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    Clinical Trial Results:
    A Randomized, Double-blind, Comparative Study of Abiraterone Acetate Plus Low dose Prednisone Plus Androgen Deprivation Therapy (ADT) Versus ADT Alone in Newly Diagnosed Subjects With High Risk, Metastatic Hormone-Naive Prostate Cancer (mHNPC)

    Summary
    EudraCT number
    		 2012-002940-26
    Trial protocol
    		 GB   CZ   FR   SE   HU   PT   FI   ES   IT   SK   DK   DE   BE   PL   BG   NL  
    Global end of trial date
    13 Feb 2022

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

    Trial information

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    Trial identification
    Sponsor protocol code
    212082PCR3011
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01715285
    WHO universal trial number (UTN)
    		 U1111-1135-7146
    Sponsors
    Sponsor organisation name
    Janssen Research & Development, LLC
    Sponsor organisation address
    920 US Highway 202 South Raritan, New Jersey, United States, 08869
    Public contact
    Clinical Registry Group, Janssen Research & Development, LLC, ClinicalTrialDisclosure@its.jnj.com
    Scientific contact
    Clinical Registry Group, Janssen Research & Development, LLC, ClinicalTrialDisclosure@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
    Final
    Date of interim/final analysis
    13 Feb 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Feb 2022
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The main objective of this study was to determine whether abiraterone acetate plus low-dose prednisone (AA-P) in combination with ADT was superior to ADT alone in improving radiographic progression-free survival (rPFS) and overall survival (OS) in subjects with mHNPC who had high-risk prognostic factors.
    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 Practice and applicable regulatory requirements.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 Feb 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 44 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 16
    Country: Number of subjects enrolled
    Australia: 8
    Country: Number of subjects enrolled
    Belgium: 13
    Country: Number of subjects enrolled
    Bulgaria: 2
    Country: Number of subjects enrolled
    Brazil: 56
    Country: Number of subjects enrolled
    Canada: 33
    Country: Number of subjects enrolled
    Chile: 7
    Country: Number of subjects enrolled
    China: 137
    Country: Number of subjects enrolled
    Colombia: 17
    Country: Number of subjects enrolled
    Czechia: 16
    Country: Number of subjects enrolled
    Germany: 8
    Country: Number of subjects enrolled
    Denmark: 28
    Country: Number of subjects enrolled
    Spain: 33
    Country: Number of subjects enrolled
    Finland: 9
    Country: Number of subjects enrolled
    France: 14
    Country: Number of subjects enrolled
    United Kingdom: 37
    Country: Number of subjects enrolled
    Hungary: 34
    Country: Number of subjects enrolled
    Israel: 30
    Country: Number of subjects enrolled
    Italy: 39
    Country: Number of subjects enrolled
    Japan: 70
    Country: Number of subjects enrolled
    Korea, Republic of: 32
    Country: Number of subjects enrolled
    Mexico: 38
    Country: Number of subjects enrolled
    Malaysia: 6
    Country: Number of subjects enrolled
    Netherlands: 10
    Country: Number of subjects enrolled
    New Zealand: 11
    Country: Number of subjects enrolled
    Poland: 42
    Country: Number of subjects enrolled
    Portugal: 39
    Country: Number of subjects enrolled
    Romania: 43
    Country: Number of subjects enrolled
    Russian Federation: 184
    Country: Number of subjects enrolled
    Slovakia: 31
    Country: Number of subjects enrolled
    Sweden: 22
    Country: Number of subjects enrolled
    Turkey: 35
    Country: Number of subjects enrolled
    Ukraine: 79
    Country: Number of subjects enrolled
    South Africa: 20
    Worldwide total number of subjects
    1199
    EEA total number of subjects
    383
    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)
    454
    From 65 to 84 years
    728
    85 years and over
    17

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 1209 subjects were enrolled and 1199 were randomised to treatment groups.10 subjects from Russian site were excluded from the analysis due to noncompliance with International Conference on Harmonisation Good Clinical Practice guidelines at site. The remaining 1199 randomised subjects comprised the intent-to-treat population.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Abiraterone Acetate+Prednisone+ADT
    Arm description
    		 Subjects received abiraterone acetate tablet at a total dose of 1000 milligrams (mg) plus 5 mg capsule of prednisone orally once daily until disease progression, withdrawal of consent or unacceptable toxicity. Stable regimen of androgen deprivation therapy (ADT) was administered.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Abiraterone Acetate
    Investigational medicinal product code
    Other name
    Zytiga
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Abiraterone acetate of 1000 mg (4 tablets of 250 mg) per day until disease progression, withdrawal of consent or unacceptable toxicity.

