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    Clinical Trial Results:
    A Randomized, Double Blind, Multicenter, Parallel-Group, Phase III Study to Evaluate Efficacy and Safety of DCVAC/PCa Versus Placebo in Men with Metastatic Castration Resistant Prostate Cancer Eligible for 1st Line Chemotherapy

    Summary
    EudraCT number
    		 2012-002814-38
    Trial protocol
    		 SE   GB   DE   BE   CZ   IT   NL   ES   HU   PT   BG   SK   PL   HR   AT   LV   LT   DK   FR  
    Global end of trial date
    28 Jan 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Feb 2021
    First version publication date
    07 Feb 2021
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    SP005
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02111577
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    SOTIO a.s.
    Sponsor organisation address
    Jankovcova 1518/2, Prague, Czechia,
    Public contact
    Clinical Trials Sotio, SOTIO a.s., +420 224175111, clinicaltrial@sotio.com
    Scientific contact
    Clinical Trials Sotio, SOTIO a.s., +420 224175111, clinicaltrial@sotio.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
    03 Jul 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Dec 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Jan 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary: The primary objective was to show superiority of treatment with DCVAC/PCa in addition to standard of care chemotherapy (docetaxel plus prednisone) over placebo in addition to standard of care chemotherapy (docetaxel plus prednisone) in men with metastatic castration resistant prostate cancer as measured by overall survival. Key secondary: The key secondary objectives included assessments of safety, treatment group comparison with regard to radiographic progression-free survival, time to prostate-specific antigen progression, time to first occurrence of skeletal-related events. Other secondary: To show clinical benefit of treatment with DCVAC/PCa plus standard of care over placebo in addition to standard of care with regard to time to radiographic progression or skeletal-related events, proportion of patients with skeletal-related events.
    Protection of trial subjects
    Not applicable
    Background therapy
    		 Docetaxel 75 mg/m2 intravenously every 3 weeks plus prednisone 5 mg orally twice daily or equivalent
    Evidence for comparator
    		 -
    Actual start date of recruitment
    26 May 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 48
    Country: Number of subjects enrolled
    Poland: 130
    Country: Number of subjects enrolled
    Portugal: 30
    Country: Number of subjects enrolled
    Slovakia: 64
    Country: Number of subjects enrolled
    Spain: 32
    Country: Number of subjects enrolled
    Sweden: 5
    Country: Number of subjects enrolled
    United Kingdom: 96
    Country: Number of subjects enrolled
    Croatia: 24
    Country: Number of subjects enrolled
    Austria: 19
    Country: Number of subjects enrolled
    Belgium: 31
    Country: Number of subjects enrolled
    Bulgaria: 25
    Country: Number of subjects enrolled
    Czech Republic: 142
    Country: Number of subjects enrolled
    Denmark: 2
    Country: Number of subjects enrolled
    France: 30
    Country: Number of subjects enrolled
    Germany: 143
    Country: Number of subjects enrolled
    Hungary: 42
    Country: Number of subjects enrolled
    Italy: 22
    Country: Number of subjects enrolled
    Latvia: 2
    Country: Number of subjects enrolled
    Lithuania: 11
    Country: Number of subjects enrolled
    Belarus: 31
    Country: Number of subjects enrolled
    Serbia: 36
    Country: Number of subjects enrolled
    United States: 217
    Worldwide total number of subjects
    1182
    EEA total number of subjects
    898
    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)
    379
    From 65 to 84 years
    793
    85 years and over
    10

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 SP005 was conducted at 176 clinical sites. Recruitment (screening) started on 26-May-2014 and ended on 09-Oct-2017. Patients: - Screened: 1637 - Randomized: 1182 - Analyzed for efficacy: 1182 - Analyzed for safety: 1128

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 DCVAC/PCa
    Arm description
    		 Patients randomized to receive DCVAC/PCa concurrently with docetaxel plus prednisone every 3 weeks (± 7 days). DCVAC/PCa was administered at least 7 days before or and at least 7 days after the nearest chemotherapy (days 8-15 of chemotherapy cycles). After discontinuation of chemotherapy for any reason, each following dose of DCVAC/PCa was given every 4 weeks (-7/+14 days) for up to a total of 15 doses.
    Arm type
    		 Experimental

    Investigational medicinal product name
    DCVAC/PCa
    Investigational medicinal product code
    Not applicable
    Other name
    Stapuldencel
    Pharmaceutical forms
    Dispersion for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous injection of approximately 1×10e7 autologous dendritic cells

    Arm title
    		 Placebo
    Arm description
    		 Patients randomized to receive placebo concurrently with docetaxel plus prednisone every 3 weeks (± 7 days). Placebo was administered at least 7 days before or and at least 7 days after the nearest chemotherapy (days 8-15 of chemotherapy cycles). After discontinuation of chemotherapy for any reason, each following dose of placebo was given every 4 weeks (-7/+14 days) for up to a total of 15 doses.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Not applicable
    Other name
    Not applicable
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous injection of aqueous, serum-free, animal protein-free balanced electrolyte solution

    Number of subjects in period 1
    		DCVAC/PCa Placebo
    Started
    787
    395
    Completed
    188
    106
    Not completed
    599
    289
         Consent withdrawn by subject
    51
    23
         Medical monitor's decision (active hepatitis B)
    1
    -
         Failure To produce study treatment
    6
    -
         Disease progression
    -
    1
         Adverse event, non-fatal
    1
    1
         Death due to underlying disease
    518
    254
         Lost to follow-up
    19
    10
         Unable to tolerate leukapheresis
    1
    -
         Protocol deviation
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    DCVAC/PCa
    Reporting group description
    		 Patients randomized to receive DCVAC/PCa concurrently with docetaxel plus prednisone every 3 weeks (± 7 days). DCVAC/PCa was administered at least 7 days before or and at least 7 days after the nearest chemotherapy (days 8-15 of chemotherapy cycles). After discontinuation of chemotherapy for any reason, each following dose of DCVAC/PCa was given every 4 weeks (-7/+14 days) for up to a total of 15 doses.

