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    Clinical Trial Results:
    A Phase III, Multicenter, Randomized Study of Atezolizumab (Anti-Pd-L1 Antibody) in Combination with Enzalutamide Versus Enzalutamide Alone in Patients with Metastatic Castration-Resistant Prostate Cancer After Failure of an Androgen Synthesis Inhibitor and Failure of, Ineligibility for, or Refusal of a Taxane Regimen.

    Summary
    EudraCT number
    		 2016-003092-22
    Trial protocol
    		 HU   CZ   DK   DE   AT   GB   ES   PL   BE   GR   FR   IT  
    Global end of trial date
    20 Dec 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Dec 2023
    First version publication date
    29 Dec 2023
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CO39385
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Hoffmann-La Roche
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    Roche Trial Information Hotline, Roche Trial Information Hotline, +41 61 6878333,
    Scientific contact
    Medical Communications, Hoffmann-La Roche, +41 800 8218590, genentech@druginfo.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
    31 Jul 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Dec 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This is a Phase III, multicenter, randomized, open-label study designed to evaluate the safety and efficacy of atezolizumab in combination with enzalutamide compared with enzalutamide alone in patients with mCRPC after failure of an androgen synthesis inhibitor (e.g., abiraterone) and failure of, ineligibility for, or refusal of a taxane regimen.
    Protection of trial subjects
    The study was conducted in accordance with the principles of the “Declaration of Helsinki” and Good Clinical Practice (GCP) guidelines according to the regulations and procedures described in the protocol.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    10 Jan 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 30
    Country: Number of subjects enrolled
    Austria: 18
    Country: Number of subjects enrolled
    Belgium: 5
    Country: Number of subjects enrolled
    Canada: 50
    Country: Number of subjects enrolled
    Switzerland: 5
    Country: Number of subjects enrolled
    China: 42
    Country: Number of subjects enrolled
    Czechia: 12
    Country: Number of subjects enrolled
    Germany: 9
    Country: Number of subjects enrolled
    Denmark: 14
    Country: Number of subjects enrolled
    Spain: 99
    Country: Number of subjects enrolled
    France: 26
    Country: Number of subjects enrolled
    United Kingdom: 38
    Country: Number of subjects enrolled
    Greece: 27
    Country: Number of subjects enrolled
    Hungary: 19
    Country: Number of subjects enrolled
    Italy: 28
    Country: Number of subjects enrolled
    Japan: 49
    Country: Number of subjects enrolled
    Korea, Democratic People's Republic of: 9
    Country: Number of subjects enrolled
    Poland: 81
    Country: Number of subjects enrolled
    Russian Federation: 33
    Country: Number of subjects enrolled
    Taiwan: 29
    Country: Number of subjects enrolled
    United States: 136
    Worldwide total number of subjects
    759
    EEA total number of subjects
    338
    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)
    187
    From 65 to 84 years
    534
    85 years and over
    38

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Study recruited predefined subject population as per inclusion and exclusion criteria

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Atezolizumab + Enzalutamide
    Arm description
    		 Participants received atezolizumab along with enzalutamide until investigator-assessed confirmed radiographic disease progression per PCWG3 criteria or unacceptable toxicity.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Atezolizumab and Enzalutamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution, Solution for injection
    Routes of administration
    Oral use, Intravenous use
    Dosage and administration details
    Atezolizumab along with enzalutamide until investigator-assessed confirmed radiographic disease progression per PCWG3 criteria or unacceptable toxicity.

    Arm title
    		 Enzalutamide
    Arm description
    		 Participants received enzalutamide alone until investigator-assessed confirmed radiographic disease progression per PCWG3 criteria or unacceptable toxicity.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Enzalutamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Enzalutamide alone until investigator-assessed confirmed radiographic disease progression per PCWG3 criteria or unacceptable toxicity.

    Number of subjects in period 1
    		Atezolizumab + Enzalutamide Enzalutamide
    Started
    379
    380
    Completed
    17
    10
    Not completed
    362
    370
         Adverse event, serious fatal
    210
    184
         Terminated by the Sponsor
    100
    126
         Physician decision
    1
    3
         Consent withdrawn by subject
    37
    44
         Lost to follow-up
    12
    12
         Started new therapy, loss of contact
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Atezolizumab + Enzalutamide
    Reporting group description
    		 Participants received atezolizumab along with enzalutamide until investigator-assessed confirmed radiographic disease progression per PCWG3 criteria or unacceptable toxicity.

    Reporting group title
    Enzalutamide
    Reporting group description
    		 Participants received enzalutamide alone until investigator-assessed confirmed radiographic disease progression per PCWG3 criteria or unacceptable toxicity.