    Investigational medicinal product name
    Androgen deprivation therapy (ADT)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Stable regimen of ADT, that is, lutenizing hormone releasing hormone (LHRH) agonists or surgical castration according to local guidelines until disease progression, withdrawal of consent or unacceptable toxicity.

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Prednisone 5 mg once daily until disease progression, withdrawal of consent or unacceptable toxicity.

    Arm title
    		 Placebo + ADT
    Arm description
    		 Subjects received placebo matched to abiraterone acetate plus prednisone orally once daily until disease progression, withdrawal of consent or unacceptable toxicity. Stable regimen of ADT was administered.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo (matched to abiraterone acetate)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to abiraterone acetate once daily until disease progression, withdrawal of consent or unacceptable toxicity.

    Investigational medicinal product name
    ADT
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Stable regimen of ADT, that is, lutenizing hormone releasing hormone (LHRH) agonists or surgical castration according to local guidelines until disease progression, withdrawal of consent or unacceptable toxicity.

    Investigational medicinal product name
    Placebo (matched to prednisone)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to prednisone once daily until disease progression, withdrawal of consent or unacceptable toxicity.

    Number of subjects in period 1
    		Abiraterone Acetate+Prednisone+ADT Placebo + ADT
    Started
    597
    602
    Completed
    0
    72
    Not completed
    597
    530
         Adverse event, serious fatal
    43
    25
         Physician decision
    21
    23
         Consent withdrawn by subject
    52
    47
         Non-compliance with Study Drug
    4
    2
         Adverse event, non-fatal
    53
    31
         Progressive Disease
    254
    388
         Lost to follow-up
    3
    2
         unspecified
    167
    12
    Period 2
    Period 2 title
    Open-label (OL) Extension Phase
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 DB Period Placebo to OLE Abiraterone Acetate
    Arm description
    		 Subjects who were originally randomised to the Placebo group were permitted to crossover to Abiraterone Acetate plus Prednisone treatment in open-label extension phase to receive abiraterone acetate tablet at a total dose of 1000 mg plus 5 mg capsule of prednisone orally once daily until disease progression, withdrawal of consent or unacceptable toxicity. Stable regimen of ADT was administered.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Abiraterone Acetate
    Investigational medicinal product code
    Other name
    Zytiga
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Abiraterone acetate of 1000 mg (4 tablets of 250 mg) per day until disease progression, withdrawal of consent or unacceptable toxicity.

    Investigational medicinal product name
    Androgen deprivation therapy (ADT)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Stable regimen of ADT, that is, lutenizing hormone releasing hormone (LHRH) agonists or surgical castration according to local guidelines until disease progression, withdrawal of consent or unacceptable toxicity.

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Prednisone 5 mg once daily until disease progression, withdrawal of consent or unacceptable toxicity.

    Number of subjects in period 2
    		DB Period Placebo to OLE Abiraterone Acetate
    Started
    72
    Completed
    0
    Not completed
    72
         Adverse event, serious fatal
    4
         Consent withdrawn by subject
    6
         Adverse event, non-fatal
    1
         Progressive Disease
    1
         unspecified
    60

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Abiraterone Acetate+Prednisone+ADT
    Reporting group description
    		 Subjects received abiraterone acetate tablet at a total dose of 1000 milligrams (mg) plus 5 mg capsule of prednisone orally once daily until disease progression, withdrawal of consent or unacceptable toxicity. Stable regimen of androgen deprivation therapy (ADT) was administered.

    Reporting group title
    Placebo + ADT
    Reporting group description
    		 Subjects received placebo matched to abiraterone acetate plus prednisone orally once daily until disease progression, withdrawal of consent or unacceptable toxicity. Stable regimen of ADT was administered.

    Reporting group values
    		 Abiraterone Acetate+Prednisone+ADT Placebo + ADT Total
    Number of subjects
    		 597 602 1199
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 221 233 454
        From 65 to 84 years
    		 367 361 728
        85 years and over
    		 9 8 17
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    		 67.3 ± 8.48 66.8 ± 8.72 -
    Title for Gender
    Units: subjects
        Male
    		 597 602 1199

    End points

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    End points reporting groups
    Reporting group title
    Abiraterone Acetate+Prednisone+ADT
    Reporting group description
    		 Subjects received abiraterone acetate tablet at a total dose of 1000 milligrams (mg) plus 5 mg capsule of prednisone orally once daily until disease progression, withdrawal of consent or unacceptable toxicity. Stable regimen of androgen deprivation therapy (ADT) was administered.