    Reporting group title
    Placebo
    Reporting group description
    		 Patients randomized to receive placebo concurrently with docetaxel plus prednisone every 3 weeks (± 7 days). Placebo was administered at least 7 days before or and at least 7 days after the nearest chemotherapy (days 8-15 of chemotherapy cycles). After discontinuation of chemotherapy for any reason, each following dose of placebo was given every 4 weeks (-7/+14 days) for up to a total of 15 doses.

    Reporting group values
    		 DCVAC/PCa Placebo Total
    Number of subjects
    		 787 395 1182
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 272 107 379
        From 65-84 years
    		 509 284 793
        85 years and over
    		 6 4 10
    Gender categorical
    Units: Subjects
        Female
    		 0 0 0
        Male
    		 787 395 1182

    End points

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    End points reporting groups
    Reporting group title
    DCVAC/PCa
    Reporting group description
    		 Patients randomized to receive DCVAC/PCa concurrently with docetaxel plus prednisone every 3 weeks (± 7 days). DCVAC/PCa was administered at least 7 days before or and at least 7 days after the nearest chemotherapy (days 8-15 of chemotherapy cycles). After discontinuation of chemotherapy for any reason, each following dose of DCVAC/PCa was given every 4 weeks (-7/+14 days) for up to a total of 15 doses.

    Reporting group title
    Placebo
    Reporting group description
    		 Patients randomized to receive placebo concurrently with docetaxel plus prednisone every 3 weeks (± 7 days). Placebo was administered at least 7 days before or and at least 7 days after the nearest chemotherapy (days 8-15 of chemotherapy cycles). After discontinuation of chemotherapy for any reason, each following dose of placebo was given every 4 weeks (-7/+14 days) for up to a total of 15 doses.

    Primary: Overall survival, intention-to-treat population

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    End point title
    		 Overall survival, intention-to-treat population
    End point description
    Intention-to-treat population definition: All randomized patients
    End point type
    Primary
    End point timeframe
    From randomization to death due to any cause
    End point values
    		 DCVAC/PCa Placebo
    Number of subjects analysed
    787
    395
    Units: Months
        median (confidence interval 95%)
    23.9 (21.6 to 25.3)
    24.3 (22.6 to 26.0)
    Statistical analysis title
    		 Stratified
    Statistical analysis description
    Stratified by region (US vs other), prior abiraterone (Yes vs No), prior enzalutamide (Yes vs No) and ECOG score (0, 1 vs 2)
    Comparison groups
    DCVAC/PCa v Placebo
    Number of subjects included in analysis
    1182
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.596
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.042
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.895
         upper limit
    		 1.213
    Statistical analysis title
    		 Unstratified
    Comparison groups
    DCVAC/PCa v Placebo
    Number of subjects included in analysis
    1182
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.648
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.036
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.891
         upper limit
    		 1.204

    Secondary: Overall survival, per protocol population

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    End point title
    		 Overall survival, per protocol population
    End point description
    Per protocol population definition: A subset of all randomized patients characterized by the following criteria: - had at least 1 post-baseline efficacy assessment - did not have any major protocol violation that would affect the endpoints being assessed - received at least 8 doses of DCVAC/PCa or placebo
    End point type
    Secondary
    End point timeframe
    From randomization to death due to any cause
    End point values
    		 DCVAC/PCa Placebo
    Number of subjects analysed
    438
    284
    Units: Months
        median (confidence interval 95%)
    29.7 (26.9 to 32.3)
    26.7 (24.7 to 28.8)
    Statistical analysis title
    		 Stratified
    Statistical analysis description
    Stratified by region (US vs other), prior abiraterone (Yes vs No), prior enzalutamide (Yes vs No) and ECOG score (0, 1 vs 2)
    Comparison groups
    DCVAC/PCa v Placebo
    Number of subjects included in analysis
    722
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.335
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.908
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.746
         upper limit
    		 1.105
    Statistical analysis title
    		 Unstratified
    Comparison groups
    DCVAC/PCa v Placebo
    Number of subjects included in analysis
    722
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.192
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.879
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.725
         upper limit
    		 1.067

    Secondary: Overall survival, intention-to-treat population, patients with abiraterone as prior therapy

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    End point title
    		 Overall survival, intention-to-treat population, patients with abiraterone as prior therapy
    End point description
    Intention-to-treat population definition: All randomized patients with abiraterone as prior therapy
    End point type
    Secondary
    End point timeframe
    From randomization to death due to any cause
    End point values
    		 DCVAC/PCa Placebo
    Number of subjects analysed
    187
    103
    Units: Months
        median (confidence interval 95%)
    16.6 (14.9 to 19.7)
    21.0 (16.6 to 24.1)
    Statistical analysis title
    		 Stratified
    Statistical analysis description
    Stratified by region (US vs other), prior enzalutamide (Yes vs No) and ECOG score (0, 1 vs 2)
    Comparison groups
    DCVAC/PCa v Placebo
    Number of subjects included in analysis
    290
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.071
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.312
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.976
         upper limit
    		 1.762
    Statistical analysis title
    		 Unstratified
    Comparison groups
    DCVAC/PCa v Placebo
    Number of subjects included in analysis
    290
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.09
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.283
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.961
         upper limit
    		 1.712

    Secondary: Overall survival, intention-to-treat population, patients with enzalutamide as prior therapy

