)
    This version publication date
    29 Mar 2022
    First version publication date
    29 Mar 2022
    Other versions

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    56021927PCR3002
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02489318
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Aragon Pharmaceuticals, Inc
    Sponsor organisation address
    10990 Wilshire Blvd., Suite 440, Los Angeles, CA, United States, 90024
    Public contact
    Clinical Registry Group, Aragon Pharmaceuticals, Inc, ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Clinical Registry Group, Aragon Pharmaceuticals, Inc, ClinicalTrialsEU@its.jnj.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
    Interim
    Date of interim/final analysis
    07 Sep 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 Sep 2020
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this study was to determine if the addition of apalutamide to androgen deprivation therapy (ADT) provides superior efficacy in improving overall survival (OS) or radiographic progression-free survival (rPFS) for subjects with castration-sensitive prostate cancer mCSPC.
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practices and applicable regulatory requirements. The safety evaluations included monitoring of adverse events, clinical laboratory parameters (hematology, serum chemistry, fasting lipids, Thyroid stimulating hormone [TSH] and Prostate-specific antigen [PSA]), vital sign measurements, physical examinations, electrocardiograms, (collected at screening only) and Eastern Cooperative Oncology Group performance score.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    09 Dec 2015
    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
    Argentina: 37
    Country: Number of subjects enrolled
    Australia: 11
    Country: Number of subjects enrolled
    Brazil: 92
    Country: Number of subjects enrolled
    Canada: 30
    Country: Number of subjects enrolled
    China: 94
    Country: Number of subjects enrolled
    Czechia: 31
    Country: Number of subjects enrolled
    Germany: 17
    Country: Number of subjects enrolled
    Spain: 20
    Country: Number of subjects enrolled
    France: 16
    Country: Number of subjects enrolled
    United Kingdom: 36
    Country: Number of subjects enrolled
    Hungary: 24
    Country: Number of subjects enrolled
    Israel: 14
    Country: Number of subjects enrolled
    Italy: 34
    Country: Number of subjects enrolled
    Japan: 51
    Country: Number of subjects enrolled
    Korea, Republic of: 76
    Country: Number of subjects enrolled
    Mexico: 48
    Country: Number of subjects enrolled
    Poland: 19
    Country: Number of subjects enrolled
    Romania: 11
    Country: Number of subjects enrolled
    Russian Federation: 131
    Country: Number of subjects enrolled
    Sweden: 16
    Country: Number of subjects enrolled
    Turkey: 50
    Country: Number of subjects enrolled
    Ukraine: 102
    Country: Number of subjects enrolled
    United States: 92
    Worldwide total number of subjects
    1052
    EEA total number of subjects
    188
    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)
    331
    From 65 to 84 years
    701
    85 years and over
    20

    Subject disposition

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    Recruitment
    Recruitment details
    Response/progression or adverse events that occurred during a non-randomized switch-over to apalutamide+ADT were not counted towards efficacy or safety endpoints, respectively.

    Pre-assignment
    Screening details
    Per protocol, 208 subjects randomized to receive placebo+ADT were switched over to receive apalutamide+ADT after interim analysis and unblinding. Randomized treatment disposition has been reported in subject disposition.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo + Androgen Deprivation Therapy (ADT)
    Arm description
    Subjects received matching placebo (4 tablets) orally once daily (qd) along with ADT (gonadotropin releasing hormone analog [GnRHa] or surgical castration) as standard of care therapy in each 28-day treatment cycle. The choice of the GnRHa (agonist or antagonist) was at discretion of the investigator. In the event of a positive result at interim or final analysis subjects in treatment phase had opportunity to receive Apalutamide +ADT. Subjects received treatment until radiographic progression or unequivocal clinical progression, unacceptable toxicity, or death.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received matching placebo along with ADT orally once daily at pre-specified timepoints.

    Arm title
    Apalutamide + ADT
    Arm description
    Subjects received JNJ-56021927 (apalutamide) 240 milligrams (mg) (4*60 mg tablets) orally qd along with ADT (gonadotropin releasing hormone analog [GnRHa] or surgical castration) as standard of care therapy in each 28-day treatment cycle. The choice of the GnRHa (agonist or antagonist) was at discretion of the investigator. Subjects received treatment until radiographic progression or unequivocal clinical progression, unacceptable toxicity, or death.
    Arm type
    Experimental

    Investigational medicinal product name
    Apalutamide
    Investigational medicinal product code
    Other name
    JNJ-56021927
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received apalutamide 240 mg (4*60 mg) tablets orally along with ADT at pre-specified timepoints.