    Reporting group title
    Placebo + ADT
    Reporting group description
    		 Subjects received placebo matched to abiraterone acetate plus prednisone orally once daily until disease progression, withdrawal of consent or unacceptable toxicity. Stable regimen of ADT was administered.
    Reporting group title
    DB Period Placebo to OLE Abiraterone Acetate
    Reporting group description
    		 Subjects who were originally randomised to the Placebo group were permitted to crossover to Abiraterone Acetate plus Prednisone treatment in open-label extension phase to receive abiraterone acetate tablet at a total dose of 1000 mg plus 5 mg capsule of prednisone orally once daily until disease progression, withdrawal of consent or unacceptable toxicity. Stable regimen of ADT was administered.

    Primary: Radiographic Progression-Free Survival (rPFS)

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    End point title
    		 Radiographic Progression-Free Survival (rPFS)
    End point description
    rPFS: defined as time (in months) interval from randomisation to first date of radiographic progression or death. Radiographic progression included progression by bone scan (according to modified Prostate Cancer Working Group2 criteria), defined as at least 2 new lesions on bone scan and progression of soft tissue lesions by computed tomography or magnetic resonance imaging (according to Response Evaluation Criteria in Solid Tumors [RECIST]1.1 criteria). As per RECIST guideline, progression requires 20 percent increase in sum of diameters of all target lesions and minimum absolute increase of 5 millimeters (mm) in sum as compared to nadir sum of diameter. Intention to treat (ITT) analysis set included all subjects randomised into the study and who were classified according to their assigned treatment group, regardless of the actual treatment received. Here, '99999' was used as a space filler which signifies that upper limit of 95%CI was not estimable due to lesser number of events.
    End point type
    Primary
    End point timeframe
    Up to 44 months
    End point values
    		 Abiraterone Acetate+Prednisone+ADT Placebo + ADT
    Number of subjects analysed
    597
    602
    Units: Months
        median (confidence interval 95%)
    33.02 (29.57 to 99999)
    14.78 (14.69 to 18.27)
    Statistical analysis title
    		 Abiraterone Acetate+Prednisone+ADT, Placebo + ADT
    Comparison groups
    Placebo + ADT v Abiraterone Acetate+Prednisone+ADT
    Number of subjects included in analysis
    1199
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.466
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.394
         upper limit
    		 0.55

    Primary: Overall Survival (OS) 

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    End point title
    		 Overall Survival (OS) 
    End point description
    Overall survival was defined as the time from randomisation to date of death from any cause. ITT analysis set included all subjects randomised into the study and who were classified according to their assigned treatment group, regardless of the actual treatment received. Here, '99999' was used as a space filler which signifies that upper limit of 95% CI was not estimable due to lesser number of events.
    End point type
    Primary
    End point timeframe
    Up to 66 months
    End point values
    		 Abiraterone Acetate+Prednisone+ADT Placebo + ADT
    Number of subjects analysed
    597
    602
    Units: months
        median (confidence interval 95%)
    53.32 (48.23 to 99999)
    36.53 (33.54 to 39.95)
    Statistical analysis title
    		 Abiraterone Acetate+Prednisone+ADT, Placebo + ADT
    Comparison groups
    Abiraterone Acetate+Prednisone+ADT v Placebo + ADT
    Number of subjects included in analysis
    1199
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.661
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.564
         upper limit
    		 0.775

    Secondary: Time to Initiation of Chemotherapy

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    End point title
    		 Time to Initiation of Chemotherapy
    End point description
    Time to initiation of chemotherapy was defined as the time (in months) interval from the date of randomisation to the date of initiation of cytotoxic chemotherapy for prostate cancer. ITT analysis set included all subjects randomised into the study and who were classified according to their assigned treatment group, regardless of the actual treatment received. Here, '99999' was used as a space filler which signifies that median and upper limit of 95% CI was not estimable due to lesser number of events.
    End point type
    Secondary
    End point timeframe
    Up to 66 months
    End point values
    		 Abiraterone Acetate+Prednisone+ADT Placebo + ADT
    Number of subjects analysed
    597
    602
    Units: months
        median (confidence interval 95%)
    99999 (62.62 to 99999)
    57.59 (38.18 to 99999)
    No statistical analyses for this end point

    Secondary: Time to Subsequent Therapy for Prostate Cancer

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    End point title
    		 Time to Subsequent Therapy for Prostate Cancer
    End point description
    Time to subsequent therapy was defined as the time interval from the date of randomisation to the date of initiation of subsequent therapy for prostate cancer. ITT analysis set included all subjects randomised into the study and who were classified according to their assigned treatment group, regardless of the actual treatment received. Here, '99999' was used as a space filler which signifies that upper limit of 95% CI was not estimable due to lesser number of events.
    End point type
    Secondary
    End point timeframe
    Up to 66 months
    End point values
    		 Abiraterone Acetate+Prednisone+ADT Placebo + ADT
    Number of subjects analysed
    597
    602
    Units: Months
        median (confidence interval 95%)
    54.87 (46.42 to 99999)
    21.22 (18.56 to 23.49)
    No statistical analyses for this end point