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    End point title
    		 Overall survival, intention-to-treat population, patients with enzalutamide as prior therapy
    End point description
    Intention-to-treat population definition: All randomized patients with enzalutamide as prior therapy
    End point type
    Secondary
    End point timeframe
    From randomization to death due to any cause
    End point values
    		 DCVAC/PCa Placebo
    Number of subjects analysed
    137
    60
    Units: Months
        median (confidence interval 95%)
    15.2 (13.3 to 18.3)
    21.4 (15.1 to 26.5)
    Statistical analysis title
    		 Stratified
    Statistical analysis description
    Stratified by region (US vs other), prior abiraterone (Yes vs No) and ECOG score (0, 1 vs 2)
    Comparison groups
    DCVAC/PCa v Placebo
    Number of subjects included in analysis
    197
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.049
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.461
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1
         upper limit
    		 2.134
    Statistical analysis title
    		 Unstratified
    Comparison groups
    DCVAC/PCa v Placebo
    Number of subjects included in analysis
    197
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.053
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.436
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.993
         upper limit
    		 2.077

    Secondary: Overall survival, intention-to-treat population, patients with neither abiraterone nor enzalutamide as prior therapy

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    End point title
    		 Overall survival, intention-to-treat population, patients with neither abiraterone nor enzalutamide as prior therapy
    End point description
    Intention-to-treat population definition: All randomized patients with neither abiraterone nor enzalutamide as prior therapy
    End point type
    Secondary
    End point timeframe
    From randomization to death due to any cause
    End point values
    		 DCVAC/PCa Placebo
    Number of subjects analysed
    546
    271
    Units: Months
        median (confidence interval 95%)
    26.7 (25.2 to 28.8)
    25.7 (23.8 to 28.3)
    Statistical analysis title
    		 Stratified
    Statistical analysis description
    Stratified by region (US vs other) and ECOG score (0, 1 vs 2)
    Comparison groups
    DCVAC/PCa v Placebo
    Number of subjects included in analysis
    817
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.501
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.938
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.779
         upper limit
    		 1.13
    Statistical analysis title
    		 Unstratified
    Comparison groups
    DCVAC/PCa v Placebo
    Number of subjects included in analysis
    817
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.512
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.781
         upper limit
    		 1.131

    Secondary: Radiological progression-free survival, intention-to-treat population

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    End point title
    		 Radiological progression-free survival, intention-to-treat population
    End point description
    Intention-to-treat population definition: All randomized patients
    End point type
    Secondary
    End point timeframe
    Time from randomization to the date of the earliest objective evidence of either radiographic progression of bone lesions, radiographic progression of soft tissue lesions, or death due to any cause
    End point values
    		 DCVAC/PCa Placebo
    Number of subjects analysed
    787
    395
    Units: Months
        median (confidence interval 95%)
    11.1 (11.0 to 11.4)
    11.1 (10.8 to 11.4)
    Statistical analysis title
    		 Stratified
    Statistical analysis description
    Stratified by region (US vs other), prior abiraterone (Yes vs No), prior enzalutamide (Yes vs No) and ECOG score (0, 1 vs 2)
    Comparison groups
    DCVAC/PCa v Placebo
    Number of subjects included in analysis
    1182
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.886
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.863
         upper limit
    		 1.136
    Statistical analysis title
    		 Unstratified
    Comparison groups
    DCVAC/PCa v Placebo
    Number of subjects included in analysis
    1182
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.992
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.001
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.875
         upper limit
    		 1.145

    Secondary: Radiological progression-free survival, per protocol population

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    End point title
    		 Radiological progression-free survival, per protocol population
    End point description
    Per protocol population definition: A subset of all randomized patients characterized by the following criteria: - had at least 1 post-baseline efficacy assessment - did not have any major protocol violation that would affect the endpoints being assessed - received at least 8 doses of DCVAC/PCa or placebo
    End point type
    Secondary
    End point timeframe
    Time from randomization to the date of the earliest objective evidence of either radiographic progression of bone lesions, radiographic progression of soft tissue lesions, or death due to any cause
    End point values
    		 DCVAC/PCa Placebo
    Number of subjects analysed
    438
    284
    Units: Months
        median (confidence interval 95%)
    11.2 (11.1 to 11.7)
    11.2 (11.0 to 11.8)
    Statistical analysis title
    		 Stratified
    Statistical analysis description
    Stratified by region (US vs other), prior abiraterone (Yes vs No), prior enzalutamide (Yes vs No) and ECOG score (0, 1 vs 2)
    Comparison groups
    DCVAC/PCa v Placebo
    Number of subjects included in analysis
    722
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.994
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.001
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.847
         upper limit
    		 1.184
    Statistical analysis title
    		 Unstratified
    Comparison groups
    DCVAC/PCa v Placebo
    Number of subjects included in analysis
    722
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.982
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.002
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.851
         upper limit
    		 1.18

    Secondary: Time to PSA progression, intention-to-treat population

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    End point title
    		 Time to PSA progression, intention-to-treat population
    End point description
    Intention-to-treat population definition: All randomized patients
    End point type
    Secondary
    End point timeframe
    Time from randomization to the date of the earliest objective evidence of PSA progression (PSA absolute increase ≥ 2 ng/mL and ≥ 25% above nadir or baseline values providing confirmation by a second consecutive value obtained at least 3 weeks later)
    End point values
    		 DCVAC/PCa Placebo
    Number of subjects analysed
    787
    395
    Units: Months
        median (confidence interval 95%)
    10.5 (9.7 to 10.6)
    10.6 (10.4 to 10.7)
    Statistical analysis title
    		 Stratified
    Statistical analysis description
    Stratified by region (US vs other), prior abiraterone (Yes vs No), prior enzalutamide (Yes vs No) and ECOG score (0, 1 vs 2)
    Comparison groups
    DCVAC/PCa v Placebo
    Number of subjects included in analysis
    1182
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.392
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.077
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.909
         upper limit
    		 1.277
    Statistical analysis title
    		 Unstratified
    Comparison groups
    DCVAC/PCa v Placebo
    Number of subjects included in analysis
    1182
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.439
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.068
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.905
         upper limit
    		 1.262

