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    Clinical Trial Results:
    A Phase III, Multicenter, Randomized, Placebo-Controlled Study of Atezolizumab (Anti-PD-L1 Antibody) as Monotherapy and in Combination With Platinum-Based Chemotherapy in Patients With Untreated Locally Advanced or Metastatic Urothelial Carcinoma

    Summary
    EudraCT number
    		 2016-000250-35
    Trial protocol
    		 ES   CZ   EE   GR   PL   SI   GB   FI   NL   PT   BE   IT  
    Global end of trial date

    Results information
    Results version number
    		 v1
    This version publication date
    08 Sep 2023
    First version publication date
    08 Sep 2023
    Other versions
    		 v2 , v3

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    WO30070
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02807636
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, 41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, 41 616878333, global.trial_information@roche.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Interim
    Date of interim/final analysis
    31 Aug 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Aug 2022
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    This study evaluated the efficacy of atezolizumab given as monotherapy or in combination with platinum-based chemotherapy versus placebo in combination with platinum-based chemotherapy in participants with locally advanced or metastatic urothelial carcinoma who have not received prior systemic therapy.
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Jun 2016
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 39 Months
    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
    Belgium: 10
    Country: Number of subjects enrolled
    Bosnia and Herzegovina: 12
    Country: Number of subjects enrolled
    Brazil: 61
    Country: Number of subjects enrolled
    Canada: 21
    Country: Number of subjects enrolled
    Chile: 13
    Country: Number of subjects enrolled
    China: 40
    Country: Number of subjects enrolled
    Czechia: 27
    Country: Number of subjects enrolled
    Spain: 204
    Country: Number of subjects enrolled
    Estonia: 7
    Country: Number of subjects enrolled
    Finland: 5
    Country: Number of subjects enrolled
    United Kingdom: 8
    Country: Number of subjects enrolled
    Georgia: 18
    Country: Number of subjects enrolled
    Greece: 47
    Country: Number of subjects enrolled
    Hong Kong: 17
    Country: Number of subjects enrolled
    Israel: 1
    Country: Number of subjects enrolled
    Italy: 94
    Country: Number of subjects enrolled
    Japan: 58
    Country: Number of subjects enrolled
    Korea, Republic of: 72
    Country: Number of subjects enrolled
    Mexico: 14
    Country: Number of subjects enrolled
    Malaysia: 5
    Country: Number of subjects enrolled
    Netherlands: 12
    Country: Number of subjects enrolled
    Poland: 33
    Country: Number of subjects enrolled
    Portugal: 7
    Country: Number of subjects enrolled
    Romania: 9
    Country: Number of subjects enrolled
    Russian Federation: 68
    Country: Number of subjects enrolled
    Singapore: 8
    Country: Number of subjects enrolled
    Serbia: 22
    Country: Number of subjects enrolled
    Slovenia: 17
    Country: Number of subjects enrolled
    Thailand: 23
    Country: Number of subjects enrolled
    Turkey: 91
    Country: Number of subjects enrolled
    Taiwan: 42
    Country: Number of subjects enrolled
    Ukraine: 27
    Country: Number of subjects enrolled
    United States: 77
    Country: Number of subjects enrolled
    South Africa: 13
    Worldwide total number of subjects
    1213
    EEA total number of subjects
    472
    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)
    447
    From 65 to 84 years
    744
    85 years and over
    22

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled in 221 sites in 35 countries.

    Pre-assignment
    Screening details
    		 Stage 1 included atezolizumab+gemcitabine+carboplatin arm or placebo+gemcitabine+carboplatin arm. Participants ineligible for cisplatin-based chemo were enrolled in this stage. Stage 2 included addition of atezolizumab monotherapy arm and allowed participants who were eligible for cisplatin-based chemotherapy.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Subject
    Blinding implementation details
    In the Atezolizumab+Gemcitabine+Carboplatin/Cisplatin arm, participants received blinded atezolizumab plus open-label platinum-based chemotherapy. In the placebo arm, participants received blinded placebo matched to atezolizumab plus open-label platinum-based chemotherapy. In the Atezolizumab Monotherapy arm, eligible participants received open-label atezolizumab as monotherapy.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo+Gemcitabine+Carboplatin/Cisplatin
    Arm description
    		 Participants received blinded placebo matched to atezolizumab in combination with open-label platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin).
    Arm type
    		 Placebo

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Carboplatin was administered at doses to achieve area under the concentration-time curve (AUC) of 4.5 milligram per milliliter into minute (mg/mL*min) by IV infusion on Day 1 of each 21-day cycle until investigator-assessed disease progression per RECIST v1.1 or unacceptable toxicity.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo matched to atezolizumab was administered by IV infusion on Day 1 of each 21-day cycle until investigator-assessed disease progression per RECIST v1.1. In specific circumstances treatment may continue beyond disease progression.

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cisplatin was administered at a dose of 70 mg/m^2 by IV infusion on Day 1 of each 21-day cycle until investigator-assessed disease progression per RECIST v1.1 or unacceptable toxicity.

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Gemcitabine was administered at a dose of 1000 milligrams per square meter (mg/m^2) by IV infusion on Day 1 and Day 8 of each 21-day cycle, until investigator-assessed disease progression per RECIST v1.1 or unacceptable toxicity.

    Arm title
    		 Atezolizumab+Gemcitabine+Carboplatin/Cisplatin
    Arm description
    		 Participants received blinded atezolizumab in combination with open-label platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Atezolizumab
    Investigational medicinal product code
    Other name
    Tecentriq
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Atezolizumab was administered at a fixed dose of 1200 milligrams (mg) by intravenous (IV) infusion on Day 1 of each 21-day cycle until investigator-assessed disease progression per RECIST v1.1. In specific circumstances treatment may continue beyond disease progression.

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cisplatin was administered at a dose of 70 mg/m^2 by IV infusion on Day 1 of each 21-day cycle until investigator-assessed disease progression per RECIST v1.1 or unacceptable toxicity.

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Gemcitabine was administered at a dose of 1000 milligrams per square meter (mg/m^2) by IV infusion on Day 1 and Day 8 of each 21-day cycle, until investigator-assessed disease progression per RECIST v1.1 or unacceptable toxicity.

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Carboplatin was administered at doses to achieve area under the concentration-time curve (AUC) of 4.5 milligram per milliliter into minute (mg/mL*min) by IV infusion on Day 1 of each 21-day cycle until investigator-assessed disease progression per RECIST v1.1 or unacceptable toxicity.

    Arm title
    		 Atezolizumab Monotherapy
    Arm description
    		 Eligible participants received open-label atezolizumab as monotherapy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Atezolizumab
    Investigational medicinal product code
    Other name
    Tecentriq
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Atezolizumab was administered at a fixed dose of 1200 milligrams (mg) by intravenous (IV) infusion on Day 1 of each 21-day cycle until investigator-assessed disease progression per RECIST v1.1. In specific circumstances treatment may continue beyond disease progression.