    Reporting group values
    		 Atezolizumab + Enzalutamide Enzalutamide Total
    Number of subjects
    		 379 380 759
    Age Categorical
    Units: Participants
        <=18 years
    		 0 0 0
        Between 18 and 65 years
    		 97 90 187
        >=65 years
    		 282 290 572
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 70.3 ( 8.3 ) 70.6 ( 8.5 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 0 0 0
        Male
    		 379 380 759
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 1 1
        Asian
    		 71 65 136
        Native Hawaiian or Other Pacific Islander
    		 1 0 1
        Black or African American
    		 7 7 14
        White
    		 279 287 566
        More than one race
    		 2 0 2
        Unknown or Not Reported
    		 19 20 39
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 18 11 29
        Not Hispanic or Latino
    		 337 345 682
        Unknown or Not Reported
    		 24 24 48

    End points

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    End points reporting groups
    Reporting group title
    Atezolizumab + Enzalutamide
    Reporting group description
    		 Participants received atezolizumab along with enzalutamide until investigator-assessed confirmed radiographic disease progression per PCWG3 criteria or unacceptable toxicity.

    Reporting group title
    Enzalutamide
    Reporting group description
    		 Participants received enzalutamide alone until investigator-assessed confirmed radiographic disease progression per PCWG3 criteria or unacceptable toxicity.

    Primary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    Overall Survival is defined as the time from randomization to death from any cause.
    End point type
    Primary
    End point timeframe
    Baseline until death from any cause (up to approximately 42 months)
    End point values
    		 Atezolizumab + Enzalutamide Enzalutamide
    Number of subjects analysed
    379
    380
    Units: Months
        median (confidence interval 95%)
    15.2 (14.0 to 17.0)
    16.6 (14.7 to 18.4)
    Statistical analysis title
    		 Overall Survival
    Statistical analysis description
    Stratified Analysis
    Comparison groups
    Atezolizumab + Enzalutamide v Enzalutamide
    Number of subjects included in analysis
    759
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.2786
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.118
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.913
         upper limit
    		 1.37
    Statistical analysis title
    		 Overall Survival (OS)
    Statistical analysis description
    Unstratified Analysis
    Comparison groups
    Atezolizumab + Enzalutamide v Enzalutamide
    Number of subjects included in analysis
    759
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.094
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.184
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.971
         upper limit
    		 1.445

    Secondary: Percentage of Participants who Survived at Month 6 and 12

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    End point title
    		 Percentage of Participants who Survived at Month 6 and 12
    End point description
    OS (Overall Survival is defined as the time from randomization to death from any cause) probability at 6 and 12 months
    End point type
    Secondary
    End point timeframe
    Months 6, 12
    End point values
    		 Atezolizumab + Enzalutamide Enzalutamide
    Number of subjects analysed
    379
    380
    Units: Percentage of Participants
    number (confidence interval 95%)
        6 Months
    85.12 (81.45 to 88.78)
    85.32 (81.67 to 88.97)
        12 Months
    60.61 (55.52 to 65.71)
    64.65 (59.60 to 69.70)
    Statistical analysis title
    		 Percentage of Overall survival
    Statistical analysis description
    Difference in Event Free Rate - 6 months
    Comparison groups
    Atezolizumab + Enzalutamide v Enzalutamide
    Number of subjects included in analysis
    759
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.9391
    Method
    		 z-test
    Parameter type
    		 Difference in Event Free Rate
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.38
         upper limit
    		 4.97

    Secondary: Time to First Symptomatic Skeletal Event (SSE)

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    End point title
    		 Time to First Symptomatic Skeletal Event (SSE)
    End point description
    An SSE is defined as external beam radiation therapy to relieve skeletal symptoms (including initiation of radium-223 dichloride or other types of radionuclide therapy to treat symptoms of bone metastases), new symptomatic pathologic bone fracture, clinically apparent occurrence of spinal cord compression, or tumor related orthopedic surgical intervention. 9999 value represents Not Available data
    End point type
    Secondary
    End point timeframe
    Baseline up to end of study (up to approximately 42 months)
    End point values
    		 Atezolizumab + Enzalutamide Enzalutamide
    Number of subjects analysed
    379
    380
    Units: Months
        median (confidence interval 95%)
    24.1 (24.1 to 9999)
    24.9 (24.9 to 9999)
    No statistical analyses for this end point

    Secondary: Radiographic Progression-Free Survival (rPFS), as Assessed by the Investigator and Adapted From the PCWG3 Criteria