    Number of subjects in period 1
    Placebo + Androgen Deprivation Therapy (ADT) Apalutamide + ADT
    Started
    527
    525
    Completed
    527
    524
    Not completed
    0
    1
         Consent withdrawn by subject
    -
    1
    Period 2
    Period 2 title
    Treated
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo + Androgen Deprivation Therapy (ADT)
    Arm description
    Subjects received matching placebo (4 tablets) orally once daily (qd) along with ADT (gonadotropin releasing hormone analog [GnRHa] or surgical castration) as standard of care therapy in each 28-day treatment cycle. The choice of the GnRHa (agonist or antagonist) was at discretion of the investigator. In the event of a positive result at interim or final analysis subjects in treatment phase had opportunity to receive Apalutamide +ADT. Subjects received treatment until radiographic progression or unequivocal clinical progression, unacceptable toxicity, or death.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received matching placebo along with ADT orally once daily at pre-specified timepoints.

    Arm title
    Apalutamide + ADT
    Arm description
    Subjects received JNJ-56021927 (apalutamide) 240 milligrams (mg) (4*60 mg tablets) orally qd along with ADT (gonadotropin releasing hormone analog [GnRHa] or surgical castration) as standard of care therapy in each 28-day treatment cycle. The choice of the GnRHa (agonist or antagonist) was at discretion of the investigator. Subjects received treatment until radiographic progression or unequivocal clinical progression, unacceptable toxicity, or death.
    Arm type
    Experimental

    Investigational medicinal product name
    Apalutamide
    Investigational medicinal product code
    Other name
    JNJ-56021927
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received apalutamide 240 mg (4*60 mg) tablets orally along with ADT at pre-specified timepoints.

    Number of subjects in period 2
    Placebo + Androgen Deprivation Therapy (ADT) Apalutamide + ADT
    Started
    527
    524
    Completed
    208
    0
    Not completed
    319
    524
         Adverse event, not serious
    6
    30
         Physician decision
    4
    6
         Consent withdrawn by subject
    37
    36
         Adverse event, non-fatal
    8
    18
         Death
    18
    25
         Other, progressive disease
    245
    138
         Unspecified
    -
    2
         Other, ongoing
    -
    267
         Protocol deviation
    1
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo + Androgen Deprivation Therapy (ADT)
    Reporting group description
    Subjects received matching placebo (4 tablets) orally once daily (qd) along with ADT (gonadotropin releasing hormone analog [GnRHa] or surgical castration) as standard of care therapy in each 28-day treatment cycle. The choice of the GnRHa (agonist or antagonist) was at discretion of the investigator. In the event of a positive result at interim or final analysis subjects in treatment phase had opportunity to receive Apalutamide +ADT. Subjects received treatment until radiographic progression or unequivocal clinical progression, unacceptable toxicity, or death.

    Reporting group title
    Apalutamide + ADT
    Reporting group description
    Subjects received JNJ-56021927 (apalutamide) 240 milligrams (mg) (4*60 mg tablets) orally qd along with ADT (gonadotropin releasing hormone analog [GnRHa] or surgical castration) as standard of care therapy in each 28-day treatment cycle. The choice of the GnRHa (agonist or antagonist) was at discretion of the investigator. Subjects received treatment until radiographic progression or unequivocal clinical progression, unacceptable toxicity, or death.

    Reporting group values
    Placebo + Androgen Deprivation Therapy (ADT) Apalutamide + ADT Total
    Number of subjects
    527 525 1052
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    182 149 331
        From 65 to 84 years
    335 366 701
        85 years and over
    10 10 20
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    67.9 ± 8.42 68.9 ± 8.11 -
    Title for Gender
    Units: subjects
        Male
    527 525 1052
    Region of Enrollment
    Units: Subjects
        Argentina
    20 17 37
        Australia
    5 6 11
        Brazil
    38 54 92
        Canada
    16 14 30
        China
    46 48 94
        Czech Republic
    12 19 31
        France
    8 8 16
        Germany
    10 7 17
        Hungary
    11 13 24
        Israel
    8 6 14
        Italy
    18 16 34
        Japan
    23 28 51
        Mexico
    25 23 48
        Poland
    12 7 19
        Romania
    7 4 11
        Korea, Republic Of
    41 35 76
        Russia
    66 65 131
        Spain
    12 8 20
        Sweden
    8 8 16
        Turkey
    22 28 50
        Ukraine
    60 42 102
        United States
    59 69 128
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    11 6 17
        Asian
    112 119 231
        Native Hawaiian or Other Pacific Islander
    0 0 0
        Black or African American
    9 10 19
        White
    365 354 719
        More than one race
    0 1 1
        Unknown or Not Reported
    30 35 65

    End points

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    End points reporting groups
    Reporting group title
    Placebo + Androgen Deprivation Therapy (ADT)
    Reporting group description
    Subjects received matching placebo (4 tablets) orally once daily (qd) along with ADT (gonadotropin releasing hormone analog [GnRHa] or surgical castration) as standard of care therapy in each 28-day treatment cycle. The choice of the GnRHa (agonist or antagonist) was at discretion of the investigator. In the event of a positive result at interim or final analysis subjects in treatment phase had opportunity to receive Apalutamide +ADT. Subjects received treatment until radiographic progression or unequivocal clinical progression, unacceptable toxicity, or death.