    Number of subjects in period 1
    		Placebo+Gemcitabine+Carboplatin/Cisplatin Atezolizumab+Gemcitabine+Carboplatin/Cisplatin Atezolizumab Monotherapy
    Started
    400
    451
    362
    Completed
    0
    0
    0
    Not completed
    400
    451
    362
         Consent withdrawn by subject
    39
    27
    23
         Protocol Deviation
    2
    -
    -
         Ongoing in study
    52
    84
    67
         Death
    298
    327
    266
         Symptomatic Deterioration
    -
    1
    -
         Lost to follow-up
    9
    12
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo+Gemcitabine+Carboplatin/Cisplatin
    Reporting group description
    		 Participants received blinded placebo matched to atezolizumab in combination with open-label platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin).

    Reporting group title
    Atezolizumab+Gemcitabine+Carboplatin/Cisplatin
    Reporting group description
    		 Participants received blinded atezolizumab in combination with open-label platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin).

    Reporting group title
    Atezolizumab Monotherapy
    Reporting group description
    		 Eligible participants received open-label atezolizumab as monotherapy.

    Reporting group values
    		 Placebo+Gemcitabine+Carboplatin/Cisplatin Atezolizumab+Gemcitabine+Carboplatin/Cisplatin Atezolizumab Monotherapy Total
    Number of subjects
    		 400 451 362 1213
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 153 152 142 447
        From 65-84 years
    		 240 290 214 744
        85 years and over
    		 7 9 6 22
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 66.4 ( 9.5 ) 67.5 ( 9.7 ) 67.0 ( 9.1 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 102 113 82 297
        Male
    		 298 338 280 916
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 44 41 40 125
        Not Hispanic or Latino
    		 350 402 311 1063
        Unknown or Not Reported
    		 6 8 11 25
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 3 4 2 9
        Asian
    		 85 90 94 269
        Native Hawaiian or Other Pacific Islander
    		 0 0 1 1
        Black or African American
    		 0 6 1 7
        White
    		 305 346 260 911
        More than one race
    		 0 0 1 1
        Unknown or Not Reported
    		 7 5 3 15

    End points

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    End points reporting groups
    Reporting group title
    Placebo+Gemcitabine+Carboplatin/Cisplatin
    Reporting group description
    		 Participants received blinded placebo matched to atezolizumab in combination with open-label platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin).

    Reporting group title
    Atezolizumab+Gemcitabine+Carboplatin/Cisplatin
    Reporting group description
    		 Participants received blinded atezolizumab in combination with open-label platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin).

    Reporting group title
    Atezolizumab Monotherapy
    Reporting group description
    		 Eligible participants received open-label atezolizumab as monotherapy.

    Primary: Investigator Assessed Progression-Free Survival (PFS) in the Placebo+Gemcitabine+Carboplatin/Cisplatin Arm Versus Atezolizumab +Gemcitabine+Carboplatin/Cisplatin Arm

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    End point title
    		 Investigator Assessed Progression-Free Survival (PFS) in the Placebo+Gemcitabine+Carboplatin/Cisplatin Arm Versus Atezolizumab +Gemcitabine+Carboplatin/Cisplatin Arm [1]
    End point description
    PFS is defined as the time from randomization to the first documented disease progression as determined by the investigator with the use of RECIST v1.1, or death from any cause, whichever occurs first.
    End point type
    Primary
    End point timeframe
    Baseline up to first documented disease progression or death, whichever occurs first (up to approximately 35 months)
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistical analysis reported as per the specified arms for the end point.
    End point values
    		 Placebo+Gemcitabine+Carboplatin/Cisplatin Atezolizumab+Gemcitabine+Carboplatin/Cisplatin
    Number of subjects analysed
    400
    451
    Units: Months
        median (confidence interval 95%)
    6.34 (6.24 to 7.00)
    8.18 (6.51 to 8.34)
    Statistical analysis title
    		 PFS Statistical Analysis
    Statistical analysis description
    Stratification factors: Enrollment stage, PD-L1 status, Bajorin risk score/presence of liver metastases, and investigator choice of chemotherapy.
    Comparison groups
    Placebo+Gemcitabine+Carboplatin/Cisplatin v Atezolizumab+Gemcitabine+Carboplatin/Cisplatin
    Number of subjects included in analysis
    851
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0073 [2]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 0.96
    Notes
    [2] - inverse normal combination

    Primary: Overall Survival (OS) in Atezolizumab+Gemcitabine+Carboplatin/Cisplatin Arm Versus Placebo+Gemcitabine+Carboplatin/Cisplatin Arm

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    End point title
    		 Overall Survival (OS) in Atezolizumab+Gemcitabine+Carboplatin/Cisplatin Arm Versus Placebo+Gemcitabine+Carboplatin/Cisplatin Arm [3]
    End point description
    OS is defined as the time from randomization to death due to any cause.
    End point type
    Primary
    End point timeframe
    Baseline until death due to any cause (up to approximately 73 months)
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistical analysis reported as per the specified arms for the end point.
    End point values
    		 Placebo+Gemcitabine+Carboplatin/Cisplatin Atezolizumab+Gemcitabine+Carboplatin/Cisplatin
    Number of subjects analysed
    400
    451
    Units: Months
        median (confidence interval 95%)
    13.44 (11.99 to 15.34)
    16.13 (14.19 to 18.76)
    Statistical analysis title
    		 OS Statistical Analysis
    Statistical analysis description
    Stratification factors: Enrollment stage, PD-L1 status, Bajorin risk score/presence of liver metastases, and investigator choice of chemotherapy.
    Comparison groups
    Placebo+Gemcitabine+Carboplatin/Cisplatin v Atezolizumab+Gemcitabine+Carboplatin/Cisplatin
    Number of subjects included in analysis
    851
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.023 [4]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.73
         upper limit
    		 1
    Notes
    [4] - one-sided, inverse normal combination

    Primary: Overall Survival (OS) in Atezolizumab Monotherapy Arm Versus Placebo+Gemcitabine+Carboplatin/Cisplatin Arm

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    End point title
    		 Overall Survival (OS) in Atezolizumab Monotherapy Arm Versus Placebo+Gemcitabine+Carboplatin/Cisplatin Arm [5]
    End point description
    OS is defined as the time from randomization to death due to any cause.
    End point type
    Primary
    End point timeframe
    Baseline until death due to any cause (up to approximately 73 months)
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistical analysis reported as per the specified arms for the end point.
    End point values
    		 Placebo+Gemcitabine+Carboplatin/Cisplatin Atezolizumab Monotherapy
    Number of subjects analysed
    359
    360
    Units: Months
        median (confidence interval 95%)
    13.34 (11.89 to 15.61)
    15.21 (13.14 to 17.68)
    Statistical analysis title
    		 OS Statistical Analysis
    Comparison groups
    Placebo+Gemcitabine+Carboplatin/Cisplatin v Atezolizumab Monotherapy
    Number of subjects included in analysis
    719
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3968 [6]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.82
         upper limit
    		 1.16
    Notes
    [6] - one-sided