    Secondary: Time to PSA progression, per protocol population

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    End point title
    		 Time to PSA progression, per protocol population
    End point description
    Per protocol population definition: A subset of all randomized patients characterized by the following criteria: - had at least 1 post-baseline efficacy assessment - did not have any major protocol violation that would affect the endpoints being assessed - received at least 8 doses of DCVAC/PCa or placebo
    End point type
    Secondary
    End point timeframe
    Time from randomization to the date of the earliest objective evidence of PSA progression (PSA absolute increase ≥ 2 ng/mL and ≥ 25% above nadir or baseline values providing confirmation by a second consecutive value obtained at least 3 weeks later)
    End point values
    		 DCVAC/PCa Placebo
    Number of subjects analysed
    438
    284
    Units: Months
        median (confidence interval 95%)
    10.5 (10.4 to 10.7)
    10.6 (10.4 to 10.7)
    Statistical analysis title
    		 Stratified
    Statistical analysis description
    Stratified by region (US vs other), prior abiraterone (Yes vs No), prior enzalutamide (Yes vs No) and ECOG score (0, 1 vs 2)
    Comparison groups
    DCVAC/PCa v Placebo
    Number of subjects included in analysis
    722
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.754
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.857
         upper limit
    		 1.238
    Statistical analysis title
    		 Unstratified
    Comparison groups
    DCVAC/PCa v Placebo
    Number of subjects included in analysis
    722
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.924
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.009
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.844
         upper limit
    		 1.207

    Secondary: Time to first skeletal-related event, intention-to-treat population

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    End point title
    		 Time to first skeletal-related event, intention-to-treat population
    End point description
    Intention-to-treat population definition: All randomized patients; "1000000" means "not reached"
    End point type
    Secondary
    End point timeframe
    Time from randomization to the date of the first skeletal-related event
    End point values
    		 DCVAC/PCa Placebo
    Number of subjects analysed
    787
    395
    Units: Months
        median (confidence interval 95%)
    1000000 (1000000 to 1000000)
    1000000 (1000000 to 1000000)
    Statistical analysis title
    		 Stratified
    Statistical analysis description
    Stratified by region (US vs other), prior abiraterone (Yes vs No), prior enzalutamide (Yes vs No) and ECOG score (0, 1 vs 2)
    Comparison groups
    DCVAC/PCa v Placebo
    Number of subjects included in analysis
    1182
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.732
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.918
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.563
         upper limit
    		 1.497
    Statistical analysis title
    		 Unstratified
    Comparison groups
    DCVAC/PCa v Placebo
    Number of subjects included in analysis
    1182
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.713
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.913
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.561
         upper limit
    		 1.485

    Secondary: Time to first skeletal-related event, per protocol population

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    End point title
    		 Time to first skeletal-related event, per protocol population
    End point description
    Per protocol population definition: A subset of all randomized patients characterized by the following criteria: - had at least 1 post-baseline efficacy assessment - did not have any major protocol violation that would affect the endpoints being assessed - received at least 8 doses of DCVAC/PCa or placebo "1000000" means "not reached"
    End point type
    Secondary
    End point timeframe
    Time from randomization to the date of the first skeletal-related event
    End point values
    		 DCVAC/PCa Placebo
    Number of subjects analysed
    438
    284
    Units: Months
        median (confidence interval 95%)
    1000000 (1000000 to 1000000)
    1000000 (1000000 to 1000000)
    Statistical analysis title
    		 Stratified
    Statistical analysis description
    Stratified by region (US vs other), prior abiraterone (Yes vs No), prior enzalutamide (Yes vs No) and ECOG score (0, 1 vs 2)
    Comparison groups
    DCVAC/PCa v Placebo
    Number of subjects included in analysis
    722
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.694
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.891
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 1.587
    Statistical analysis title
    		 Unstratified
    Comparison groups
    DCVAC/PCa v Placebo
    Number of subjects included in analysis
    722
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.661
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.496
         upper limit
    		 1.562

    Secondary: Time to radiological progression or skeletal-related event, intention-to-treat population

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    End point title
    		 Time to radiological progression or skeletal-related event, intention-to-treat population
    End point description
    Intention-to-treat population definition: All randomized patients
    End point type
    Secondary
    End point timeframe
    Time from randomization to the date of the first radiological progression or skeletal-related event
    End point values
    		 DCVAC/PCa Placebo
    Number of subjects analysed
    787
    395
    Units: Months
        median (confidence interval 95%)
    11.1 (10.9 to 11.3)
    10.9 (10.5 to 11.2)
    Statistical analysis title
    		 Stratified
    Statistical analysis description
    Stratified by region (US vs other), prior abiraterone (Yes vs No), prior enzalutamide (Yes vs No) and ECOG score (0, 1 vs 2)
    Comparison groups
    DCVAC/PCa v Placebo
    Number of subjects included in analysis
    1182
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.111
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.895
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.781
         upper limit
    		 1.027
    Statistical analysis title
    		 Unstratified
    Comparison groups
    DCVAC/PCa v Placebo
    Number of subjects included in analysis
    1182
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.184
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.913
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.798
         upper limit
    		 1.044

    Secondary: Time to radiological progression or skeletal-related event, per protocol population