    Reporting group title
    Apalutamide + ADT
    Reporting group description
    Subjects received JNJ-56021927 (apalutamide) 240 milligrams (mg) (4*60 mg tablets) orally qd along with ADT (gonadotropin releasing hormone analog [GnRHa] or surgical castration) as standard of care therapy in each 28-day treatment cycle. The choice of the GnRHa (agonist or antagonist) was at discretion of the investigator. Subjects received treatment until radiographic progression or unequivocal clinical progression, unacceptable toxicity, or death.
    Reporting group title
    Placebo + Androgen Deprivation Therapy (ADT)
    Reporting group description
    Subjects received matching placebo (4 tablets) orally once daily (qd) along with ADT (gonadotropin releasing hormone analog [GnRHa] or surgical castration) as standard of care therapy in each 28-day treatment cycle. The choice of the GnRHa (agonist or antagonist) was at discretion of the investigator. In the event of a positive result at interim or final analysis subjects in treatment phase had opportunity to receive Apalutamide +ADT. Subjects received treatment until radiographic progression or unequivocal clinical progression, unacceptable toxicity, or death.

    Reporting group title
    Apalutamide + ADT
    Reporting group description
    Subjects received JNJ-56021927 (apalutamide) 240 milligrams (mg) (4*60 mg tablets) orally qd along with ADT (gonadotropin releasing hormone analog [GnRHa] or surgical castration) as standard of care therapy in each 28-day treatment cycle. The choice of the GnRHa (agonist or antagonist) was at discretion of the investigator. Subjects received treatment until radiographic progression or unequivocal clinical progression, unacceptable toxicity, or death.

    Primary: Radiographic Progression-free Survival (rPFS)

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    End point title
    Radiographic Progression-free Survival (rPFS)
    End point description
    rPFS as assessed by the investigator was defined as the duration from the date of randomization to the date of first documentation of radiographic progressive disease or death due to any cause, whichever occurred first. Radiographic progressive disease was defined as progression of soft tissue lesions measured by computed tomography (CT) or magnetic resonance imaging (MRI) as defined by modified Response evaluation criteria in solid tumors (RECIST) 1.1. Intent to treat (ITT) population included all randomized participants classified according to their assigned treatment group, regardless of the actual treatment received. Here "99999" signifies that the median, lower limit and upper limit of confidence interval (CI) were not estimable due to lesser number of events for Apalutamide + ADT arm.
    End point type
    Primary
    End point timeframe
    Up to 35 months
    End point values
    Placebo + Androgen Deprivation Therapy (ADT) Apalutamide + ADT
    Number of subjects analysed
    527
    525
    Units: months
        median (confidence interval 95%)
    22.08 (18.46 to 32.92)
    99999 (99999 to 99999)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo + Androgen Deprivation Therapy (ADT) v Apalutamide + ADT
    Number of subjects included in analysis
    1052
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.484
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.391
         upper limit
    0.6

    Primary: Overall Survival (OS)

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    End point title
    Overall Survival (OS)
    End point description
    OS was defined as the time from date of randomization to date of death from any cause. ITT population included all randomized subjects classified according to their assigned treatment group, regardless of the actual treatment received. Here "99999" signifies that the upper limit of CI was not estimable due to lesser number of events for Placebo + Androgen Deprivation Therapy [ADT] arm and the median, lower limit and upper limit of CI were not estimable due to lesser number of events for Apalutamide + ADT arm.
    End point type
    Primary
    End point timeframe
    Up to 57 months
    End point values
    Placebo + Androgen Deprivation Therapy (ADT) Apalutamide + ADT
    Number of subjects analysed
    527
    525
    Units: months
        median (confidence interval 95%)
    52.17 (41.86 to 99999)
    99999 (99999 to 99999)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo + Androgen Deprivation Therapy (ADT) v Apalutamide + ADT
    Number of subjects included in analysis
    1052
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.651
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.534
         upper limit
    0.793

    Secondary: Time to Initiation of Cytotoxic Chemotherapy

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    End point title
    Time to Initiation of Cytotoxic Chemotherapy
    End point description
    Time to initiation of cytotoxic chemotherapy was defined as the time from date of randomization to the date of initiation of cytotoxic chemotherapy for prostate cancer. ITT population included all randomized subjects classified according to their assigned treatment group, regardless of the actual treatment received. Here "99999" signifies that the median, lower limit and upper limit of CI were not estimable due to lesser number of events for both the arms.
    End point type
    Secondary
    End point timeframe
    Up to 57 months
    End point values
    Placebo + Androgen Deprivation Therapy (ADT) Apalutamide + ADT
    Number of subjects analysed
    527
    525
    Units: months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo + Androgen Deprivation Therapy (ADT) v Apalutamide + ADT
    Number of subjects included in analysis
    1052
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.469
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.35
         upper limit
    0.63