    Secondary: Objective Response Rate (ORR)

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    End point title
    		 Objective Response Rate (ORR) [7]
    End point description
    Objective response rate (ORR) is defined as the proportion of participants with a confirmed objective response, either complete response (CR) or partial response (PR), observed on two assessments >= 28 days apart per RECIST v1.1, based on investigator assessment.
    End point type
    Secondary
    End point timeframe
    Baseline up to disease progression, death, or loss of follow-up, whichever occurs first (up to approximately 73 months)
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistical analysis reported as per the specified arms for the end point.
    End point values
    		 Placebo+Gemcitabine+Carboplatin/Cisplatin Atezolizumab+Gemcitabine+Carboplatin/Cisplatin
    Number of subjects analysed
    397
    447
    Units: Percentage of Participants
        number (confidence interval 95%)
    44.8 (39.87 to 49.88)
    48.1 (43.38 to 52.84)
    No statistical analyses for this end point

    Secondary: Duration of response (DOR)

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    End point title
    		 Duration of response (DOR) [8]
    End point description
    Duration of response (DOR) is defined for participants with an objective response as the time from the first documented objective response to documented disease progression per RECIST v1.1, based on investigator assessment, or death due to any cause, whichever occurs first.
    End point type
    Secondary
    End point timeframe
    From first documented objective response (CR or PR) to disease progression, death, or loss of follow-up, whichever occurs first (up to approximately 73 months)
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistical analysis reported as per the specified arms for the end point.
    End point values
    		 Placebo+Gemcitabine+Carboplatin/Cisplatin Atezolizumab+Gemcitabine+Carboplatin/Cisplatin
    Number of subjects analysed
    178
    215
    Units: Months
        number (confidence interval 95%)
    8.15 (6.34 to 8.61)
    9.13 (8.02 to 10.64)
    No statistical analyses for this end point

    Secondary: IRF-PFS

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    End point title
    		 IRF-PFS [9]
    End point description
    Independent review facility PFS (IRF-PFS) is defined as the time from randomization to the first documented disease progression as determined by blinded independent central review with use of RECIST v1.1, or death due to any cause, whichever occurs first.
    End point type
    Secondary
    End point timeframe
    Randomization to first documented disease progression or death from any cause (up to 35 months)
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistical analysis reported as per the specified arms for the end point.
    End point values
    		 Placebo+Gemcitabine+Carboplatin/Cisplatin Atezolizumab+Gemcitabine+Carboplatin/Cisplatin
    Number of subjects analysed
    400
    451
    Units: Months
        number (confidence interval 95%)
    6.34 (6.24 to 8.05)
    7.10 (6.31 to 8.25)
    Statistical analysis title
    		 IRF-PFS Statistical Analysis
    Statistical analysis description
    Stratification factors: Enrollment stage, PD-L1 status, Bajorin risk score/presence of liver metastases, and investigator choice of chemotherapy.
    Comparison groups
    Placebo+Gemcitabine+Carboplatin/Cisplatin v Atezolizumab+Gemcitabine+Carboplatin/Cisplatin
    Number of subjects included in analysis
    851
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0373 [10]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.73
         upper limit
    		 1.01
    Notes
    [10] - inverse normal combination

    Secondary: OS Event Free Rate

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    End point title
    		 OS Event Free Rate [11]
    End point description
    Overall Survival (OS) Event Free Rate at 1 Year.
    End point type
    Secondary
    End point timeframe
    Year 1
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistical analysis reported as per the specified arms for the end point.
    End point values
    		 Placebo+Gemcitabine+Carboplatin/Cisplatin Atezolizumab+Gemcitabine+Carboplatin/Cisplatin
    Number of subjects analysed
    400
    451
    Units: Percentage
        number (confidence interval 95%)
    55.00 (49.98 to 60.02)
    60.00 (55.39 to 64.61)
    Statistical analysis title
    		 OS Event Free Rate Statistical Analysis
    Statistical analysis description
    Stratification factors: Enrollment stage, PD-L1 status, Bajorin risk score/presence of liver metastases, and investigator choice of chemotherapy.
    Comparison groups
    Placebo+Gemcitabine+Carboplatin/Cisplatin v Atezolizumab+Gemcitabine+Carboplatin/Cisplatin
    Number of subjects included in analysis
    851
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1509
    Method
    		 Z-test
    Parameter type
    		 Difference in Event Free Rate
    Point estimate
    5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.82
         upper limit
    		 11.81

    Secondary: PFS Event Free Rate

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    End point title
    		 PFS Event Free Rate [12]
    End point description
    Progression Free Survival (PFS) Event Free Rate at Year 1
    End point type
    Secondary
    End point timeframe
    Year 1
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistical analysis reported as per the specified arms for the end point.
    End point values
    		 Placebo+Gemcitabine+Carboplatin/Cisplatin Atezolizumab+Gemcitabine+Carboplatin/Cisplatin
    Number of subjects analysed
    400
    451
    Units: Percentage
        number (confidence interval 95%)
    22.17 (17.93 to 26.42)
    30.47 (26.00 to 34.93)
    Statistical analysis title
    		 PFS Event Free Rate Statistical Analysis
    Statistical analysis description
    Stratification factors: Enrollment stage, PD-L1 status, Bajorin risk score/presence of liver metastases, and investigator choice of chemotherapy.
    Comparison groups
    Placebo+Gemcitabine+Carboplatin/Cisplatin v Atezolizumab+Gemcitabine+Carboplatin/Cisplatin
    Number of subjects included in analysis
    851
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0083
    Method
    		 Z-test
    Parameter type
    		 Difference in Event Free Rate
    Point estimate
    -8.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.45
         upper limit
    		 -2.13

    Secondary: Time to Deterioration in Global Health Status as Measured by the EORTC QLQ-C30 Score in the Placebo+Gemcitabine+Carboplatin/Cisplatin Arm Versus Atezolizumab +Gemcitabine+Carboplatin/Cisplatin Arm