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    End point title
    		 Time to radiological progression or skeletal-related event, per protocol population
    End point description
    Per protocol population definition: A subset of all randomized patients characterized by the following criteria: - had at least 1 post-baseline efficacy assessment - did not have any major protocol violation that would affect the endpoints being assessed - received at least 8 doses of DCVAC/PCa or placebo
    End point type
    Secondary
    End point timeframe
    Time from randomization to the date of the first radiological progression or skeletal-related event
    End point values
    		 DCVAC/PCa Placebo
    Number of subjects analysed
    438
    284
    Units: Months
        median (confidence interval 95%)
    11.1 (11.0 to 11.5)
    11.1 (10.8 to 11.3)
    Statistical analysis title
    		 Stratified
    Statistical analysis description
    Stratified by region (US vs other), prior abiraterone (Yes vs No), prior enzalutamide (Yes vs No) and ECOG score (0, 1 vs 2)
    Comparison groups
    DCVAC/PCa v Placebo
    Number of subjects included in analysis
    722
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.46
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.939
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.795
         upper limit
    		 1.11
    Statistical analysis title
    		 Unstratified
    Comparison groups
    DCVAC/PCa v Placebo
    Number of subjects included in analysis
    722
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.534
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.807
         upper limit
    		 1.118

    Secondary: Proportion of patients with skeletal-related events, intention-to-treat population

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    End point title
    		 Proportion of patients with skeletal-related events, intention-to-treat population
    End point description
    Intention-to-treat population definition: All randomized patients
    End point type
    Secondary
    End point timeframe
    From randomization to the end of the study
    End point values
    		 DCVAC/PCa Placebo
    Number of subjects analysed
    787
    395
    Units: Patients
    43
    26
    Statistical analysis title
    		 Stratified
    Statistical analysis description
    Adjusted by region (US vs other), prior abiraterone (Yes vs No), prior enzalutamide (Yes vs No) and ECOG score (0, 1 vs 2)
    Comparison groups
    DCVAC/PCa v Placebo
    Number of subjects included in analysis
    1182
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.485
    Method
    		 Log binomial model
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.845
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.528
         upper limit
    		 1.355

    Secondary: Proportion of patients with skeletal-related events, per protocol population

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    End point title
    		 Proportion of patients with skeletal-related events, per protocol population
    End point description
    Per protocol population definition: A subset of all randomized patients characterized by the following criteria: - had at least 1 post-baseline efficacy assessment - did not have any major protocol violation that would affect the endpoints being assessed - received at least 8 doses of DCVAC/PCa or placebo
    End point type
    Secondary
    End point timeframe
    From randomization to the end of the study
    End point values
    		 DCVAC/PCa Placebo
    Number of subjects analysed
    438
    284
    Units: Patients
    28
    20
    Statistical analysis title
    		 Stratified
    Statistical analysis description
    Adjusted by region (US vs other), prior abiraterone (Yes vs No), prior enzalutamide (Yes vs No) and ECOG score (0, 1 vs 2)
    Comparison groups
    DCVAC/PCa v Placebo
    Number of subjects included in analysis
    722
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.768
    Method
    		 Log binomial model
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.529
         upper limit
    		 1.601

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    TEAEs: Start date on or after the earliest start of chemotherapy or study treatment or AE worsened (increased in severity) on or after the earliest start of chemotherapy or study treatment. Deaths: From consent signature to study end.
    Adverse event reporting additional description
    TEAE = treatment-emergent adverse events. Causal association of the event to the administration of DCVAC/PCa was assessed by investigators. Disease progression-related events (as evaluated by investigators) were excluded from SAE reporting.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    DCVAC/PCa
    Reporting group description
    		 The safety population was comprised of all patients who received first-line chemotherapy and/or at least one dose of treatment with DCVAC/PCa and was based on the actual treatment received if this differs from that to which the patient was randomized.

    Reporting group title
    Placebo
    Reporting group description
    		 The safety population was comprised of all patients who received first-line chemotherapy and/or at least one dose of treatment with placebo and was based on the actual treatment received if this differs from that to which the patient was randomized.