    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 (in months) interval from randomisation to the first date a subject experienced a greater than or equal to (>=) 30 percent (%) increase in Brief Pain Inventory-Short Form (BPI-SF) from baseline in the BPI-SF worst pain intensity (Item 3) observed at 2 consecutive evaluations (>=4) weeks apart. BPI-SF was an 11-item questionnaire, designed to assess severity and impact of pain on daily functions. Total score ranged from 0 to 10 with 0 representing "no pain" and 10 representing" pain as bad as you can imagine. ITT analysis set included all subjects randomised into the study and who were classified according to their assigned treatment group, regardless of the actual treatment received. Here, '99999' was used as a space filler which signifies that upper limit of 95% CI was not estimable due to lesser number of events.
    End point type
    Secondary
    End point timeframe
    Up to 66 months
    End point values
    		 Abiraterone Acetate+Prednisone+ADT Placebo + ADT
    Number of subjects analysed
    597
    602
    Units: Months
        median (confidence interval 95%)
    47.41 (33.15 to 99999)
    16.62 (11.07 to 23.95)
    No statistical analyses for this end point

    Secondary: Time to Skeletal-Related Event

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    End point title
    		 Time to Skeletal-Related Event
    End point description
    Time to skeletal-related event was defined as the earliest of the following: clinical or pathological fracture, spinal cord compression, palliative radiation to bone, or surgery to bone. ITT analysis set included all subjects randomised into the study and who were classified according to their assigned treatment group, regardless of the actual treatment received. Here, '99999' was used as a space filler which signifies that median upper limit and lower limit of 95% CI was not estimable due to lesser number of events.
    End point type
    Secondary
    End point timeframe
    Up to 66 months
    End point values
    		 Abiraterone Acetate+Prednisone+ADT Placebo + ADT
    Number of subjects analysed
    597
    602
    Units: months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Time to Prostate-Specific Antigen (PSA) Progression

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    End point title
    		 Time to Prostate-Specific Antigen (PSA) Progression
    End point description
    Time to PSA progression was defined as the time (in months) interval from the date of randomisation to the date of PSA progression, according to PCWG2 criteria. PCWG2 defines PSA progression as the date that a 25 percent (%) or greater increase and an absolute increase of 2 nanogram per milliliters (ng/mL) or more from the nadir is documented, which is confirmed by a second value obtained 3 or more weeks later. ITT analysis set included all subjects randomized into the study and who were classified according to their assigned treatment group, regardless of the actual treatment received.
    End point type
    Secondary
    End point timeframe
    Up to 66 months
    End point values
    		 Abiraterone Acetate+Prednisone+ADT Placebo + ADT
    Number of subjects analysed
    597
    602
    Units: Months
        median (confidence interval 95%)
    33.31 (29.44 to 46.09)
    7.43 (7.20 to 9.20)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Day 1 up to 30 days post last dose (that is, for DB period: up to 23 months and OLE period: up to 15.6 months), deaths were collected from baseline up to end of study (up to 66 months).
    Adverse event reporting additional description
    Safety analysis set included all subjects randomised into the study and who received any part of study drugs. Only 72 deaths out of all cause mortalities contributed to discontinuation.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Abiraterone Acetate+Prednisone+ADT
    Reporting group description
    		 Subjects received abiraterone acetate tablet at a total dose of 1000 milligram (mg) plus 5 mg capsule of prednisone orally once daily until disease progression, withdrawal of consent or unacceptable toxicity. Stable regimen of androgen deprivation therapy (ADT) was administered.

    Reporting group title
    DB Period Placebo to OLE Abiraterone Acetate
    Reporting group description
    		 Subjects who were originally randomised to the Placebo group were permitted to crossover to Abiraterone Acetate plus prednisone treatment in open-label extension phase to receive abiraterone acetate tablet at a total dose of 1000 mg plus 5 mg capsule of prednisone orally once daily until disease progression, withdrawal of consent or unacceptable toxicity.

    Reporting group title
    Placebo + ADT
    Reporting group description
    		 Subjects received placebo matched to abiraterone acetate plus prednisone orally once daily until disease progression, withdrawal of consent or unacceptable toxicity. Stable regimen of ADT was administered.