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    End point title
    		 Time to Deterioration in Global Health Status as Measured by the EORTC QLQ-C30 Score in the Placebo+Gemcitabine+Carboplatin/Cisplatin Arm Versus Atezolizumab +Gemcitabine+Carboplatin/Cisplatin Arm [13]
    End point description
    Time to deterioration in global health status as measured by the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 in the Placebo+Gemcitabine+Carboplatin/Cisplatin Arm versus Atezolizumab +Gemcitabine+Carboplatin/Cisplatin Arm. Note: 999999=not evaluable.
    End point type
    Secondary
    End point timeframe
    Up to approximately 73 months
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistical analysis reported as per the specified arms for the end point.
    End point values
    		 Placebo+Gemcitabine+Carboplatin/Cisplatin Atezolizumab+Gemcitabine+Carboplatin/Cisplatin
    Number of subjects analysed
    400
    451
    Units: Months
        median (confidence interval 95%)
    12.06 (8.28 to 20.24)
    32.07 (18.40 to 999999)
    Statistical analysis title
    		 Global Health Status Statistical Analysis
    Statistical analysis description
    Strata are: Enrollment Stage, PD-L1 Status, BAJORIN Risk Factor Score and Stratum 4 for all participants.
    Comparison groups
    Placebo+Gemcitabine+Carboplatin/Cisplatin v Atezolizumab+Gemcitabine+Carboplatin/Cisplatin
    Number of subjects included in analysis
    851
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0542
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.64
         upper limit
    		 1

    Secondary: Time to Deterioration in Global Health Status as Measured by the EORTC QLQ-C30 Score in the Placebo+Gemcitabine+Carboplatin/Cisplatin Arm Versus Atezolizumab Monotherapy Arm

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    End point title
    		 Time to Deterioration in Global Health Status as Measured by the EORTC QLQ-C30 Score in the Placebo+Gemcitabine+Carboplatin/Cisplatin Arm Versus Atezolizumab Monotherapy Arm [14]
    End point description
    Time to deterioration in global health status as measured by the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 in the Placebo+Gemcitabine+Carboplatin/Cisplatin Arm versus Atezolizumab Monotherapy Arm. Note: 999999=not evaluable.
    End point type
    Secondary
    End point timeframe
    Up to approximately 73 months
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistical analysis reported as per the specified arms for the end point.
    End point values
    		 Placebo+Gemcitabine+Carboplatin/Cisplatin Atezolizumab Monotherapy
    Number of subjects analysed
    359
    360
    Units: Months
        median (confidence interval 95%)
    12.02 (8.08 to 20.24)
    23.20 (8.31 to 999999)
    Statistical analysis title
    		 Global Health Status Statistical Analysis
    Statistical analysis description
    Strata are: PD-L1 Status, BAJORIN Risk Factor Score and Stratum 4 for all participants.
    Comparison groups
    Placebo+Gemcitabine+Carboplatin/Cisplatin v Atezolizumab Monotherapy
    Number of subjects included in analysis
    719
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6139
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.74
         upper limit
    		 1.19

    Secondary: Time to Deterioration in Physical Function as Measured by the EORTC QLQ-C30 Score in the Placebo+Gemcitabine+Carboplatin/Cisplatin Arm Versus Atezolizumab Monotherapy Arm

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    End point title
    		 Time to Deterioration in Physical Function as Measured by the EORTC QLQ-C30 Score in the Placebo+Gemcitabine+Carboplatin/Cisplatin Arm Versus Atezolizumab Monotherapy Arm [15]
    End point description
    Median time to deterioration in physical function as measured by the QLQ-C30 in the Placebo+Gemcitabine+Carboplatin/Cisplatin Arm versus Atezolizumab Monotherapy Arm. Note: 999999=not evaluable.
    End point type
    Secondary
    End point timeframe
    Up to approximately 73 months
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistical analysis reported as per the specified arms for the end point.
    End point values
    		 Placebo+Gemcitabine+Carboplatin/Cisplatin Atezolizumab Monotherapy
    Number of subjects analysed
    359
    360
    Units: Months
        median (confidence interval 95%)
    16.10 (8.08 to 22.57)
    9.23 (6.24 to 17.48)
    Statistical analysis title
    		 Physical Function Statistical Analysis
    Statistical analysis description
    Strata are: Enrollment Stage, PD-L1 Status, BAJORIN Risk Factor Score and Stratum 4 for all participants.
    Comparison groups
    Placebo+Gemcitabine+Carboplatin/Cisplatin v Atezolizumab Monotherapy
    Number of subjects included in analysis
    719
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0241
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.03
         upper limit
    		 1.62

    Secondary: Time to Deterioration in Physical Function as Measured by the EORTC QLQ-C30 Score in the Placebo+Gemcitabine+Carboplatin/Cisplatin Arm Versus Atezolizumab +Gemcitabine+Carboplatin/Cisplatin Arm

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    End point title
    		 Time to Deterioration in Physical Function as Measured by the EORTC QLQ-C30 Score in the Placebo+Gemcitabine+Carboplatin/Cisplatin Arm Versus Atezolizumab +Gemcitabine+Carboplatin/Cisplatin Arm [16]
    End point description
    Median time to deterioration in physical function as measured by the QLQ-C30 in the Placebo+Gemcitabine+Carboplatin/Cisplatin Arm versus Atezolizumab +Gemcitabine+Carboplatin/Cisplatin Arm.
    End point type
    Secondary
    End point timeframe
    Up to approximately 73 months
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistical analysis reported as per the specified arms for the end point.
    End point values
    		 Placebo+Gemcitabine+Carboplatin/Cisplatin Atezolizumab+Gemcitabine+Carboplatin/Cisplatin
    Number of subjects analysed
    400
    451
    Units: Months
        median (confidence interval 95%)
    15.74 (8.28 to 22.57)
    16.39 (9.07 to 26.68)
    Statistical analysis title
    		 Physical Function Statistical Analysis
    Statistical analysis description
    Strata are: Enrollment Stage, PD-L1 Status, BAJORIN Risk Factor Score and Stratum 4 for all participants.
    Comparison groups
    Placebo+Gemcitabine+Carboplatin/Cisplatin v Atezolizumab+Gemcitabine+Carboplatin/Cisplatin
    Number of subjects included in analysis
    851
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.554
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.86
         upper limit
    		 1.32

    Secondary: Maximum Atezolizumab Serum Concentration

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    End point title
    		 Maximum Atezolizumab Serum Concentration [17]
    End point description
    Maximum atezolizumab serum concentration.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1
    Notes
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistical analysis reported as per the specified arms for the end point.
    End point values
    		 Atezolizumab+Gemcitabine+Carboplatin/Cisplatin Atezolizumab Monotherapy
    Number of subjects analysed
    394
    309
    Units: μg/ mL
        arithmetic mean (standard deviation)
    379 ( 125 )
    390 ( 129 )
    No statistical analyses for this end point