    Serious adverse events
    		 DCVAC/PCa Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    237 / 749 (31.64%)
    150 / 379 (39.58%)
         number of deaths (all causes)
    505
    254
         number of deaths resulting from adverse events
    39
    30
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of colon
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal squamous cell carcinoma
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    2 / 749 (0.27%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cancer pain
         subjects affected / exposed
    1 / 749 (0.13%)
    3 / 379 (0.79%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carcinoid tumour
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac myxoma
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chondrosarcoma
         subjects affected / exposed
    0 / 749 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic lymphocytic leukaemia
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    1 / 749 (0.13%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant pleural effusion
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aortic stenosis
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    4 / 749 (0.53%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 749 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    2 / 749 (0.27%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock
         subjects affected / exposed
    2 / 749 (0.27%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Temporal arteritis
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    0 / 749 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    0 / 749 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    3 / 749 (0.40%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter site inflammation
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Complication associated with device
         subjects affected / exposed
    0 / 749 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    5 / 749 (0.67%)
    5 / 379 (1.32%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 5
    0 / 5
    Fatigue
         subjects affected / exposed
    5 / 749 (0.67%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    6 / 749 (0.80%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 749 (0.13%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    9 / 749 (1.20%)
    6 / 379 (1.58%)
         occurrences causally related to treatment / all
    2 / 13
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    0 / 749 (0.00%)
    3 / 379 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Allergy to arthropod sting
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaphylactic reaction
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    0 / 749 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Scrotal oedema
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    4 / 749 (0.53%)
    2 / 379 (0.53%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 3
    0 / 1
    Dyspnoea
         subjects affected / exposed
    0 / 749 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrothorax
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    2 / 749 (0.27%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    2 / 749 (0.27%)
    3 / 379 (0.79%)
         occurrences causally related to treatment / all
    3 / 3
    2 / 3
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Pleural effusion
         subjects affected / exposed
    3 / 749 (0.40%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    2 / 749 (0.27%)
    2 / 379 (0.53%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    3 / 749 (0.40%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    18 / 749 (2.40%)
    15 / 379 (3.96%)
         occurrences causally related to treatment / all
    2 / 18
    2 / 15
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Pulmonary fibrosis
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    4 / 749 (0.53%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nightmare
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device occlusion
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Computerised tomogram abnormal
         subjects affected / exposed
    0 / 749 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 749 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 749 (0.00%)
    2 / 379 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis radiation
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    0 / 749 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal stoma complication
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    2 / 749 (0.27%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaw fracture
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    2 / 749 (0.27%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound complication
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiation proctitis
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skull fracture
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 749 (0.00%)
    2 / 379 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    2 / 749 (0.27%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Subdural haemorrhage
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 749 (0.00%)
    2 / 379 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Angina pectoris
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic valve stenosis
         subjects affected / exposed
    0 / 749 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    7 / 749 (0.93%)
    2 / 379 (0.53%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial tachycardia
         subjects affected / exposed
    0 / 749 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    2 / 749 (0.27%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 749 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure
         subjects affected / exposed
    2 / 749 (0.27%)
    2 / 379 (0.53%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 749 (0.13%)
    2 / 379 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    0 / 749 (0.00%)
    2 / 379 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    0 / 749 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Coronary artery disease
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    3 / 749 (0.40%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 3
    0 / 1
    Myocarditis
         subjects affected / exposed
    0 / 749 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular extrasystoles
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Amnesia
         subjects affected / exposed
    0 / 749 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain injury
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cauda equina syndrome
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    2 / 749 (0.27%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 749 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral venous thrombosis
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    2 / 749 (0.27%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Diabetic coma
         subjects affected / exposed
    0 / 749 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Ischaemic cerebral infarction
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    3 / 749 (0.40%)
    2 / 379 (0.53%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Monoparesis
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    1 / 749 (0.13%)
    2 / 379 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraparesis
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraplegia
         subjects affected / exposed
    0 / 749 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral motor neuropathy
         subjects affected / exposed
    0 / 749 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polyneuropathy
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    2 / 749 (0.27%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Superior sagittal sinus thrombosis
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    7 / 749 (0.93%)
    3 / 379 (0.79%)
         occurrences causally related to treatment / all
    1 / 8
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    2 / 749 (0.27%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertigo CNS origin
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Agranulocytosis
         subjects affected / exposed
    0 / 749 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    9 / 749 (1.20%)
    3 / 379 (0.79%)
         occurrences causally related to treatment / all
    0 / 14
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bicytopenia
         subjects affected / exposed
    0 / 749 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    25 / 749 (3.34%)
    29 / 379 (7.65%)
         occurrences causally related to treatment / all
    2 / 27
    0 / 34
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    2 / 749 (0.27%)
    2 / 379 (0.53%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    12 / 749 (1.60%)
    5 / 379 (1.32%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    4 / 749 (0.53%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Diplopia
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uveitis
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 749 (0.13%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 749 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ischaemic
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    2 / 749 (0.27%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    5 / 749 (0.67%)
    5 / 379 (1.32%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 749 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis haemorrhagic
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric antral vascular ectasia
         subjects affected / exposed
    0 / 749 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    0 / 749 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer haemorrhage
         subjects affected / exposed
    0 / 749 (0.00%)
    2 / 379 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer perforation
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastrointestinal inflammation
         subjects affected / exposed
    0 / 749 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 749 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    2 / 749 (0.27%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 749 (0.00%)
    2 / 379 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 749 (0.13%)
    3 / 379 (0.79%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstructive pancreatitis
         subjects affected / exposed
    0 / 749 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    1 / 749 (0.13%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 749 (0.13%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peptic ulcer
         subjects affected / exposed
    0 / 749 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal perforation
         subjects affected / exposed
    0 / 749 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal haemorrhage
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal stenosis
         subjects affected / exposed
    0 / 749 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 749 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 749 (0.27%)
    4 / 379 (1.06%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic cyst
         subjects affected / exposed
    0 / 749 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash erythematous
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    5 / 749 (0.67%)
    4 / 379 (1.06%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Calculus bladder
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    6 / 749 (0.80%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    6 / 749 (0.80%)
    2 / 379 (0.53%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal atrophy
         subjects affected / exposed
    0 / 749 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    3 / 749 (0.40%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 749 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    7 / 749 (0.93%)
    4 / 379 (1.06%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    1 / 749 (0.13%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 749 (0.13%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    7 / 749 (0.93%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    1 / 749 (0.13%)