    Secondary: Time to Pain Progression

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    End point title
    Time to Pain Progression
    End point description
    Time to pain progression was defined as the time from the date of randomization to the date of the first observation of pain progression.Pain progression was defined as an average increase by 2 points from baseline to greater than (>) 4 on the Brief Pain Inventory-Short Form (BPI-SF) worst pain intensity (item 3) with no decrease in opioids confirmed greater than equal to (>=) 3 weeks apart or initiation of chronic opioids,whichever occurred first. BPI-SF is a self-administered questionnaire developed to assess severity of pain and impact of pain on daily functions.Item 3=worst pain intensity asks participants to rate worst pain in prior 7-days on a 0= No pain to 10=Pain as bad as you can imagine. A lower score is better. ITT population included all randomized subjects classified according to their assigned treatment group, regardless of the actual treatment received. Here "99999" signifies that upper, lower limit of CI and median were not estimable due to lesser number of events.
    End point type
    Secondary
    End point timeframe
    Up to 57 months
    End point values
    Placebo + Androgen Deprivation Therapy (ADT) Apalutamide + ADT
    Number of subjects analysed
    527
    525
    Units: months
        median (confidence interval 95%)
    99999 (51.32 to 99999)
    99999 (99999 to 99999)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo + Androgen Deprivation Therapy (ADT) v Apalutamide + ADT
    Number of subjects included in analysis
    1052
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1966
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.868
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.7
         upper limit
    1.076

    Secondary: Time to Chronic Opioid Use

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    End point title
    Time to Chronic Opioid Use
    End point description
    Time to chronic opioid use was defined as the time from date of randomization to the first date of confirmed chronic opioid use. For subjects entering the study without receiving opioids, chronic opioid use was defined as administration of opioid analgesics lasting for greater than or equal to (>=)3 weeks for oral or >=7 days for non-oral formulations. For participants entering study already receiving opioids, chronic opioid use was defined as a >=30 percent (%) increase in total daily dose of the opioid analgesics lasting for >=3 weeks for oral or >=7 days for non-oral formulation. ITT population included all randomized subjects classified according to their assigned treatment group, regardless of the actual treatment received. Here "99999" signifies that upper, lower limit of CI and median were not estimable due to lesser number of events.
    End point type
    Secondary
    End point timeframe
    Up to 57 months
    End point values
    Placebo + Androgen Deprivation Therapy (ADT) Apalutamide + ADT
    Number of subjects analysed
    527
    525
    Units: months
        median (confidence interval 95%)
    99999 (51.32 to 99999)
    99999 (99999 to 99999)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo + Androgen Deprivation Therapy (ADT) v Apalutamide + ADT
    Number of subjects included in analysis
    1052
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1563
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.794
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.576
         upper limit
    1.094

    Secondary: Time to Skeletal-related Event (SRE)

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    End point title
    Time to Skeletal-related Event (SRE)
    End point description
    Time to SRE was defined as the time from the date of randomization to the date of the first observation of an SRE. A SRE was defined as the occurrence of either a pathological fracture, or spinal cord compression, or radiation to bone, or surgery to bone. ITT population included all randomized subjects classified according to their assigned treatment group, regardless of the actual treatment received. Here "9999" signifies that the upper limit of CI was not estimable due to lesser number of events for Placebo + Androgen Deprivation Therapy [ADT] arm and the median, lower limit and upper limit of CI were not estimable due to lesser number of events for Apalutamide + ADT arm.
    End point type
    Secondary
    End point timeframe
    Up to 57 months
    End point values
    Placebo + Androgen Deprivation Therapy (ADT) Apalutamide + ADT
    Number of subjects analysed
    527
    525
    Units: months
        median (confidence interval 95%)
    99999 (51.78 to 99999)
    99999 (99999 to 99999)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo + Androgen Deprivation Therapy (ADT) v Apalutamide + ADT
    Number of subjects included in analysis
    1052
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.3608
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.857
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.615
         upper limit
    1.194

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 57 months
    Adverse event reporting additional description
    Safety Analysis set: All subjects who received at least 1 dose of randomized study drug. For crossover subjects, adverse events after initiation of crossover treatment were summarized separately in Placebo+ADT to Apalutamide+ADT arm. However, adverse events occurred before crossover treatment were summarized in Placebo+ADT arm.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Placebo + Androgen Deprivation Therapy (ADT)
    Reporting group description
    Subjects received matching placebo (4 tablets) orally once daily (qd) along with ADT (gonadotropin releasing hormone analog [GnRHa] or surgical castration) as standard of care therapy in each 28-day treatment cycle. The choice of the GnRHa (agonist or antagonist) was at discretion of the investigator. In the event of a positive result at interim or final analysis subjects in treatment phase had opportunity to receive Apalutamide +ADT. Subjects received treatment until radiographic progression or unequivocal clinical progression, unacceptable toxicity, or death.

    Reporting group title
    Apalutamide + ADT
    Reporting group description
    Subjects received JNJ-56021927 (apalutamide) 240 milligrams (mg) (4*60 mg tablets) orally qd along with ADT (gonadotropin releasing hormone analog [GnRHa] or surgical castration) as standard of care therapy in each 28-day treatment cycle. The choice of the GnRHa (agonist or antagonist) was at discretion of the investigator. Subjects received treatment until radiographic progression or unequivocal clinical progression, unacceptable toxicity, or death.