    Secondary: Minimum Atezolizumab Serum Concentration

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    End point title
    		 Minimum Atezolizumab Serum Concentration [18]
    End point description
    Minimum atezolizumab serum concentration.
    End point type
    Secondary
    End point timeframe
    Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 8 Day 1, Cycle 16 Day 1, Cycle 24 Day 1, Cycle 32 Day 1, Day 120 post dose of last blinded (LB) atezolizumab treatment, and study drug early discontinuation
    Notes
    [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistical analysis reported as per the specified arms for the end point.
    End point values
    		 Atezolizumab+Gemcitabine+Carboplatin/Cisplatin Atezolizumab Monotherapy
    Number of subjects analysed
    382
    297
    Units: μg/ mL
    arithmetic mean (standard deviation)
        Cycle 2 Day 1 (n=382, 297)
    79.8 ( 52.5 )
    80.2 ( 46.0 )
        Cycle 3 Day 1 (n=365, 245)
    122 ( 47.2 )
    129 ( 66.0 )
        Cycle 4 Day 1 (n=321, 183)
    153 ( 70.4 )
    157 ( 63.4 )
        Cycle 8 Day 1 (n=194, 104)
    216 ( 96.8 )
    193 ( 79.8 )
        Cycle 16 Day 1 (n=40, 50)
    235 ( 103 )
    220 ( 79.8 )
        Cycle 24 Day 1 (n=36, 29)
    244 ( 75.7 )
    233 ( 92.5 )
        Cycle 32 Day 1 (n=17, 9)
    259 ( 97.2 )
    258 ( 60.5 )
        Day 120 Post Dose of LB Atezo Trt (n=67, 64)
    18.8 ( 36.9 )
    9.53 ( 12.7 )
        Study Drug Early Discontinuation (n=194, 148)
    154 ( 102 )
    124 ( 83.8 )
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Anti-Therapeutic (Anti-Atezolizumab) Antibodies (ATAs)

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    End point title
    		 Percentage of Participants With Anti-Therapeutic (Anti-Atezolizumab) Antibodies (ATAs) [19]
    End point description
    Percentage of Participants with Anti-Therapeutic (Anti-Atezolizumab) Antibodies (ATAs)
    End point type
    Secondary
    End point timeframe
    Up to approximately 35 months
    Notes
    [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistical analysis reported as per the specified arms for the end point.
    End point values
    		 Atezolizumab+Gemcitabine+Carboplatin/Cisplatin Atezolizumab Monotherapy
    Number of subjects analysed
    434
    341
    Units: Percentage of participants
    number (not applicable)
        Baseline evaluable participants (n=434, 341)
    1.2
    0.9
        Post-baseline evaluable participants (n=421, 319)
    19.7
    26.3
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Adverse Events (AEs) Assessed Using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0

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    End point title
    		 Percentage of Participants with Adverse Events (AEs) Assessed Using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline up to 90 months
    End point values
    		 Placebo+Gemcitabine+Carboplatin/Cisplatin Atezolizumab+Gemcitabine+Carboplatin/Cisplatin Atezolizumab Monotherapy
    Number of subjects analysed
    0 [20]
    0 [21]
    0 [22]
    Units: Percentage of Participants
    Notes
    [20] - This will be reported at the time of final results posting.
    [21] - This will be reported at the time of final results posting.
    [22] - This will be reported at the time of final results posting.
    No statistical analyses for this end point

    Secondary: Investigator-Assessed Progression-Free Survival (INV-PFS) in Participants Treated with Atezolizumab Montotherapy Compared With Placebo+Gemcitabine+Carboplatin/Cisplatin

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    End point title
    		 Investigator-Assessed Progression-Free Survival (INV-PFS) in Participants Treated with Atezolizumab Montotherapy Compared With Placebo+Gemcitabine+Carboplatin/Cisplatin [23]
    End point description
    PFS is defined as the time from randomization to the first documented disease progression as determined by the investigator with the use of RECIST v1.1, or death from any cause, whichever occurs first.
    End point type
    Secondary
    End point timeframe
    Baseline up to disease progression, death, or loss of follow-up, whichever occurs first (assessed at baseline, every 9 weeks for 54 weeks and every 12 weeks thereafter up to 35 months)
    Notes
    [23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistical analysis reported as per the specified arms for the end point.
    End point values
    		 Placebo+Gemcitabine+Carboplatin/Cisplatin Atezolizumab Monotherapy
    Number of subjects analysed
    359
    360
    Units: Months
        median (confidence interval 95%)
    6.31 (6.24 to 6.74)
    2.69 (2.20 to 4.04)
    Statistical analysis title
    		 INV-PFS Statistical Analysis
    Statistical analysis description
    Stratification factors: PD-L1 status and Bajorin risk score/presence of liver metastases and investigator choice of chemotherapy.
    Comparison groups
    Placebo+Gemcitabine+Carboplatin/Cisplatin v Atezolizumab Monotherapy
    Number of subjects included in analysis
    719
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.19
         upper limit
    		 1.69

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first study drug to the data cutoff date: 31 August 2022 (up to approximately 73 months)
    Adverse event reporting additional description
    The safety population was defined as participants who received any amount of any component of study treatment. Participants were analyzed according to the treatment received.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Placebo+Gemcitabine+Carboplatin/Cisplatin
    Reporting group description
    		 Participants received blinded placebo matched to atezolizumab in combination with open-label platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin).

    Reporting group title
    Atezolizumab Monotherapy
    Reporting group description
    		 Eligible participants received open-label atezolizumab as monotherapy.

    Reporting group title
    Atezolizumab+Gemcitabine+Carboplatin/Cisplatin
    Reporting group description
    		 Participants received blinded atezolizumab in combination with open-label platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin).