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    End point title
    		 Radiographic Progression-Free Survival (rPFS), as Assessed by the Investigator and Adapted From the PCWG3 Criteria
    End point description
    rPFS is defined as the time from randomization to the earliest occurrence of one of the following: - A participant is considered to have progressed by bone scan if: The first bone scan with ≥2 new lesions compared to baseline is observed < 12 weeks from randomization and is confirmed by a second bone scan taken ≥6 weeks later showing ≥2 additional new lesions (a total of ≥4 new lesions compared to baseline); the date of progression is the date of the first post-treatment scan, OR After the first post-treatment scan, ≥2 new lesions are observed relative to the first post-treatment scan, which is confirmed on a subsequent scan ≥6 weeks later; the date of progression is the date of the post-treatment scan when ≥2 new lesions were first documented. - Progression of soft tissue lesions, as defined per PCWG3 modified RECIST v1.1 - Death from any cause
    End point type
    Secondary
    End point timeframe
    Baseline until disease progression or death from any cause (up to approximately 42 months)
    End point values
    		 Atezolizumab + Enzalutamide Enzalutamide
    Number of subjects analysed
    379
    380
    Units: Months
        median (confidence interval 95%)
    4.2 (4.1 to 5.3)
    4.1 (3.7 to 4.5)
    Statistical analysis title
    		 r-Progression free survival
    Statistical analysis description
    Unstratified Analysis
    Comparison groups
    Atezolizumab + Enzalutamide v Enzalutamide
    Number of subjects included in analysis
    759
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.3157
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.917
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.775
         upper limit
    		 1.086
    Statistical analysis title
    		 OS
    Statistical analysis description
    Stratified Analysis
    Comparison groups
    Atezolizumab + Enzalutamide v Enzalutamide
    Number of subjects included in analysis
    759
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.2366
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.899
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.754
         upper limit
    		 1.072

    Secondary: Percentage of Participants With Greater Than (>) 50 Percent (%) Decrease in Prostate-Specific Antigen (PSA) From Baseline

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    End point title
    		 Percentage of Participants With Greater Than (>) 50 Percent (%) Decrease in Prostate-Specific Antigen (PSA) From Baseline
    End point description
    PSA response rate, defined as a > 50% decrease in PSA from baseline that is confirmed after ≥ 3 weeks by a consecutive confirmatory PSA measurement
    End point type
    Secondary
    End point timeframe
    Baseline until disease progression (up to approximately 42 months)
    End point values
    		 Atezolizumab + Enzalutamide Enzalutamide
    Number of subjects analysed
    379
    380
    Units: Percentage of Participants
        number (confidence interval 95%)
    25.9 (21.5 to 30.5)
    24.2 (20.0 to 28.7)
    Statistical analysis title
    		 With >50% Decrease in PSA From Baseline
    Comparison groups
    Atezolizumab + Enzalutamide v Enzalutamide
    Number of subjects included in analysis
    759
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Difference in 50% Decrease Response Rate
    Point estimate
    1.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.5
         upper limit
    		 7.8

    Secondary: Percentage of Participants Who are Radiographic Progression-Free, as Assessed by the Investigator and Adapted From the PCWG3 Criteria

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    End point title
    		 Percentage of Participants Who are Radiographic Progression-Free, as Assessed by the Investigator and Adapted From the PCWG3 Criteria
    End point description
    rPFS is defined as the time from randomization to the earliest occurrence of one of the following: - A participant is considered to have progressed by bone scan if: The first bone scan with ≥2 new lesions compared to baseline is observed < 12 weeks from randomization and is confirmed by a second bone scan taken ≥6 weeks later showing ≥2 additional new lesions (a total of ≥4 new lesions compared to baseline); the date of progression is the date of the first post-treatment scan, OR After the first post-treatment scan, ≥2 new lesions are observed relative to the first post-treatment scan, which is confirmed on a subsequent scan ≥6 weeks later; the date of progression is the date of the post-treatment scan when ≥2 new lesions were first documented. - Progression of soft tissue lesions, as defined per PCWG3 modified RECIST v1.1 - Death from any cause
    End point type
    Secondary
    End point timeframe
    Months 6, 12
    End point values
    		 Atezolizumab + Enzalutamide Enzalutamide
    Number of subjects analysed
    379
    380
    Units: Percentage of Participants
    number (confidence interval 95%)
        6 months
    41.84 (36.09 to 47.60)
    39.64 (33.86 to 45.42)
        12 months
    14.89 (10.74 to 19.05)
    13.45 (9.42 to 17.49)
    Statistical analysis title
    		 Percentage of r- progression free survival
    Statistical analysis description
    Difference in Event Free Rate - 12 months
    Comparison groups
    Atezolizumab + Enzalutamide v Enzalutamide
    Number of subjects included in analysis
    759
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.6262
    Method
    		 z-test
    Parameter type
    		 Difference in Event Free Rate
    Point estimate
    1.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.35
         upper limit
    		 7.23
    Statistical analysis title
    		 Radiographic progression free survival
    Statistical analysis description
    Difference in Event Free Rate - 6 months
    Comparison groups
    Atezolizumab + Enzalutamide v Enzalutamide
    Number of subjects included in analysis
    759
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.5959
    Method
    		 z-test
    Parameter type
    		 Difference in Event Free Rate
    Point estimate
    2.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.95
         upper limit
    		 10.37