    Reporting group title
    Placebo + ADT to Apalutamide + ADT
    Reporting group description
    After interim analysis and unblinding, participants receiving placebo +ADT crossed over to receive 240 mg apalutamide orally qd along with ADT in open-label extension phase.

    Serious adverse events
    Placebo + Androgen Deprivation Therapy (ADT) Apalutamide + ADT Placebo + ADT to Apalutamide + ADT
    Total subjects affected by serious adverse events
         subjects affected / exposed
    115 / 527 (21.82%)
    153 / 524 (29.20%)
    29 / 208 (13.94%)
         number of deaths (all causes)
    35
    31
    10
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of Colon
         subjects affected / exposed
    0 / 527 (0.00%)
    2 / 524 (0.38%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Adrenal Neoplasm
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Benign Lung Neoplasm
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bladder Cancer
         subjects affected / exposed
    1 / 527 (0.19%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Burkitt's Lymphoma
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cancer Pain
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric Cancer
         subjects affected / exposed
    1 / 527 (0.19%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Leiomyosarcoma
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung Carcinoma Cell Type Unspecified Stage I
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung Neoplasm Malignant
         subjects affected / exposed
    1 / 527 (0.19%)
    2 / 524 (0.38%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meningioma
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastases to Central Nervous System
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Non-Small Cell Lung Cancer
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory Papilloma
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Squamous Cell Carcinoma
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep Vein Thrombosis
         subjects affected / exposed
    1 / 527 (0.19%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 527 (0.00%)
    3 / 524 (0.57%)
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 527 (0.00%)
    2 / 524 (0.38%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Exercise Tolerance Decreased
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    3 / 527 (0.57%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gait Disturbance
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General Physical Health Deterioration
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Non-Cardiac Chest Pain
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 524 (0.00%)
    2 / 208 (0.96%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oedema
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Performance Status Decreased
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral Swelling
         subjects affected / exposed
    2 / 527 (0.38%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 527 (0.19%)
    2 / 524 (0.38%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign Prostatic Hyperplasia
         subjects affected / exposed
    2 / 527 (0.38%)
    2 / 524 (0.38%)
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute Pulmonary Oedema
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute Respiratory Failure
         subjects affected / exposed
    0 / 527 (0.00%)
    2 / 524 (0.38%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic Obstructive Pulmonary Disease
         subjects affected / exposed
    3 / 527 (0.57%)
    3 / 524 (0.57%)
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 527 (0.38%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemothorax
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hydrothorax
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Organising Pneumonia
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Paranasal Cyst
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural Effusion
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleuritic Pain
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax Spontaneous
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Embolism
         subjects affected / exposed
    1 / 527 (0.19%)
    3 / 524 (0.57%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Haemorrhage
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Mass
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Oedema
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory Failure
         subjects affected / exposed
    1 / 527 (0.19%)
    3 / 524 (0.57%)
    2 / 208 (0.96%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional State
         subjects affected / exposed
    1 / 527 (0.19%)
    2 / 524 (0.38%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mental Status Changes
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Suicidal Ideation
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Suicide Attempt
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device Malfunction
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    International Normalised Ratio Increased
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Weight Decreased
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Acetabulum Fracture
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ankle Fracture
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Brain Contusion
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clavicle Fracture
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Comminuted Fracture
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 527 (0.19%)
    3 / 524 (0.57%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femoral Neck Fracture
         subjects affected / exposed
    1 / 527 (0.19%)
    3 / 524 (0.57%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femur Fracture
         subjects affected / exposed
    0 / 527 (0.00%)
    2 / 524 (0.38%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Forearm Fracture
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hand Fracture
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip Fracture
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Incisional Hernia
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ligament Sprain
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower Limb Fracture
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Patella Fracture
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Radius Fracture
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rib Fracture
         subjects affected / exposed
    0 / 527 (0.00%)
    2 / 524 (0.38%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skull Fracture
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Soft Tissue Injury
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal Compression Fracture
         subjects affected / exposed
    0 / 527 (0.00%)
    4 / 524 (0.76%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subarachnoid Haematoma
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subdural Haematoma
         subjects affected / exposed
    0 / 527 (0.00%)
    2 / 524 (0.38%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subdural Haemorrhage
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thoracic Vertebral Fracture
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tibia Fracture
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Traumatic Fracture
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute Coronary Syndrome
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute Myocardial Infarction
         subjects affected / exposed
    0 / 527 (0.00%)
    3 / 524 (0.57%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina Pectoris
         subjects affected / exposed
    2 / 527 (0.38%)
    3 / 524 (0.57%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina Unstable
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aortic Valve Disease Mixed
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arteriosclerosis Coronary Artery
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial Fibrillation
         subjects affected / exposed
    0 / 527 (0.00%)
    2 / 524 (0.38%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular Block Complete
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac Amyloidosis