    Serious adverse events
    		 Placebo+Gemcitabine+Carboplatin/Cisplatin Atezolizumab Monotherapy Atezolizumab+Gemcitabine+Carboplatin/Cisplatin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    196 / 389 (50.39%)
    163 / 354 (46.05%)
    243 / 454 (53.52%)
         number of deaths (all causes)
    304
    267
    340
         number of deaths resulting from adverse events
    4
    3
    9
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lipoma
         subjects affected / exposed
    0 / 389 (0.00%)
    1 / 354 (0.28%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 389 (0.00%)
    1 / 354 (0.28%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant pleural effusion
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal carcinoma
         subjects affected / exposed
    0 / 389 (0.00%)
    1 / 354 (0.28%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tumour associated fever
         subjects affected / exposed
    0 / 389 (0.00%)
    2 / 354 (0.56%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    0 / 389 (0.00%)
    1 / 354 (0.28%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    2 / 389 (0.51%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Embolism venous
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral venous disease
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Leriche syndrome
         subjects affected / exposed
    0 / 389 (0.00%)
    1 / 354 (0.28%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Jugular vein thrombosis
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    0 / 389 (0.00%)
    1 / 354 (0.28%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    1 / 389 (0.26%)
    1 / 354 (0.28%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Nephrostomy
         subjects affected / exposed
    0 / 389 (0.00%)
    1 / 354 (0.28%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Euthanasia
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Nephrostomy tube removal
         subjects affected / exposed
    2 / 389 (0.51%)
    1 / 354 (0.28%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 389 (0.51%)
    3 / 354 (0.85%)
    4 / 454 (0.88%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    7 / 389 (1.80%)
    2 / 354 (0.56%)
    6 / 454 (1.32%)
         occurrences causally related to treatment / all
    1 / 7
    0 / 2
    0 / 6
         deaths causally related to treatment / all
    1 / 7
    0 / 2
    0 / 6
    Fatigue
         subjects affected / exposed
    4 / 389 (1.03%)
    2 / 354 (0.56%)
    3 / 454 (0.66%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Malaise
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    2 / 454 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    0 / 389 (0.00%)
    1 / 354 (0.28%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Accidental death
         subjects affected / exposed
    0 / 389 (0.00%)
    1 / 354 (0.28%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Suprapubic pain
         subjects affected / exposed
    0 / 389 (0.00%)
    1 / 354 (0.28%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sudden cardiac death
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    12 / 389 (3.08%)
    9 / 354 (2.54%)
    18 / 454 (3.96%)
         occurrences causally related to treatment / all
    4 / 13
    4 / 10
    8 / 19
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    2 / 389 (0.51%)
    4 / 354 (1.13%)
    5 / 454 (1.10%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic shock
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anaphylactic reaction
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    0 / 389 (0.00%)
    1 / 354 (0.28%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Prostatitis
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vaginal haemorrhage
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    0 / 389 (0.00%)
    1 / 354 (0.28%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 389 (0.00%)
    1 / 354 (0.28%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    2 / 389 (0.51%)
    1 / 354 (0.28%)
    2 / 454 (0.44%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 389 (0.26%)
    5 / 354 (1.41%)
    7 / 454 (1.54%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 5
    4 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Dyspnoea exertional
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 389 (0.26%)
    3 / 354 (0.85%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    4 / 389 (1.03%)
    1 / 354 (0.28%)
    7 / 454 (1.54%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
    2 / 8
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Pneumothorax
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    3 / 389 (0.77%)
    4 / 354 (1.13%)
    7 / 454 (1.54%)
         occurrences causally related to treatment / all
    3 / 3
    5 / 5
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Pleurisy
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 389 (0.26%)
    2 / 354 (0.56%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    2 / 389 (0.51%)
    0 / 354 (0.00%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 389 (0.00%)
    1 / 354 (0.28%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    1 / 389 (0.26%)
    1 / 354 (0.28%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Completed suicide
         subjects affected / exposed
    0 / 389 (0.00%)
    1 / 354 (0.28%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Anxiety
         subjects affected / exposed
    0 / 389 (0.00%)
    1 / 354 (0.28%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device occlusion
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device dislocation
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    12 / 389 (3.08%)
    0 / 354 (0.00%)
    14 / 454 (3.08%)
         occurrences causally related to treatment / all
    18 / 18
    0 / 0
    23 / 23
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 389 (0.00%)
    1 / 354 (0.28%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    6 / 389 (1.54%)
    0 / 354 (0.00%)
    3 / 454 (0.66%)
         occurrences causally related to treatment / all
    3 / 7
    0 / 0
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    7 / 389 (1.80%)
    0 / 354 (0.00%)
    3 / 454 (0.66%)
         occurrences causally related to treatment / all
    8 / 8
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 389 (0.00%)
    1 / 354 (0.28%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    3 / 389 (0.77%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Incisional hernia
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 389 (0.00%)
    1 / 354 (0.28%)
    2 / 454 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 389 (0.26%)
    1 / 354 (0.28%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multiple fractures
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Postoperative adhesion
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Procedural intestinal perforation
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    0 / 389 (0.00%)
    1 / 354 (0.28%)
    2 / 454 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stoma prolapse
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stoma site haemorrhage
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stoma site pain
         subjects affected / exposed
    0 / 389 (0.00%)
    1 / 354 (0.28%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 389 (0.00%)
    1 / 354 (0.28%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 389 (0.00%)
    1 / 354 (0.28%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Transfusion reaction
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Unintentional medical device removal
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract stoma complication
         subjects affected / exposed
    0 / 389 (0.00%)
    1 / 354 (0.28%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urostomy complication
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Congenital cystic kidney disease
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    2 / 454 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 389 (0.26%)
    1 / 354 (0.28%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Cardiac failure
         subjects affected / exposed
    0 / 389 (0.00%)
    1 / 354 (0.28%)
    3 / 454 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 389 (0.26%)
    1 / 354 (0.28%)
    2 / 454 (0.44%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Angina unstable
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 389 (0.00%)
    1 / 354 (0.28%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    1 / 389 (0.26%)
    2 / 354 (0.56%)
    3 / 454 (0.66%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 3
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    0 / 389 (0.00%)
    1 / 354 (0.28%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    0 / 389 (0.00%)
    1 / 354 (0.28%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinus arrest
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Myocardial infarction
         subjects affected / exposed
    2 / 389 (0.51%)
    0 / 354 (0.00%)
    2 / 454 (0.44%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Ataxia
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Autoimmune encephalopathy
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Central nervous system haemorrhage
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hemianopia
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    2 / 454 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Embolic stroke
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Intraventricular haemorrhage
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Demyelination
         subjects affected / exposed
    0 / 389 (0.00%)
    1 / 354 (0.28%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    2 / 454 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Cerebral ischaemia