    Secondary: Percentage of Participant With Objective Response, as Determined by the Investigator Through use of PCWG3 Criteria

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    End point title
    		 Percentage of Participant With Objective Response, as Determined by the Investigator Through use of PCWG3 Criteria
    End point description
    Objective response rate in soft tissue lesions, defined as the percentage of participants with either a CR or PR on two consecutive occasions ≥ 6 weeks apart, as determined by the investigator through use of PCWG3 criteria
    End point type
    Secondary
    End point timeframe
    Baseline until disease progression or death from any cause (up to approximately 42 months)
    End point values
    		 Atezolizumab + Enzalutamide Enzalutamide
    Number of subjects analysed
    131
    135
    Units: Percentage of Participants
        number (confidence interval 95%)
    13.7 (8.4 to 20.7)
    7.4 (3.7 to 13.0)
    No statistical analyses for this end point

    Secondary: Time to PSA Progression, Assessed as per PCWG3 Criteria

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    End point title
    		 Time to PSA Progression, Assessed as per PCWG3 Criteria
    End point description
    In participants with no PSA decline from baseline, PSA progression is defined as a ≥25% increase and an absolute increase of ≥2 ng/mL above the baseline value, ≥12 weeks after baseline. In participants with an initial PSA decline from baseline, PSA progression is defined as a ≥25% increase and an absolute increase of ≥2 ng/mL above the nadir value, which is confirmed by a consecutive second value obtained ≥3 weeks later.
    End point type
    Secondary
    End point timeframe
    Baseline until disease progression (up to approximately 42 months)
    End point values
    		 Atezolizumab + Enzalutamide Enzalutamide
    Number of subjects analysed
    379
    380
    Units: Months
        median (confidence interval 95%)
    2.8 (2.8 to 2.9)
    2.8 (2.8 to 2.9)
    Statistical analysis title
    		 Time to PSA Progression
    Statistical analysis description
    Stratified Analysis
    Comparison groups
    Atezolizumab + Enzalutamide v Enzalutamide
    Number of subjects included in analysis
    759
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.6857
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.037
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.869
         upper limit
    		 1.238
    Statistical analysis title
    		 Time to PSA Progression
    Statistical analysis description
    Unstratified Analysis
    Comparison groups
    Atezolizumab + Enzalutamide v Enzalutamide
    Number of subjects included in analysis
    759
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.5359
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.055
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.89
         upper limit
    		 1.251

    Secondary: Percentage of Participants With Adverse Events

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    End point title
    		 Percentage of Participants With Adverse Events
    End point description
    Verbatim description of adverse events will be coded to MedDRA preferred terms and graded according to NCI CTCAE v4.0.
    End point type
    Secondary
    End point timeframe
    Baseline up to end of study (up to approximately 42 month)
    End point values
    		 Atezolizumab + Enzalutamide Enzalutamide
    Number of subjects analysed
    374
    376
    Units: Percentage of Participants
    number (not applicable)
        Participants with at least one adverse event
    96.8
    92.3
        Participants with at least 1 treatment AE
    78.1
    51.6
    No statistical analyses for this end point

    Secondary: Minimum Observed Serum Concentration (Cmin) of Atezolizumab

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    End point title
    		 Minimum Observed Serum Concentration (Cmin) of Atezolizumab
    End point description
    Atezolizumab serum concentration data (minimum [Cmin]) will be reported and summarized for each cycle where collected as appropriate. 9999 value represents Not Available data
    End point type
    Secondary
    End point timeframe
    Pre-infusion (0 hour[hr]) on Day 1 Cycles 1, 2, 3, 4, 8, 12, 16 (Cycle length: 21 days); treatment discontinuation visit, 120 days after last dose (up to approximately 42 months)
    End point values
    		 Atezolizumab + Enzalutamide Enzalutamide
    Number of subjects analysed
    377
    376
    Units: microgram/mL
    number (not applicable)
        Cycle 1, Day 1, pre-dose
    9999
    9999
        Cycle 1, Day 1, 30 min post-dose
    160
    9999
        Cycle 2, Day 1, pre-dose
    0.0300
    9999
        Cycle 3, Day 1, pre-dose
    0.0300
    9999
        Cycle 4, Day 1, pre-dose
    3.46
    9999
        Cycle 8, Day 1, pre-dose
    0.0300
    9999
        Cycle 12, Day 1, pre-dose
    0.0300
    9999
        Cycle 16, Day 1, pre-dose
    0.0300
    9999
        Safety visit
    0.0300
    9999
        Study Completion/Early Discontinuation
    0.0300
    9999
        Study Completion/Early Discontinuation pre-dose
    35.2
    9999
        Unscheduled
    50.5
    9999
        Unscheduled Predose
    4.24
    9999
    No statistical analyses for this end point