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac Disorder
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac Failure
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac Failure Chronic
         subjects affected / exposed
    1 / 527 (0.19%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac Failure Congestive
         subjects affected / exposed
    1 / 527 (0.19%)
    2 / 524 (0.38%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cor Pulmonale Chronic
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary Artery Occlusion
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary Artery Stenosis
         subjects affected / exposed
    0 / 527 (0.00%)
    3 / 524 (0.57%)
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mitral Valve Disease
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial Infarction
         subjects affected / exposed
    0 / 527 (0.00%)
    8 / 524 (1.53%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 9
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial Ischaemia
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinoatrial Block
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinus Node Dysfunction
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Supraventricular Extrasystoles
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Supraventricular Tachycardia
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular Fibrillation
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cauda Equina Syndrome
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral Haemorrhage
         subjects affected / exposed
    0 / 527 (0.00%)
    2 / 524 (0.38%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular Accident
         subjects affected / exposed
    1 / 527 (0.19%)
    4 / 524 (0.76%)
    3 / 208 (1.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cognitive Disorder
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diplegia
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage Intracranial
         subjects affected / exposed
    1 / 527 (0.19%)
    1 / 524 (0.19%)
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Iiird Nerve Paresis
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic Stroke
         subjects affected / exposed
    0 / 527 (0.00%)
    2 / 524 (0.38%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Paraplegia
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 527 (0.19%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal Cord Compression
         subjects affected / exposed
    6 / 527 (1.14%)
    2 / 524 (0.38%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subarachnoid Haemorrhage
         subjects affected / exposed
    0 / 527 (0.00%)
    2 / 524 (0.38%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    6 / 527 (1.14%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coagulopathy
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile Neutropenia
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo Positional
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Open Angle Glaucoma
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal Distension
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal Pain Lower
         subjects affected / exposed
    0 / 527 (0.00%)
    2 / 524 (0.38%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anal Fistula
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 527 (0.19%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyschezia
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric Ulcer Perforation
         subjects affected / exposed
    1 / 527 (0.19%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal Haemorrhage
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic Erosive Gastritis
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inguinal Hernia
         subjects affected / exposed
    1 / 527 (0.19%)
    3 / 524 (0.57%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large Intestinal Ulcer Perforation
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large Intestine Polyp
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Proctalgia
         subjects affected / exposed
    0 / 527 (0.00%)
    2 / 524 (0.38%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Terminal Ileitis
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile Duct Stone
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholangitis Acute
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis Acute
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic Cirrhosis
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic Failure
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Drug Eruption
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute Kidney Injury
         subjects affected / exposed
    1 / 527 (0.19%)
    3 / 524 (0.57%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bladder Perforation
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bladder Tamponade
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Calculus Bladder
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Calculus Urinary
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysuria
         subjects affected / exposed
    1 / 527 (0.19%)
    3 / 524 (0.57%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    3 / 527 (0.57%)
    10 / 524 (1.91%)
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 13
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    4 / 527 (0.76%)
    2 / 524 (0.38%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 527 (0.19%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal Disorder
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal Failure
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ureteric Obstruction
         subjects affected / exposed
    0 / 527 (0.00%)
    2 / 524 (0.38%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    2 / 527 (0.38%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urethral Stenosis
         subjects affected / exposed
    2 / 527 (0.38%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary Bladder Haematoma
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary Retention
         subjects affected / exposed
    9 / 527 (1.71%)
    4 / 524 (0.76%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary Tract Obstruction
         subjects affected / exposed
    0 / 527 (0.00%)
    3 / 524 (0.57%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Goitre
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperparathyroidism
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 527 (0.00%)
    4 / 524 (0.76%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthropathy
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Back Pain
         subjects affected / exposed
    6 / 527 (1.14%)
    4 / 524 (0.76%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bone Pain
         subjects affected / exposed
    2 / 527 (0.38%)
    0 / 524 (0.00%)
    2 / 208 (0.96%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intervertebral Disc Protrusion
         subjects affected / exposed
    1 / 527 (0.19%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbar Spinal Stenosis
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Muscular Weakness
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal Pain
         subjects affected / exposed
    1 / 527 (0.19%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    4 / 527 (0.76%)
    1 / 524 (0.19%)
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain in Extremity
         subjects affected / exposed
    1 / 527 (0.19%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pathological Fracture
         subjects affected / exposed
    4 / 527 (0.76%)
    2 / 524 (0.38%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rheumatoid Arthritis
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rotator Cuff Syndrome
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal Abscess
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abscess Jaw
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abscess Oral
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchiolitis
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 527 (0.19%)
    3 / 524 (0.57%)
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    2 / 527 (0.38%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis Infective
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridium Difficile Colitis