    2 / 379 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bursitis
         subjects affected / exposed
    0 / 749 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    0 / 749 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteitis
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 749 (0.13%)
    2 / 379 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis of jaw
         subjects affected / exposed
    5 / 749 (0.67%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    0 / 749 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periarthritis
         subjects affected / exposed
    0 / 749 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal infection
         subjects affected / exposed
    0 / 749 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess limb
         subjects affected / exposed
    0 / 749 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess oral
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess soft tissue
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    1 / 749 (0.13%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary tract infection
         subjects affected / exposed
    0 / 749 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    2 / 749 (0.27%)
    2 / 379 (0.53%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter site cellulitis
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    3 / 749 (0.40%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis orbital
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    2 / 749 (0.27%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    1 / 749 (0.13%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Complicated appendicitis
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus infection
         subjects affected / exposed
    0 / 749 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus oesophagitis
         subjects affected / exposed
    0 / 749 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermo-hypodermitis
         subjects affected / exposed
    0 / 749 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 749 (0.13%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterococcal bacteraemia
         subjects affected / exposed
    0 / 749 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis infectious
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    1 / 749 (0.13%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 749 (0.27%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis norovirus
         subjects affected / exposed
    0 / 749 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 749 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 749 (0.00%)
    2 / 379 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis infective
         subjects affected / exposed
    0 / 749 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    3 / 749 (0.40%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 749 (0.13%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 749 (0.00%)
    2 / 379 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    7 / 749 (0.93%)
    5 / 379 (1.32%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Osteomyelitis
         subjects affected / exposed
    2 / 749 (0.27%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraspinal abscess
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Perirectal abscess
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 749 (0.13%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    18 / 749 (2.40%)
    11 / 379 (2.90%)
         occurrences causally related to treatment / all
    0 / 18
    0 / 13
         deaths causally related to treatment / all
    0 / 3
    0 / 2
    Pneumonia mycoplasmal
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    0 / 749 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 749 (0.13%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Rectal abscess
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 749 (0.13%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    8 / 749 (1.07%)
    5 / 379 (1.32%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 5
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Septic shock
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal abscess
         subjects affected / exposed
    0 / 749 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    2 / 749 (0.27%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    2 / 749 (0.27%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal sepsis
         subjects affected / exposed
    0 / 749 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheobronchitis
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    10 / 749 (1.34%)
    8 / 379 (2.11%)
         occurrences causally related to treatment / all
    0 / 13
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection staphylococcal
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    3 / 749 (0.40%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral sepsis
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    6 / 749 (0.80%)
    4 / 379 (1.06%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic metabolic decompensation
         subjects affected / exposed
    1 / 749 (0.13%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    0 / 749 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 749 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 749 (0.13%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    4 / 749 (0.53%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 DCVAC/PCa Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    670 / 749 (89.45%)
    365 / 379 (96.31%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    43 / 749 (5.74%)
    34 / 379 (8.97%)
         occurrences all number
    56
    44
    Hypotension
         subjects affected / exposed
    40 / 749 (5.34%)
    28 / 379 (7.39%)
         occurrences all number
    48
    39
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    106 / 749 (14.15%)
    69 / 379 (18.21%)
         occurrences all number
    156
    107
    Fatigue
         subjects affected / exposed
    268 / 749 (35.78%)
    152 / 379 (40.11%)
         occurrences all number
    374
    219
    Mucosal inflammation
         subjects affected / exposed
    28 / 749 (3.74%)
    22 / 379 (5.80%)
         occurrences all number
    33
    37
    Oedema peripheral
         subjects affected / exposed
    121 / 749 (16.15%)
    87 / 379 (22.96%)
         occurrences all number
    146
    107
    Pyrexia
         subjects affected / exposed
    76 / 749 (10.15%)
    42 / 379 (11.08%)
         occurrences all number
    104
    64
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    82 / 749 (10.95%)
    47 / 379 (12.40%)
         occurrences all number
    95
    54
    Dyspnoea
         subjects affected / exposed
    82 / 749 (10.95%)
    55 / 379 (14.51%)
         occurrences all number
    103
    65
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    32 / 749 (4.27%)
    24 / 379 (6.33%)
         occurrences all number
    33
    25
    Investigations
    Weight decreased
         subjects affected / exposed
    46 / 749 (6.14%)
    24 / 379 (6.33%)
         occurrences all number
    48
    25
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    41 / 749 (5.47%)
    33 / 379 (8.71%)
         occurrences all number
    47
    40
    Dysgeusia
         subjects affected / exposed
    80 / 749 (10.68%)
    59 / 379 (15.57%)
         occurrences all number
    105
    91
    Headache
         subjects affected / exposed
    35 / 749 (4.67%)
    27 / 379 (7.12%)
         occurrences all number
    38
    33
    Hypoaesthesia
         subjects affected / exposed
    32 / 749 (4.27%)
    20 / 379 (5.28%)
         occurrences all number
    41
    25
    Neuropathy peripheral
         subjects affected / exposed
    83 / 749 (11.08%)
    54 / 379 (14.25%)
         occurrences all number
    110
    59
    Paraesthesia
         subjects affected / exposed
    76 / 749 (10.15%)
    33 / 379 (8.71%)
         occurrences all number
    95
    42
    Peripheral sensory neuropathy
         subjects affected / exposed
    36 / 749 (4.81%)
    28 / 379 (7.39%)
         occurrences all number
    39
    31
    Polyneuropathy
         subjects affected / exposed
    44 / 749 (5.87%)
    24 / 379 (6.33%)
         occurrences all number
    47
    28
    Taste disorder
         subjects affected / exposed
    37 / 749 (4.94%)
    21 / 379 (5.54%)
         occurrences all number
    39
    23
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    123 / 749 (16.42%)
    76 / 379 (20.05%)
         occurrences all number
    159
    96
    Leukopenia
         subjects affected / exposed
    63 / 749 (8.41%)
    33 / 379 (8.71%)
         occurrences all number
    103
    74
    Neutropenia
         subjects affected / exposed
    103 / 749 (13.75%)
    54 / 379 (14.25%)
         occurrences all number
    177
    92
    Eye disorders
    Lacrimation increased
         subjects affected / exposed
    29 / 749 (3.87%)
    30 / 379 (7.92%)
         occurrences all number
    29
    32
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    28 / 749 (3.74%)
    23 / 379 (6.07%)
         occurrences all number
    31
    26
    Constipation
         subjects affected / exposed
    111 / 749 (14.82%)
    71 / 379 (18.73%)
         occurrences all number
    133
    94
    Diarrhoea
         subjects affected / exposed
    204 / 749 (27.24%)
    115 / 379 (30.34%)
         occurrences all number
    338
    183
    Dyspepsia
         subjects affected / exposed
    44 / 749 (5.87%)
    22 / 379 (5.80%)
         occurrences all number
    47
    26
    Nausea
         subjects affected / exposed
    150 / 749 (20.03%)
    96 / 379 (25.33%)
         occurrences all number
    196
    142
    Stomatitis
         subjects affected / exposed
    39 / 749 (5.21%)
    24 / 379 (6.33%)
         occurrences all number
    54
    35
    Vomiting
         subjects affected / exposed
    78 / 749 (10.41%)
    43 / 379 (11.35%)
         occurrences all number
    97
    53
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    222 / 749 (29.64%)
    130 / 379 (34.30%)
         occurrences all number
    224
    131
    Nail disorder
         subjects affected / exposed
    38 / 749 (5.07%)
    28 / 379 (7.39%)
         occurrences all number
    41
    28
    Rash
         subjects affected / exposed
    36 / 749 (4.81%)
    22 / 379 (5.80%)
         occurrences all number
    40
    25
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    114 / 749 (15.22%)
    74 / 379 (19.53%)
         occurrences all number
    153
    110
    Back pain
         subjects affected / exposed
    113 / 749 (15.09%)
    67 / 379 (17.68%)
         occurrences all number
    135
    79
    Bone pain
         subjects affected / exposed
    78 / 749 (10.41%)
    26 / 379 (6.86%)
         occurrences all number
    91
    29
    Muscular weakness
         subjects affected / exposed
    32 / 749 (4.27%)
    23 / 379 (6.07%)
         occurrences all number
    36
    26
    Musculoskeletal pain
         subjects affected / exposed
    46 / 749 (6.14%)
    24 / 379 (6.33%)
         occurrences all number
    51
    28
    Myalgia
         subjects affected / exposed
    53 / 749 (7.08%)
    32 / 379 (8.44%)
         occurrences all number
    74
    47
    Pain in extremity
         subjects affected / exposed
    87 / 749 (11.62%)
    55 / 379 (14.51%)
         occurrences all number
    104
    74
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    33 / 749 (4.41%)
    22 / 379 (5.80%)
         occurrences all number
    39
    26
    Upper respiratory tract infection
         subjects affected / exposed
    34 / 749 (4.54%)
    20 / 379 (5.28%)
         occurrences all number
    41
    23
    Urinary tract infection
         subjects affected / exposed
    53 / 749 (7.08%)
    39 / 379 (10.29%)
         occurrences all number
    76
    66
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    110 / 749 (14.69%)
    79 / 379 (20.84%)
         occurrences all number
    137
    102
    Hyperglycaemia
         subjects affected / exposed
    56 / 749 (7.48%)
    27 / 379 (7.12%)
         occurrences all number
    81
    41