    Secondary: Maximum Observed Serum Concentration (Cmax) of Atezolizumab

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    End point title
    		 Maximum Observed Serum Concentration (Cmax) of Atezolizumab
    End point description
    Atezolizumab serum concentration data (maximum [Cmax]) will be reported and summarized for each cycle where collected as appropriate. 9999 value represents Not Available data
    End point type
    Secondary
    End point timeframe
    Pre-infusion (0 hr) on Day 1 Cycles 1, 2, 3, 4, 8, 12, 16 (Cycle length: 21 days); 0.5 hr post-infusion (infusion duration: 60 minutes [min]) on Day 1 Cycle 1; treatment discontinuation visit, 120 days after last dose (up to approximately 42 months)
    End point values
    		 Atezolizumab + Enzalutamide Enzalutamide
    Number of subjects analysed
    377
    376
    Units: Microgram/mL
    number (not applicable)
        Cycle 1, Day 1, pre-dose
    0
    9999
        Cycle 1, Day 1, 30 min post-dose
    1420
    9999
        Cycle 2, Day 1, pre-dose
    637
    9999
        Cycle 3, Day 1, pre-dose
    643
    9999
        Cycle 4, Day 1, pre-dose
    941
    9999
        Cycle 8, Day 1, pre-dose
    832
    9999
        Cycle 12, Day 1, pre-dose
    534
    9999
        Safety visit
    72.1
    9999
        Study Completion/Early Discontinuation
    391
    9999
        Study Completion/Early Discontinuation pre-dose
    121
    9999
        Unscheduled
    50.5
    9999
        Unscheduled pre-dose
    146
    9999
        Cycle 16, Day 1, pre-dose
    465
    9999
    No statistical analyses for this end point

    Secondary: Plasma Concentration of Enzalutamide

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    End point title
    		 Plasma Concentration of Enzalutamide
    End point description
    Plasma concentrations of Enzalutamide will be reported and summarized using descriptive statistics for each cycle and treatment arm, as appropriate. 9999 value represents Not Available data
    End point type
    Secondary
    End point timeframe
    Predose (0 hr) and 1 hr postdose on Day 1 Cycle 1 and 3 (Cycle length: 21 days); pre-dose (within 1 hr) on Day 1 Cycle 8
    End point values
    		 Atezolizumab + Enzalutamide Enzalutamide
    Number of subjects analysed
    141
    137
    Units: Microgram/mL
    arithmetic mean (standard deviation)
        Cycle 1 Day 1 Predose
    9999 ( 9999 )
    9999 ( 9999 )
        Cycle 1 Day 1 1 Hr Post
    2.69 ( 1.61 )
    3.86 ( 2.86 )
        Cycle 3 Day 1 Predose
    13.6 ( 3.41 )
    14.0 ( 2.82 )
        Cycle 3 Day 1 1 Hr Post
    14.7 ( 3.47 )
    16.3 ( 3.13 )
        Cycle 8 Day 1 Predose
    12.8 ( 3.62 )
    13.1 ( 3.40 )
        Unscheduled Predose
    9999 ( 9999 )
    10.5 ( 9999 )
    No statistical analyses for this end point

    Secondary: Plasma Concentration of N-Desmethyl Enzalutamide

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    End point title
    		 Plasma Concentration of N-Desmethyl Enzalutamide
    End point description
    Plasma concentrations of N-Desmethyl Enzalutamide will be reported and summarized using descriptive statistics for each cycle and treatment arm, as appropriate. 9999 value represents Not Available data
    End point type
    Secondary
    End point timeframe
    Predose (0 hr) and 1 hr postdose on Day 1 Cycle 1 and 3 (Cycle length: 21 days); pre-dose (within 1 hr) on Day 1 Cycle 8
    End point values
    		 Atezolizumab + Enzalutamide Enzalutamide
    Number of subjects analysed
    141 [1]
    137
    Units: Microgram/mL
    arithmetic mean (standard deviation)
        Cycle 1 Day 1 Predose
    9999 ( 9999 )
    9999 ( 9999 )
        Cycle 1 Day 1 1 Hr Post
    9999 ( 9999 )
    9999 ( 9999 )
        Cycle 3 Day 1 Predose
    11.9 ( 3.75 )
    12.3 ( 3.20 )
        Cycle 3 Day 1 1 Hr Post
    11.1 ( 3.55 )
    11.3 ( 3.13 )
        Cycle 8 Day 1 Predose
    13.6 ( 4.68 )
    13.8 ( 4.86 )
        Unscheduled Predose
    9999 ( 9999 )
    13.3 ( 9999 )
    Notes
    [1] - 9999 value represents Not Available data
    No statistical analyses for this end point