    Serious adverse events
    		 Abiraterone Acetate+Prednisone+ADT DB Period Placebo to OLE Abiraterone Acetate Placebo + ADT
    Total subjects affected by serious adverse events
         subjects affected / exposed
    192 / 597 (32.16%)
    4 / 72 (5.56%)
    151 / 602 (25.08%)
         number of deaths (all causes)
    275
    4
    339
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder Neoplasm
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Adenocarcinoma of Colon
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    B-Cell Lymphoma
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bladder Transitional Cell Carcinoma
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cancer Pain
         subjects affected / exposed
    2 / 597 (0.34%)
    0 / 72 (0.00%)
    0 / 602 (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
    Chronic Lymphocytic Leukaemia
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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
    Chronic Lymphocytic Leukaemia Stage 3
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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
    Lung Adenocarcinoma
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colon Cancer
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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
    Colon Neoplasm
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lentigo Maligna
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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
    Leukaemia
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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
    Chronic Myeloid Leukaemia
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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
    Malignant Melanoma
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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
    Malignant Neoplasm of Renal Pelvis
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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 Meninges
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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
    Neoplasm Malignant
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transitional Cell Carcinoma
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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
    Neuroendocrine Tumour
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal Carcinoma
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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
    Plasma Cell Myeloma
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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
    Rectal Cancer
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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
    Neoplasm of Thymus
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep Vein Thrombosis
         subjects affected / exposed
    4 / 597 (0.67%)
    0 / 72 (0.00%)
    4 / 602 (0.66%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood Pressure Fluctuation
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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 Dissection
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angiopathy
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aortic Aneurysm
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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
    Hypertension
         subjects affected / exposed
    2 / 597 (0.34%)
    0 / 72 (0.00%)
    2 / 602 (0.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertensive Crisis
         subjects affected / exposed
    2 / 597 (0.34%)
    0 / 72 (0.00%)
    0 / 602 (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
    Intermittent Claudication
         subjects affected / exposed
    2 / 597 (0.34%)
    0 / 72 (0.00%)
    0 / 602 (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
    Peripheral Vascular Disorder
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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
    Surgical and medical procedures
    Lipoma Excision
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chest Pain
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device Dislocation
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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
    General Physical Health Deterioration
         subjects affected / exposed
    2 / 597 (0.34%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    3 / 602 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multi-Organ Failure
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Non-Cardiac Chest Pain
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    2 / 602 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oedema Peripheral
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hernia Pain
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral Swelling
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    6 / 597 (1.01%)
    0 / 72 (0.00%)
    2 / 602 (0.33%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic Reaction
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Prostatic Haemorrhage
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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
    Pelvic Pain
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Benign Prostatic Hyperplasia
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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
    Prostatitis
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic Obstructive Pulmonary Disease
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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 Chronic
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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
    Bronchiectasis
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oropharyngeal Pain
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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
    Epistaxis
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Emphysema
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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
    Dyspnoea
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    3 / 602 (0.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysphonia
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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
    Pneumonia Aspiration
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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
    Pneumonitis
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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
    Pleural Effusion
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    4 / 602 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Mass
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Embolism
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Oedema
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory Failure
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional State
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mental Disorder
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    2 / 597 (0.34%)
    0 / 72 (0.00%)
    0 / 602 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    2 / 597 (0.34%)
    0 / 72 (0.00%)
    0 / 602 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Biopsy Liver
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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
    Blood Glucose Abnormal
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Platelet Count Decreased
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood Testosterone Increased
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femoral Neck Fracture
         subjects affected / exposed
    2 / 597 (0.34%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femur Fracture
         subjects affected / exposed
    2 / 597 (0.34%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fracture