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Cerebral artery embolism
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysaesthesia
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic cerebral infarction
         subjects affected / exposed
    0 / 389 (0.00%)
    1 / 354 (0.28%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    3 / 454 (0.66%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbosacral radiculopathy
         subjects affected / exposed
    0 / 389 (0.00%)
    1 / 354 (0.28%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Miller Fisher syndrome
         subjects affected / exposed
    0 / 389 (0.00%)
    1 / 354 (0.28%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myasthenia gravis
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myasthenic syndrome
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neuralgia
         subjects affected / exposed
    0 / 389 (0.00%)
    1 / 354 (0.28%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Paraparesis
         subjects affected / exposed
    0 / 389 (0.00%)
    1 / 354 (0.28%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 389 (0.26%)
    1 / 354 (0.28%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 389 (0.00%)
    2 / 354 (0.56%)
    3 / 454 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 389 (0.00%)
    1 / 354 (0.28%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tremor
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    2 / 454 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    2 / 454 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematotoxicity
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    9 / 389 (2.31%)
    0 / 354 (0.00%)
    14 / 454 (3.08%)
         occurrences causally related to treatment / all
    8 / 9
    0 / 0
    15 / 15
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    19 / 389 (4.88%)
    4 / 354 (1.13%)
    30 / 454 (6.61%)
         occurrences causally related to treatment / all
    22 / 26
    1 / 4
    29 / 34
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    4 / 389 (1.03%)
    0 / 354 (0.00%)
    6 / 454 (1.32%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    4 / 389 (1.03%)
    0 / 354 (0.00%)
    8 / 454 (1.76%)
         occurrences causally related to treatment / all
    5 / 5
    0 / 0
    10 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Myelosuppression
         subjects affected / exposed
    3 / 389 (0.77%)
    0 / 354 (0.00%)
    3 / 454 (0.66%)
         occurrences causally related to treatment / all
    7 / 7
    0 / 0
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymph node pain
         subjects affected / exposed
    0 / 389 (0.00%)
    2 / 354 (0.56%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytosis
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    22 / 389 (5.66%)
    1 / 354 (0.28%)
    21 / 454 (4.63%)
         occurrences causally related to treatment / all
    28 / 28
    1 / 1
    30 / 30
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Ear and labyrinth disorders
    Deafness
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Enterocutaneous fistula
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    3 / 389 (0.77%)
    3 / 354 (0.85%)
    4 / 454 (0.88%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 3
    4 / 4
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 389 (0.26%)
    1 / 354 (0.28%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 389 (0.26%)
    1 / 354 (0.28%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Autoimmune pancreatitis
         subjects affected / exposed
    0 / 389 (0.00%)
    1 / 354 (0.28%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 389 (0.00%)
    2 / 354 (0.56%)
    2 / 454 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal incarcerated hernia
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal hernia
         subjects affected / exposed
    1 / 389 (0.26%)
    1 / 354 (0.28%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enterovesical fistula
         subjects affected / exposed
    0 / 389 (0.00%)
    1 / 354 (0.28%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoids thrombosed
         subjects affected / exposed
    0 / 389 (0.00%)
    1 / 354 (0.28%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hiatus hernia
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileal ulcer
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    3 / 389 (0.77%)
    3 / 354 (0.85%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    3 / 389 (0.77%)
    8 / 354 (2.26%)
    3 / 454 (0.66%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 9
    2 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Rectal obstruction
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mechanical ileus
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Obstruction gastric
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 389 (0.00%)
    1 / 354 (0.28%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 389 (0.00%)
    1 / 354 (0.28%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    0 / 389 (0.00%)
    1 / 354 (0.28%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 389 (0.26%)
    2 / 354 (0.56%)
    2 / 454 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    2 / 389 (0.51%)
    0 / 354 (0.00%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Volvulus
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 389 (0.77%)
    0 / 354 (0.00%)
    5 / 454 (1.10%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    5 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatitis
         subjects affected / exposed
    0 / 389 (0.00%)
    1 / 354 (0.28%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Cholecystitis
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    2 / 454 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 389 (0.00%)
    1 / 354 (0.28%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 389 (0.00%)
    1 / 354 (0.28%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
    Hepatic function abnormal
         subjects affected / exposed
    0 / 389 (0.00%)
    1 / 354 (0.28%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Autoimmune hepatitis
         subjects affected / exposed
    0 / 389 (0.00%)
    2 / 354 (0.56%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    0 / 389 (0.00%)
    1 / 354 (0.28%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertransaminasaemia
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatitis toxic
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin necrosis
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pruritus
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dermatomyositis
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dermal cyst
         subjects affected / exposed
    0 / 389 (0.00%)
    1 / 354 (0.28%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Bladder pain
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bladder tamponade
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Autoimmune nephritis
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anuria
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    12 / 389 (3.08%)
    8 / 354 (2.26%)
    15 / 454 (3.30%)
         occurrences causally related to treatment / all
    7 / 12
    0 / 8
    9 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
    Calculus urinary
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    10 / 389 (2.57%)
    13 / 354 (3.67%)
    10 / 454 (2.20%)
         occurrences causally related to treatment / all
    0 / 11
    2 / 13
    5 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    3 / 389 (0.77%)
    3 / 354 (0.85%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pollakiuria
         subjects affected / exposed
    0 / 389 (0.00%)
    1 / 354 (0.28%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Proteinuria
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tubulointerstitial nephritis
         subjects affected / exposed
    0 / 389 (0.00%)
    1 / 354 (0.28%)
    3 / 454 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal disorder
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    2 / 389 (0.51%)
    8 / 354 (2.26%)
    3 / 454 (0.66%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 8
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Renal impairment
         subjects affected / exposed
    1 / 389 (0.26%)
    2 / 354 (0.56%)
    5 / 454 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Renal injury
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal tubular injury
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal artery stenosis
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    3 / 389 (0.77%)
    2 / 354 (0.56%)
    7 / 454 (1.54%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 2
    0 / 7
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    2 / 389 (0.51%)
    4 / 354 (1.13%)
    5 / 454 (1.10%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary fistula
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ureteric obstruction
         subjects affected / exposed
    0 / 389 (0.00%)
    1 / 354 (0.28%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    1 / 389 (0.26%)
    1 / 354 (0.28%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypopituitarism
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypophysitis
         subjects affected / exposed
    0 / 389 (0.00%)
    1 / 354 (0.28%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Adrenal insufficiency
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 389 (0.00%)
    1 / 354 (0.28%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    1 / 389 (0.26%)
    1 / 354 (0.28%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fistula
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Groin pain
         subjects affected / exposed
    0 / 389 (0.00%)
    1 / 354 (0.28%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myositis