    Secondary: Number of Participants With Anti-Drug Antibodies (ADAs) to Atezolizumab

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    End point title
    		 Number of Participants With Anti-Drug Antibodies (ADAs) to Atezolizumab
    End point description
    The numbers and proportions of ADA-positive participants and ADA-negative participants at baseline (baseline prevalence) and after baseline (post-baseline incidence) will be summarized by treatment group.
    End point type
    Secondary
    End point timeframe
    Predose (0 hr) on Day 1 Cycles 1, 2, 3, 4, 8, 12, 16 (Cycle length: 21 days); at atezolizumab discontinuation visit (30 days after last dose); 120 days after last dose of atezolizumab; up to 42 months
    End point values
    		 Atezolizumab + Enzalutamide Enzalutamide
    Number of subjects analysed
    379 [2]
    380 [3]
    Units: Number of Participants
    number (not applicable)
        With Positive Sample at Baseline
    2
    9999
        Without Positive Sample at Baseline
    368
    9999
        Positive ADA treatment induced
    52
    9999
        Positive ADA: treatment enhanced
    0
    9999
        Patients with no positive samples at baseline
    368
    9999
        Post-baseline evaluable patients
    372
    9999
        Participants negative for Treatment Emergent ADA
    52
    9999
        Negative ADA treatment induced
    52
    9999
        Negative ADA treatment enhanced
    0
    9999
        Patients negative for Treatment Emergent ADA
    320
    9999
        Negative ADA Treatment unaffected
    2
    9999
    Notes
    [2] - ITT population 386 analyzed
    [3] - ITT population
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Baseline to Up To 4 years and 11 Months
    Adverse event reporting additional description
    ATEZOLIZUMAB + ENZALUTAMIDE and ENZALUTAMIDE Arms
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18
    Reporting groups
    Reporting group title
    ENZALUTAMIDE
    Reporting group description
    		 ENZALUTAMIDE

    Reporting group title
    ATEZOLIZUMAB + ENZALUTAMIDE
    Reporting group description
    		 ATEZOLIZUMAB + ENZALUTAMIDE