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fournier's Gangrene
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infected Lymphocele
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    2 / 527 (0.38%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Kidney Infection
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Klebsiella Infection
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Localised Infection
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower Respiratory Tract Infection
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Muscle Abscess
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 527 (0.19%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 527 (0.57%)
    10 / 524 (1.91%)
    3 / 208 (1.44%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 13
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia Bacterial
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Tuberculosis
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis Acute
         subjects affected / exposed
    0 / 527 (0.00%)
    2 / 524 (0.38%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 527 (0.38%)
    0 / 524 (0.00%)
    2 / 208 (0.96%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic Shock
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal Infection
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    2 / 527 (0.38%)
    5 / 524 (0.95%)
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 527 (0.19%)
    5 / 524 (0.95%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral Infection
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral Upper Respiratory Tract Infection
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 524 (0.00%)
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetes Mellitus
         subjects affected / exposed
    0 / 527 (0.00%)
    3 / 524 (0.57%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetes Mellitus Inadequate Control
         subjects affected / exposed
    1 / 527 (0.19%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 527 (0.19%)
    2 / 524 (0.38%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 527 (0.19%)
    1 / 524 (0.19%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    2 / 527 (0.38%)
    0 / 524 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo + Androgen Deprivation Therapy (ADT) Apalutamide + ADT Placebo + ADT to Apalutamide + ADT
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    472 / 527 (89.56%)
    469 / 524 (89.50%)
    136 / 208 (65.38%)
    Vascular disorders
    Hot Flush
         subjects affected / exposed
    87 / 527 (16.51%)
    121 / 524 (23.09%)
    3 / 208 (1.44%)
         occurrences all number
    96
    136
    3
    Hypertension
         subjects affected / exposed
    84 / 527 (15.94%)
    100 / 524 (19.08%)
    13 / 208 (6.25%)
         occurrences all number
    153
    200
    16
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    45 / 527 (8.54%)
    40 / 524 (7.63%)
    8 / 208 (3.85%)
         occurrences all number
    63
    54
    9
    Fatigue
         subjects affected / exposed
    87 / 527 (16.51%)
    107 / 524 (20.42%)
    15 / 208 (7.21%)
         occurrences all number
    97
    144
    20
    Oedema Peripheral
         subjects affected / exposed
    41 / 527 (7.78%)
    32 / 524 (6.11%)
    4 / 208 (1.92%)
         occurrences all number
    50
    45
    4
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    33 / 527 (6.26%)
    40 / 524 (7.63%)
    4 / 208 (1.92%)
         occurrences all number
    37
    46
    5
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    33 / 527 (6.26%)
    28 / 524 (5.34%)
    5 / 208 (2.40%)
         occurrences all number
    35
    37
    5
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    42 / 527 (7.97%)
    25 / 524 (4.77%)
    4 / 208 (1.92%)
         occurrences all number
    71
    33
    5
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    43 / 527 (8.16%)
    18 / 524 (3.44%)
    5 / 208 (2.40%)
         occurrences all number
    71
    26
    7
    Blood Alkaline Phosphatase Increased
         subjects affected / exposed
    32 / 527 (6.07%)
    18 / 524 (3.44%)
    3 / 208 (1.44%)
         occurrences all number
    54
    28
    6
    Weight Decreased
         subjects affected / exposed
    29 / 527 (5.50%)
    43 / 524 (8.21%)
    9 / 208 (4.33%)
         occurrences all number
    39
    66
    11
    Weight Increased
         subjects affected / exposed
    92 / 527 (17.46%)
    55 / 524 (10.50%)
    7 / 208 (3.37%)
         occurrences all number
    143
    86
    8
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    36 / 527 (6.83%)
    47 / 524 (8.97%)
    8 / 208 (3.85%)
         occurrences all number
    53
    59
    14
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    35 / 527 (6.64%)
    24 / 524 (4.58%)
    7 / 208 (3.37%)
         occurrences all number
    43
    34
    7
    Headache
         subjects affected / exposed
    31 / 527 (5.88%)
    44 / 524 (8.40%)
    12 / 208 (5.77%)
         occurrences all number
    46
    59
    14
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    71 / 527 (13.47%)
    68 / 524 (12.98%)
    13 / 208 (6.25%)
         occurrences all number
    125
    95
    18
    Leukopenia
         subjects affected / exposed
    21 / 527 (3.98%)
    29 / 524 (5.53%)
    8 / 208 (3.85%)
         occurrences all number
    35
    54
    11
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    57 / 527 (10.82%)
    58 / 524 (11.07%)
    6 / 208 (2.88%)
         occurrences all number
    72
    68
    8
    Diarrhoea
         subjects affected / exposed
    35 / 527 (6.64%)
    56 / 524 (10.69%)
    11 / 208 (5.29%)
         occurrences all number
    43
    71
    16
    Nausea
         subjects affected / exposed
    44 / 527 (8.35%)
    41 / 524 (7.82%)
    12 / 208 (5.77%)
         occurrences all number
    55
    52
    14
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    25 / 527 (4.74%)
    58 / 524 (11.07%)
    13 / 208 (6.25%)
         occurrences all number
    30
    73
    14
    Rash
         subjects affected / exposed
    23 / 527 (4.36%)
    106 / 524 (20.23%)
    26 / 208 (12.50%)
         occurrences all number
    31
    202
    42
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    30 / 527 (5.69%)
    35 / 524 (6.68%)
    3 / 208 (1.44%)
         occurrences all number
    36
    40
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    82 / 527 (15.56%)
    101 / 524 (19.27%)
    15 / 208 (7.21%)
         occurrences all number
    110
    133
    17
    Back Pain
         subjects affected / exposed
    108 / 527 (20.49%)
    106 / 524 (20.23%)
    11 / 208 (5.29%)
         occurrences all number
    144
    151
    14
    Bone Pain
         subjects affected / exposed
    53 / 527 (10.06%)
    39 / 524 (7.44%)
    0 / 208 (0.00%)
         occurrences all number
    75
    54
    0
    Musculoskeletal Pain
         subjects affected / exposed
    41 / 527 (7.78%)
    39 / 524 (7.44%)
    5 / 208 (2.40%)
         occurrences all number
    52
    59
    5
    Pain in Extremity
         subjects affected / exposed
    67 / 527 (12.71%)
    69 / 524 (13.17%)
    8 / 208 (3.85%)
         occurrences all number
    93
    91
    8
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    47 / 527 (8.92%)
    44 / 524 (8.40%)
    6 / 208 (2.88%)
         occurrences all number
    62
    73
    8
    Upper Respiratory Tract Infection
         subjects affected / exposed
    29 / 527 (5.50%)
    40 / 524 (7.63%)
    6 / 208 (2.88%)
         occurrences all number
    46
    46
    7
    Urinary Tract Infection
         subjects affected / exposed
    22 / 527 (4.17%)
    28 / 524 (5.34%)
    4 / 208 (1.92%)
         occurrences all number
    31
    47
    5
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    27 / 527 (5.12%)
    32 / 524 (6.11%)
    11 / 208 (5.29%)
         occurrences all number
    32
    38
    12
    Hypercholesterolaemia
         subjects affected / exposed
    8 / 527 (1.52%)
    34 / 524 (6.49%)
    7 / 208 (3.37%)
         occurrences all number
    8
    37
    7
    Hyperkalaemia
         subjects affected / exposed
    27 / 527 (5.12%)
    47 / 524 (8.97%)
    16 / 208 (7.69%)
         occurrences all number
    40
    87
    23