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Head Injury
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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
    Hip Fracture
         subjects affected / exposed
    2 / 597 (0.34%)
    0 / 72 (0.00%)
    0 / 602 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbar Vertebral Fracture
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    2 / 602 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Laceration
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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
    Lower Limb Fracture
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Kidney Rupture
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal Compression Fracture
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    2 / 602 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thermal Burn
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Traumatic Fracture
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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 Intracranial Haemorrhage
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Upper Limb Fracture
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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 Traumatic
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post Procedural Haematoma
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Procedural Pain
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pubis Fracture
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Phimosis
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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 disorders
    Atrial Flutter
         subjects affected / exposed
    2 / 597 (0.34%)
    0 / 72 (0.00%)
    0 / 602 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute Myocardial Infarction
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina Pectoris
         subjects affected / exposed
    3 / 597 (0.50%)
    0 / 72 (0.00%)
    0 / 602 (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
    Atrial Fibrillation
         subjects affected / exposed
    2 / 597 (0.34%)
    0 / 72 (0.00%)
    0 / 602 (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
    Acute Coronary Syndrome
         subjects affected / exposed
    5 / 597 (0.84%)
    0 / 72 (0.00%)
    0 / 602 (0.00%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac Failure
         subjects affected / exposed
    3 / 597 (0.50%)
    0 / 72 (0.00%)
    0 / 602 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac Failure Acute
         subjects affected / exposed
    2 / 597 (0.34%)
    0 / 72 (0.00%)
    0 / 602 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac Failure Chronic
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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
    Myocardial Ischaemia
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mitral Valve Incompetence
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial Infarction
         subjects affected / exposed
    3 / 597 (0.50%)
    0 / 72 (0.00%)
    0 / 602 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary Artery Disease
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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
    Pericardial Effusion
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinus Node Dysfunction
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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
    Nervous system disorders
    Balance Disorder
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Brain Compression
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Carotid Artery Stenosis
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral Haemorrhage
         subjects affected / exposed
    2 / 597 (0.34%)
    0 / 72 (0.00%)
    0 / 602 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral Ischaemia
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    2 / 602 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular Accident
         subjects affected / exposed
    2 / 597 (0.34%)
    0 / 72 (0.00%)
    3 / 602 (0.50%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Cognitive Disorder
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coma
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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 Infarction
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lacunar Infarction
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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
    Loss of Consciousness
         subjects affected / exposed
    2 / 597 (0.34%)
    0 / 72 (0.00%)
    0 / 602 (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
    Myasthenia Gravis
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nerve Compression
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic Stroke
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysarthria
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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
    Epilepsy
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Guillain-Barre Syndrome
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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
    Haemorrhagic Stroke
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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
    Neuralgia
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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
    Optic Nerve Compression
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Paraparesis
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    3 / 602 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Paraplegia
         subjects affected / exposed
    2 / 597 (0.34%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient Ischaemic Attack
         subjects affected / exposed
    2 / 597 (0.34%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Speech Disorder
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal Cord Compression
         subjects affected / exposed
    11 / 597 (1.84%)
    0 / 72 (0.00%)
    11 / 602 (1.83%)
         occurrences causally related to treatment / all
    0 / 13
    0 / 0
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Syncope
         subjects affected / exposed
    2 / 597 (0.34%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Radiculitis
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular Encephalopathy
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Lymphadenitis
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    6 / 597 (1.01%)
    1 / 72 (1.39%)
    6 / 602 (1.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 1
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    2 / 597 (0.34%)
    0 / 72 (0.00%)
    0 / 602 (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
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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
    Glaucoma
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Dental Caries
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal Mass
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal Pain
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    3 / 602 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    4 / 602 (0.66%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Duodenal Ulcer
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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
    Duodenitis
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric Ulcer
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric Ulcer Perforation
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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
    Intestinal Ischaemia
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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 Haemorrhage
         subjects affected / exposed
    2 / 597 (0.34%)
    0 / 72 (0.00%)
    0 / 602 (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
    Inguinal Hernia
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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