    Serious adverse events
    		 ENZALUTAMIDE ATEZOLIZUMAB + ENZALUTAMIDE
    Total subjects affected by serious adverse events
         subjects affected / exposed
    87 / 376 (23.14%)
    139 / 374 (37.17%)
         number of deaths (all causes)
    191
    219
         number of deaths resulting from adverse events
    1
    7
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder cancer
         subjects affected / exposed
    1 / 376 (0.27%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    1 / 376 (0.27%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cancer
         subjects affected / exposed
    1 / 376 (0.27%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    1 / 376 (0.27%)
    2 / 374 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour rupture
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Peripheral artery thrombosis
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 376 (0.27%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 376 (0.27%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 376 (0.27%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pelvic venous thrombosis
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Bladder neoplasm surgery
         subjects affected / exposed
    1 / 376 (0.27%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Necrosis
         subjects affected / exposed
    1 / 376 (0.27%)
    0 / 374 (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
    0 / 376 (0.00%)
    2 / 374 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    2 / 376 (0.53%)
    5 / 374 (1.34%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 376 (0.27%)
    3 / 374 (0.80%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Complication of device insertion
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    2 / 376 (0.53%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Fatigue
         subjects affected / exposed
    3 / 376 (0.80%)
    3 / 374 (0.80%)
         occurrences causally related to treatment / all
    1 / 4
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 376 (0.27%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza like illness
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 376 (0.27%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 376 (0.53%)
    6 / 374 (1.60%)
         occurrences causally related to treatment / all
    0 / 7
    1 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Unevaluable event
         subjects affected / exposed
    1 / 376 (0.27%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaphylactic reaction
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Hypercapnia
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 376 (0.53%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrothorax
         subjects affected / exposed
    1 / 376 (0.27%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 376 (0.27%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Pulmonary embolism
         subjects affected / exposed
    1 / 376 (0.27%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    1 / 376 (0.27%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 376 (0.27%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    1 / 1
    Pleuritic pain
         subjects affected / exposed
    1 / 376 (0.27%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    1 / 376 (0.27%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 376 (0.00%)
    2 / 374 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    1 / 376 (0.27%)
    3 / 374 (0.80%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Troponin increased
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         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
    Subdural haematoma
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 376 (0.27%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple injuries
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    1 / 376 (0.27%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaw fracture
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    0 / 376 (0.00%)
    2 / 374 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 376 (0.27%)
    3 / 374 (0.80%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 376 (0.27%)
    3 / 374 (0.80%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    1 / 376 (0.27%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury
         subjects affected / exposed
    1 / 376 (0.27%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorder
         subjects affected / exposed
    1 / 376 (0.27%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    2 / 376 (0.53%)
    4 / 374 (1.07%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Cardiac failure congestive
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Autoimmune myocarditis
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         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
    2 / 376 (0.53%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Acute myocardial infarction
         subjects affected / exposed
    1 / 376 (0.27%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    1 / 376 (0.27%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiovascular insufficiency
         subjects affected / exposed
    1 / 376 (0.27%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Myocardial infarction
         subjects affected / exposed
    2 / 376 (0.53%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 376 (0.27%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocarditis
         subjects affected / exposed
    0 / 376 (0.00%)
    2 / 374 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus bradycardia
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    1 / 376 (0.27%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 376 (0.00%)
    2 / 374 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Neuropathy peripheral
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 376 (0.00%)
    2 / 374 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cerebrovascular accident
         subjects affected / exposed
    1 / 376 (0.27%)
    3 / 374 (0.80%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Cranial nerve palsies multiple
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    2 / 376 (0.53%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoaesthesia
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    IIIrd nerve paralysis
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 376 (0.27%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lacunar infarction
         subjects affected / exposed
    1 / 376 (0.27%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lethargy
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myasthenic syndrome
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Paraesthesia
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraparesis
         subjects affected / exposed
    1 / 376 (0.27%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral motor neuropathy
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    1 / 376 (0.27%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 376 (0.27%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paralysis
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Heparin-induced thrombocytopenia
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         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
    1 / 376 (0.27%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    11 / 376 (2.93%)
    9 / 374 (2.41%)
         occurrences causally related to treatment / all
    1 / 15
    1 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myelosuppression
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Deafness unilateral
         subjects affected / exposed
    1 / 376 (0.27%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Uveitis
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Papilloedema
         subjects affected / exposed
    1 / 376 (0.27%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Enteritis
         subjects affected / exposed
    1 / 376 (0.27%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 376 (0.27%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 376 (0.00%)
    2 / 374 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticular perforation
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroduodenal ulcer
         subjects affected / exposed
    1 / 376 (0.27%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 376 (0.00%)
    2 / 374 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 376 (0.00%)
    2 / 374 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 376 (0.53%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 376 (0.53%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 376 (0.27%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    1 / 376 (0.27%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatitis