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Apr 2016
    Inclusion criteria were amended based on feedback from investigators or steering committee members: inclusion criterion 2 added subjects with high-volume metastatic castration sensitive, prostate cancer (mCSPC) and removed the requirement for histologic evidence of prostate adenocarcinoma from a metastatic lesion for subjects who had been diagnosed more than 5 years prior to randomization, inclusion criterion 3 was changed to allow a single bone lesion on bone scan, inclusion criterion 4 restricted Eastern Cooperative Oncology Group (ECOG) performance status to grade 0 or 1 (removed eligibility for grade 2), exclusion criterion 8 clarified that bisphosphonates and denosumab for the management of bone metastasis are not allowed, exclusion criterion 10 incorporated blood product and growth factor support. Criteria for prior prostate cancer therapy were modified based on Steering Committee feedback. Collection of trough pharmacokinetic samples became mandatory, clarified collection (voluntary) and volume (4 mL) of PK samples for leuprolide study, and removed collection of circulating tumor cells, Local amendments to Japan and the Czech Republic were incorporated.
    02 Feb 2017
    Pharmacokinetic (PK) sub-study for leuprolide amended to allow leuprolide doses of 11.25 milligrams (mg), 22.5 mg, 30 mg, and 45 mg administered by subcutaneous or intramuscular route. Description of analysis of dual primary endpoints revised to clarify that subgroup analysis by volume of disease will be performed for both endpoints ( radiographic progression free survival [rPFS] and OS). Clarification that timing for the interim analysis of OS and final analysis of rPFS may not be in alignment if the number of death events for the interim analysis of OS would require an extended delay in the analysis of the rPFS endpoint.
    22 Feb 2018
    Open-label Extension Phase revised to include information and details for the crossover to open-label apalutamide after study unblinding, such as details on the Cross-over Eligibility Phase, timing of patient-reported outcomes and biomarker collection, information on collection of additional endpoints, timing of serum chemistry and hematology sampling. Interim analysis was revised to occur at approximately 60% of events (previously 50%), due to external data relating to study population.
    05 Sep 2018
    The 2 interim analyses planned for this study were changed to observing approximately 50 percent (%) (previously 60%) and 70% (previously 75%) of the total number of required (410) OS events, based on lower number of overall survival (OS) events and on recent data from a Phase 3 apalutamide clinical study. Updates were made to restricted concomitant medications based on the latest available information on the potential for drug interactions with apalutamide.
    16 Mar 2020
    A Long-term Extension (LTE) Phase was added to the protocol to allow subjects to continue to derive benefit from treatment (based on investigator assessment). A brief description of the LTE Phase was added to the main body and a detailed section was added as an attachment.

    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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