    Intestinal Haemorrhage
         subjects affected / exposed
    2 / 597 (0.34%)
    0 / 72 (0.00%)
    0 / 602 (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
    Gastritis
         subjects affected / exposed
    0 / 597 (0.00%)
    1 / 72 (1.39%)
    0 / 602 (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
    Intestinal Obstruction
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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
    Mouth Haemorrhage
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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
    Nausea
         subjects affected / exposed
    2 / 597 (0.34%)
    0 / 72 (0.00%)
    0 / 602 (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
    Vomiting
         subjects affected / exposed
    2 / 597 (0.34%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal Haemorrhage
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal Polyp
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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
    Peptic Ulcer
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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
    Hepatobiliary disorders
    Bile Duct Stone
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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
    Hepatitis Toxic
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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
    Hepatocellular Injury
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertransaminasaemia
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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
    Hepatobiliary Disease
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin Lesion
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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 and urinary disorders
    Acute Kidney Injury
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    2 / 602 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    8 / 597 (1.34%)
    0 / 72 (0.00%)
    3 / 602 (0.50%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Calculus Bladder
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    2 / 602 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Calculus Ureteric
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic Kidney Disease
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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
    2 / 597 (0.34%)
    0 / 72 (0.00%)
    2 / 602 (0.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bladder Outlet Obstruction
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    2 / 597 (0.34%)
    0 / 72 (0.00%)
    2 / 602 (0.33%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower Urinary Tract Symptoms
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    2 / 602 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Micturition Urgency
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    2 / 602 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pollakiuria
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal Failure
         subjects affected / exposed
    3 / 597 (0.50%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal Injury
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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
    Urethral Haemorrhage
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urethral Stenosis
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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
    Urinary Tract Obstruction
         subjects affected / exposed
    3 / 597 (0.50%)
    0 / 72 (0.00%)
    3 / 602 (0.50%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary Retention
         subjects affected / exposed
    10 / 597 (1.68%)
    0 / 72 (0.00%)
    11 / 602 (1.83%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 0
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Gouty Arthritis
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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
    Arthralgia
         subjects affected / exposed
    2 / 597 (0.34%)
    0 / 72 (0.00%)
    4 / 602 (0.66%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Back Pain
         subjects affected / exposed
    5 / 597 (0.84%)
    0 / 72 (0.00%)
    10 / 602 (1.66%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteonecrosis of Jaw
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Muscular Weakness
         subjects affected / exposed
    2 / 597 (0.34%)
    0 / 72 (0.00%)
    3 / 602 (0.50%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal Chest Pain
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    2 / 602 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bone Pain
         subjects affected / exposed
    8 / 597 (1.34%)
    0 / 72 (0.00%)
    6 / 602 (1.00%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain in Extremity
         subjects affected / exposed
    2 / 597 (0.34%)
    0 / 72 (0.00%)
    2 / 602 (0.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain in Jaw
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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
    Pathological Fracture
         subjects affected / exposed
    2 / 597 (0.34%)
    0 / 72 (0.00%)
    0 / 602 (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
    Spinal Column Stenosis
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    2 / 602 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Trismus
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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
    Spondylitis
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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
    4 / 597 (0.67%)
    0 / 72 (0.00%)
    0 / 602 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    3 / 597 (0.50%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bursitis Infective
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye Infection
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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
    Cellulitis Orbital
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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
    Device Related Infection
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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
    Fungaemia
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gangrene
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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
    Gastroenteritis
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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 Infection
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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
    Lung Infection
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Localised Infection
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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
    Lower Respiratory Tract Infection
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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
    Herpes Zoster
         subjects affected / exposed
    2 / 597 (0.34%)
    0 / 72 (0.00%)
    0 / 602 (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
    Nasopharyngitis
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Orchitis
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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
    Osteomyelitis
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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
    Pyelonephritis Acute
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    2 / 602 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Otitis Media
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    12 / 597 (2.01%)
    0 / 72 (0.00%)
    2 / 602 (0.33%)
         occurrences causally related to treatment / all
    2 / 13
    0 / 0
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis Acute
         subjects affected / exposed