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertransaminasaemia
         subjects affected / exposed
    0 / 376 (0.00%)
    2 / 374 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    0 / 376 (0.00%)
    2 / 374 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erythema multiforme
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    0 / 376 (0.00%)
    3 / 374 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    0 / 376 (0.00%)
    3 / 374 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stevens-Johnson syndrome
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 376 (0.27%)
    5 / 374 (1.34%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Haematuria
         subjects affected / exposed
    5 / 376 (1.33%)
    7 / 374 (1.87%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 376 (0.27%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 376 (0.27%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    1 / 376 (0.27%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephritis
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    0 / 376 (0.00%)
    3 / 374 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypothyroidism
         subjects affected / exposed
    0 / 376 (0.00%)
    2 / 374 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 376 (0.53%)
    4 / 374 (1.07%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    5 / 376 (1.33%)
    3 / 374 (0.80%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    2 / 376 (0.53%)
    7 / 374 (1.87%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemarthrosis
         subjects affected / exposed
    1 / 376 (0.27%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle spasms
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 376 (0.00%)
    2 / 374 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 376 (0.27%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myositis
         subjects affected / exposed
    0 / 376 (0.00%)
    3 / 374 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Neck pain
         subjects affected / exposed
    1 / 376 (0.27%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Torticollis
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Sepsis
         subjects affected / exposed
    4 / 376 (1.06%)
    4 / 374 (1.07%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonia legionella
         subjects affected / exposed
    1 / 376 (0.27%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    10 / 376 (2.66%)
    10 / 374 (2.67%)
         occurrences causally related to treatment / all
    0 / 13
    3 / 10
         deaths causally related to treatment / all
    0 / 3
    1 / 2
    Nosocomial infection
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 376 (0.27%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 376 (0.27%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Infected cyst
         subjects affected / exposed
    1 / 376 (0.27%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalitis
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 376 (0.27%)
    2 / 374 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 376 (0.27%)
    4 / 374 (1.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Superinfection
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord infection
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 376 (0.27%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative abscess
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 376 (0.53%)
    3 / 374 (0.80%)
         occurrences causally related to treatment / all
    1 / 2
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    1 / 376 (0.27%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 376 (0.00%)
    1 / 374 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 376 (0.27%)
    0 / 374 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 ENZALUTAMIDE ATEZOLIZUMAB + ENZALUTAMIDE
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    309 / 376 (82.18%)
    339 / 374 (90.64%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    22 / 376 (5.85%)
    27 / 374 (7.22%)
         occurrences all number
    22
    33
    Hot flush
         subjects affected / exposed
    21 / 376 (5.59%)
    11 / 374 (2.94%)
         occurrences all number
    23
    11
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    9 / 376 (2.39%)
    31 / 374 (8.29%)
         occurrences all number
    9
    37
    Pain
         subjects affected / exposed
    13 / 376 (3.46%)
    24 / 374 (6.42%)
         occurrences all number
    13
    26
    Oedema peripheral
         subjects affected / exposed
    28 / 376 (7.45%)
    33 / 374 (8.82%)
         occurrences all number
    31
    38
    Fatigue
         subjects affected / exposed
    103 / 376 (27.39%)
    128 / 374 (34.22%)
         occurrences all number
    116
    148
    Asthenia
         subjects affected / exposed
    63 / 376 (16.76%)
    82 / 374 (21.93%)
         occurrences all number
    68
    99
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    17 / 376 (4.52%)
    24 / 374 (6.42%)
         occurrences all number
    19
    26
    Cough
         subjects affected / exposed
    17 / 376 (4.52%)
    21 / 374 (5.61%)
         occurrences all number
    18
    22
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    29 / 376 (7.71%)
    29 / 374 (7.75%)
         occurrences all number
    30
    29
    Investigations
    Weight decreased
         subjects affected / exposed
    32 / 376 (8.51%)
    51 / 374 (13.64%)
         occurrences all number
    33
    54
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    19 / 376 (5.05%)
    21 / 374 (5.61%)
         occurrences all number
    27
    26
    Nervous system disorders
    Headache
         subjects affected / exposed
    19 / 376 (5.05%)
    31 / 374 (8.29%)
         occurrences all number
    21
    34
    Dizziness
         subjects affected / exposed
    21 / 376 (5.59%)
    26 / 374 (6.95%)
         occurrences all number
    27
    31
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    49 / 376 (13.03%)
    83 / 374 (22.19%)
         occurrences all number
    58
    98
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    32 / 376 (8.51%)
    31 / 374 (8.29%)
         occurrences all number
    35
    35
    Nausea
         subjects affected / exposed
    66 / 376 (17.55%)
    86 / 374 (22.99%)
         occurrences all number
    73
    95
    Diarrhoea
         subjects affected / exposed
    41 / 376 (10.90%)
    86 / 374 (22.99%)
         occurrences all number
    51
    109
    Constipation
         subjects affected / exposed
    62 / 376 (16.49%)
    78 / 374 (20.86%)
         occurrences all number
    65
    88
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    10 / 376 (2.66%)
    51 / 374 (13.64%)
         occurrences all number
    10
    59
    Pruritus
         subjects affected / exposed
    8 / 376 (2.13%)
    36 / 374 (9.63%)
         occurrences all number
    8
    43
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    5 / 376 (1.33%)
    21 / 374 (5.61%)
         occurrences all number
    5
    22
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    39 / 376 (10.37%)
    26 / 374 (6.95%)
         occurrences all number
    46
    32
    Musculoskeletal chest pain
         subjects affected / exposed
    15 / 376 (3.99%)
    21 / 374 (5.61%)
         occurrences all number
    16
    25
    Bone pain
         subjects affected / exposed
    34 / 376 (9.04%)
    27 / 374 (7.22%)
         occurrences all number
    38
    31
    Back pain
         subjects affected / exposed
    55 / 376 (14.63%)
    80 / 374 (21.39%)
         occurrences all number
    63
    98
    Arthralgia
         subjects affected / exposed
    64 / 376 (17.02%)
    80 / 374 (21.39%)
         occurrences all number
    94
    108
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    18 / 376 (4.79%)
    20 / 374 (5.35%)
         occurrences all number
    21
    24
    Nasopharyngitis
         subjects affected / exposed
    21 / 376 (5.59%)
    13 / 374 (3.48%)
         occurrences all number
    24
    15
    Upper respiratory tract infection
         subjects affected / exposed
    14 / 376 (3.72%)
    19 / 374 (5.08%)
         occurrences all number
    15
    21
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    104 / 376 (27.66%)
    115 / 374 (30.75%)
         occurrences all number
    120
    129

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Mar 2017
    V2
    04 Apr 2017
    V3
    29 Jun 2017
    V4
    02 Mar 2018
    V5
    23 Aug 2018
    V6
    05 Aug 2019
    V7
    14 Feb 2020
    V8

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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