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Mar 2013
    For version 1.1 positive decision was received in VHP submission.
    10 May 2013
    Version 02 was based on v.1.1 and was modified for IND submission to FDA in USA. (Key changes included – specification of 1st line chemotherapy as docetaxel and prednisone and update of DCVAC/PCa safety information based on DSUR issued in February 2013; specification of exploratory studies on biomarkers; updated list of approved 2nd line chemotherapies).
    01 Aug 2013
    Version 03 was based on v.02 and was modified per feedback received from FDA. (Key changes included –Discontinuation of DCVAC/PCa or placebo with 2nd line chemotherapy; Treatment period divided into 2 periods - concurrent treatment of 1st line chemotherapy with DCVAC/PCa or placebo and Maintenance Boosting period post docetaxel-prednisone & prior 2nd line-chemotherapy; changes connected with this design change; updated list of approved 2nd line chemotherapies; Amendment of stratification criteria, updated statistical section)
    05 Dec 2013
    Version 04 is based on v.03 and mostly operational details have been adjusted to match properly the new design in v.03 (Study drug discontinuation, End of Treatment, Follow-up for survival); secondary endpoints were modified to better fulfill PCWG2 recommendations; inclusion and exclusion criteria were modified per PCWG2 guidelines; corrected statistical section and decreased number of stratification criteria)
    16 Oct 2014
    Version 05 includes updates based on current experience from the clinical trial - clarified inclusion/exclusion criteria; updated sections on patient follow-up for long term survival; sections related to safety were updated to improve understanding. Sections on interim analysis and statistical analyses were updated based on feedback received from FDA. Section on exploratory studies was updated to include possibility of pharmacogenomics research.
    13 Jan 2015
    Change in the exclusion criterion. It is possible to shorten the washout period for ADT.
    03 Aug 2015
    Version 05.2 introduces: clarification of follow-up procedures applicable to patients for whom leukapheresis or production failed, or who have not received DCVAC/PCa or placebo for other reasons; clarification that no further radiological examinations of a patient will be required for this trial after confirmation of radiological progression or introduction of 2nd line chemotherapy; changes related to transfer of pharmacovigilance responsibilities for safety monitoring and reporting from Chiltern to SOTIO; administrative changes in the Declaration of the Investigator
    28 Aug 2015
    Version 06.0 includes the same changes as US-specific versions 05.1 and 05.2 : change in wording of the exclusion criterion that shortens the ADT washout period; clarification of follow-up procedures applicable to patients for whom leukapheresis or production failed, or who have not received DCVAC/PCa or placebo for other reasons; clarification that no further radiological examinations of a patient will be required for this trial after confirmation of radiological progression or introduction of 2nd line chemotherapy; changes related to transfer of pharmacovigilance responsibilities for safety monitoring and reporting from Chiltern to SOTIO; administrative changes in the Declaration of the Investigator; Version 06.0 additionally includes the introduction of the EQ-5D questionnaire (only in Europe) and clarification that ECOG performance status is measured also at Randomization.
    08 Mar 2018
    • Deletion of information on third-party vendors • Deletion of information on interim analysis which will not be performed • Clarification that the date of randomization is Day 1 and not Day 0 • Update of the sections on statistics according to the updated draft SAP • Clarification that ECOG performance status is measured also at Randomization (already in European v. 06.0) • Introduction of the EQ-5D questionnaire (only in Europe) (already in European v. 06.0) • Safety reporting clarifications

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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