    0 / 597 (0.00%)
    1 / 72 (1.39%)
    0 / 602 (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 Chronic
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory Tract Infection
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (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
    Sepsis
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    2 / 602 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Sinusitis
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal Sepsis
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    0 / 602 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    8 / 597 (1.34%)
    0 / 72 (0.00%)
    5 / 602 (0.83%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 597 (0.17%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal Cord Infection
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    5 / 597 (0.84%)
    0 / 72 (0.00%)
    0 / 602 (0.00%)
         occurrences causally related to treatment / all
    4 / 6
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    2 / 597 (0.34%)
    0 / 72 (0.00%)
    0 / 602 (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
    Diabetes Mellitus
         subjects affected / exposed
    0 / 597 (0.00%)
    1 / 72 (1.39%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    4 / 597 (0.67%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolic Syndrome
         subjects affected / exposed
    0 / 597 (0.00%)
    0 / 72 (0.00%)
    1 / 602 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         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
    		 Abiraterone Acetate+Prednisone+ADT DB Period Placebo to OLE Abiraterone Acetate Placebo + ADT
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    533 / 597 (89.28%)
    35 / 72 (48.61%)
    515 / 602 (85.55%)
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    100 / 597 (16.75%)
    5 / 72 (6.94%)
    77 / 602 (12.79%)
         occurrences all number
    239
    14
    135
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    91 / 597 (15.24%)
    5 / 72 (6.94%)
    68 / 602 (11.30%)
         occurrences all number
    196
    12
    141
    Weight Increased
         subjects affected / exposed
    54 / 597 (9.05%)
    0 / 72 (0.00%)
    51 / 602 (8.47%)
         occurrences all number
    85
    0
    78
    Blood Lactate Dehydrogenase Increased
         subjects affected / exposed
    40 / 597 (6.70%)
    1 / 72 (1.39%)
    32 / 602 (5.32%)
         occurrences all number
    68
    1
    48
    Vascular disorders
    Hypertension
         subjects affected / exposed
    229 / 597 (38.36%)
    4 / 72 (5.56%)
    133 / 602 (22.09%)
         occurrences all number
    639
    4
    289
    Hot Flush
         subjects affected / exposed
    92 / 597 (15.41%)
    1 / 72 (1.39%)
    76 / 602 (12.62%)
         occurrences all number
    126
    1
    88
    Nervous system disorders
    Headache
         subjects affected / exposed
    46 / 597 (7.71%)
    2 / 72 (2.78%)
    31 / 602 (5.15%)
         occurrences all number
    80
    31
    60
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    58 / 597 (9.72%)
    3 / 72 (4.17%)
    89 / 602 (14.78%)
         occurrences all number
    88
    7
    139
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    31 / 597 (5.19%)
    0 / 72 (0.00%)
    27 / 602 (4.49%)
         occurrences all number
    48
    0
    36
    Fatigue
         subjects affected / exposed
    84 / 597 (14.07%)
    1 / 72 (1.39%)
    90 / 602 (14.95%)
         occurrences all number
    132
    1
    115
    Oedema Peripheral
         subjects affected / exposed
    61 / 597 (10.22%)
    2 / 72 (2.78%)
    55 / 602 (9.14%)
         occurrences all number
    85
    4
    75
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    39 / 597 (6.53%)
    0 / 72 (0.00%)
    35 / 602 (5.81%)
         occurrences all number
    57
    0
    45
    Nausea
         subjects affected / exposed
    42 / 597 (7.04%)
    1 / 72 (1.39%)
    40 / 602 (6.64%)
         occurrences all number
    53
    1
    52
    Diarrhoea
         subjects affected / exposed
    37 / 597 (6.20%)
    0 / 72 (0.00%)
    44 / 602 (7.31%)
         occurrences all number
    47
    0
    56
    Constipation
         subjects affected / exposed
    68 / 597 (11.39%)
    2 / 72 (2.78%)
    67 / 602 (11.13%)
         occurrences all number
    85
    3
    77
    Abdominal Pain
         subjects affected / exposed
    26 / 597 (4.36%)
    0 / 72 (0.00%)
    31 / 602 (5.15%)
         occurrences all number
    41
    0
    41
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    41 / 597 (6.87%)
    2 / 72 (2.78%)
    18 / 602 (2.99%)
         occurrences all number
    53
    2
    22
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    32 / 597 (5.36%)
    1 / 72 (1.39%)
    30 / 602 (4.98%)
         occurrences all number
    36
    2
    31
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    96 / 597 (16.08%)
    4 / 72 (5.56%)
    86 / 602 (14.29%)
         occurrences all number
    154
    5
    147
    Back Pain
         subjects affected / exposed
    120 / 597 (20.10%)
    5 / 72 (6.94%)
    122 / 602 (20.27%)
         occurrences all number
    172
    8
    174
    Bone Pain
         subjects affected / exposed
    81 / 597 (13.57%)
    0 / 72 (0.00%)
    90 / 602 (14.95%)
         occurrences all number
    109
    0
    113
    Musculoskeletal Pain
         subjects affected / exposed
    32 / 597 (5.36%)
    2 / 72 (2.78%)
    42 / 602 (6.98%)
         occurrences all number
    42
    2
    58
    Pain in Extremity
         subjects affected / exposed
    72 / 597 (12.06%)
    2 / 72 (2.78%)
    69 / 602 (11.46%)
         occurrences all number
    108
    2
    95
    Infections and infestations
    Urinary Tract Infection
         subjects affected / exposed
    39 / 597 (6.53%)
    3 / 72 (4.17%)
    20 / 602 (3.32%)
         occurrences all number
    53
    3
    23
    Upper Respiratory Tract Infection
         subjects affected / exposed
    42 / 597 (7.04%)
    2 / 72 (2.78%)
    29 / 602 (4.82%)
         occurrences all number
    61
    2
    56
    Nasopharyngitis
         subjects affected / exposed
    47 / 597 (7.87%)
    0 / 72 (0.00%)
    36 / 602 (5.98%)
         occurrences all number
    80
    0
    55
    Influenza
         subjects affected / exposed
    42 / 597 (7.04%)
    3 / 72 (4.17%)
    20 / 602 (3.32%)
         occurrences all number
    53
    3
    26
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    143 / 597 (23.95%)
    9 / 72 (12.50%)
    23 / 602 (3.82%)
         occurrences all number
    323
    17
    53
    Hyperglycaemia
         subjects affected / exposed
    83 / 597 (13.90%)
    5 / 72 (6.94%)
    72 / 602 (11.96%)
         occurrences all number
    261
    12
    149
    Decreased Appetite
         subjects affected / exposed
    23 / 597 (3.85%)
    0 / 72 (0.00%)
    33 / 602 (5.48%)
         occurrences all number
    27
    0
    35

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Nov 2012
    The purpose of the amendment was to address requests and recommendations from health authorities (HA), Investigators, and Ethics Committees (ECs).
    18 Apr 2014
    The purpose of the amendment was to add radiographic progression-free survival (rPFS) as a co-primary endpoint with overall survival (OS).
    15 Feb 2017
    The purpose of the amendment was to provide clarifications to the open-label extension (OLE) Phase of the study including an outline of the open-label treatment criteria for crossover into the OLE Phase and the time and events schedules for study assessments. A Long-term Extension (LTE) Phase was added to the study. Updates were also made to the OLE Phase prednisone packaging description.

    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.
    As per protocol the long-term extension (LTE) phase was planned but LTE phase is not included as part of this study hence no data was reported for LTE phase.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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