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    3 / 389 (0.77%)
    0 / 354 (0.00%)
    3 / 454 (0.66%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteoporotic fracture
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 389 (0.00%)
    1 / 354 (0.28%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    1 / 389 (0.26%)
    1 / 354 (0.28%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 389 (0.00%)
    1 / 354 (0.28%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacterial infection
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    2 / 454 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 389 (0.26%)
    1 / 354 (0.28%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    2 / 389 (0.51%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal infection
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    0 / 389 (0.00%)
    1 / 354 (0.28%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Campylobacter infection
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    2 / 454 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    2 / 454 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Emphysematous pyelonephritis
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fungal infection
         subjects affected / exposed
    0 / 389 (0.00%)
    1 / 354 (0.28%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    0 / 389 (0.00%)
    1 / 354 (0.28%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    0 / 389 (0.00%)
    1 / 354 (0.28%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Encephalitis
         subjects affected / exposed
    0 / 389 (0.00%)
    1 / 354 (0.28%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 389 (0.00%)
    1 / 354 (0.28%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infected skin ulcer
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    2 / 389 (0.51%)
    3 / 354 (0.85%)
    2 / 454 (0.44%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 389 (0.00%)
    1 / 354 (0.28%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Kidney infection
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Klebsiella sepsis
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Muscle abscess
         subjects affected / exposed
    0 / 389 (0.00%)
    1 / 354 (0.28%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    0 / 389 (0.00%)
    1 / 354 (0.28%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Norovirus infection
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Orchitis
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pharyngitis streptococcal
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    8 / 389 (2.06%)
    8 / 354 (2.26%)
    21 / 454 (4.63%)
         occurrences causally related to treatment / all
    4 / 8
    3 / 8
    7 / 23
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    0 / 2
    Pneumonia aspiration
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Pneumonia pneumococcal
         subjects affected / exposed
    0 / 389 (0.00%)
    2 / 354 (0.56%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pseudomonal bacteraemia
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    0 / 389 (0.00%)
    1 / 354 (0.28%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    3 / 389 (0.77%)
    3 / 354 (0.85%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 389 (0.26%)
    1 / 354 (0.28%)
    4 / 454 (0.88%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    1 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 389 (0.26%)
    2 / 354 (0.56%)
    3 / 454 (0.66%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 389 (0.26%)
    1 / 354 (0.28%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    2 / 389 (0.51%)
    3 / 354 (0.85%)
    2 / 454 (0.44%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 3
    0 / 2
    Skin infection
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tracheobronchitis
         subjects affected / exposed
    0 / 389 (0.00%)
    1 / 354 (0.28%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tuberculosis
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Sepsis
         subjects affected / exposed
    7 / 389 (1.80%)
    1 / 354 (0.28%)
    7 / 454 (1.54%)
         occurrences causally related to treatment / all
    2 / 8
    0 / 1
    3 / 8
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    1 / 1
    Urinary tract infection
         subjects affected / exposed
    30 / 389 (7.71%)
    22 / 354 (6.21%)
    41 / 454 (9.03%)
         occurrences causally related to treatment / all
    8 / 42
    2 / 23
    11 / 57
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection bacterial
         subjects affected / exposed
    2 / 389 (0.51%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection fungal
         subjects affected / exposed
    0 / 389 (0.00%)
    1 / 354 (0.28%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection staphylococcal
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    4 / 389 (1.03%)
    5 / 354 (1.41%)
    3 / 454 (0.66%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 5
    1 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    Vascular device infection
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Acidosis
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cachexia
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 389 (0.26%)
    1 / 354 (0.28%)
    2 / 454 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Dehydration
         subjects affected / exposed
    2 / 389 (0.51%)
    1 / 354 (0.28%)
    2 / 454 (0.44%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetic metabolic decompensation
         subjects affected / exposed
    1 / 389 (0.26%)
    0 / 354 (0.00%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 389 (0.00%)
    2 / 354 (0.56%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypercreatininaemia
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    0 / 389 (0.00%)
    2 / 354 (0.56%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 389 (0.00%)
    1 / 354 (0.28%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    0 / 389 (0.00%)
    0 / 354 (0.00%)
    1 / 454 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    2 / 389 (0.51%)
    1 / 354 (0.28%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    2 / 389 (0.51%)
    1 / 354 (0.28%)
    0 / 454 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo+Gemcitabine+Carboplatin/Cisplatin Atezolizumab Monotherapy Atezolizumab+Gemcitabine+Carboplatin/Cisplatin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    379 / 389 (97.43%)
    300 / 354 (84.75%)
    441 / 454 (97.14%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    31 / 389 (7.97%)
    21 / 354 (5.93%)
    45 / 454 (9.91%)
         occurrences all number
    41
    26
    62
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    98 / 389 (25.19%)
    51 / 354 (14.41%)
    133 / 454 (29.30%)
         occurrences all number
    156
    76
    207
    Fatigue
         subjects affected / exposed
    122 / 389 (31.36%)
    64 / 354 (18.08%)
    134 / 454 (29.52%)
         occurrences all number
    182
    83
    185
    Malaise
         subjects affected / exposed
    24 / 389 (6.17%)
    6 / 354 (1.69%)
    18 / 454 (3.96%)
         occurrences all number
    35
    6
    34
    Oedema peripheral
         subjects affected / exposed
    56 / 389 (14.40%)
    41 / 354 (11.58%)
    53 / 454 (11.67%)
         occurrences all number
    67
    56
    68
    Pyrexia
         subjects affected / exposed
    68 / 389 (17.48%)
    43 / 354 (12.15%)
    122 / 454 (26.87%)
         occurrences all number
    113
    57
    172
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    33 / 389 (8.48%)
    25 / 354 (7.06%)
    43 / 454 (9.47%)
         occurrences all number
    43
    28
    54
    Cough
         subjects affected / exposed
    38 / 389 (9.77%)
    30 / 354 (8.47%)
    58 / 454 (12.78%)
         occurrences all number
    46
    49
    67
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    34 / 389 (8.74%)
    19 / 354 (5.37%)
    36 / 454 (7.93%)
         occurrences all number
    37
    20
    39
    Investigations
    Blood alkaline phosphatase increased
         subjects affected / exposed
    10 / 389 (2.57%)
    22 / 354 (6.21%)
    26 / 454 (5.73%)
         occurrences all number
    15
    27
    33
    Aspartate aminotransferase increased
         subjects affected / exposed
    17 / 389 (4.37%)
    22 / 354 (6.21%)
    46 / 454 (10.13%)
         occurrences all number
    28
    25
    61
    Alanine aminotransferase increased
         subjects affected / exposed
    26 / 389 (6.68%)
    24 / 354 (6.78%)
    47 / 454 (10.35%)
         occurrences all number
    32
    27
    57
    Blood creatinine increased
         subjects affected / exposed
    45 / 389 (11.57%)
    28 / 354 (7.91%)
    66 / 454 (14.54%)
         occurrences all number
    64
    33
    89
    Weight decreased
         subjects affected / exposed
    25 / 389 (6.43%)
    23 / 354 (6.50%)
    30 / 454 (6.61%)
         occurrences all number
    25
    23
    35
    White blood cell count decreased
         subjects affected / exposed
    59 / 389 (15.17%)
    1 / 354 (0.28%)
    62 / 454 (13.66%)
         occurrences all number
    166
    1
    144
    Platelet count decreased
         subjects affected / exposed
    138 / 389 (35.48%)
    5 / 354 (1.41%)
    132 / 454 (29.07%)
         occurrences all number
    331
    7
    350
    Neutrophil count decreased
         subjects affected / exposed
    129 / 389 (33.16%)
    0 / 354 (0.00%)
    119 / 454 (26.21%)
         occurrences all number
    344
    0
    331
    Nervous system disorders
    Neuropathy peripheral
         subjects affected / exposed
    23 / 389 (5.91%)
    6 / 354 (1.69%)
    17 / 454 (3.74%)
         occurrences all number
    25
    8
    19
    Headache
         subjects affected / exposed
    34 / 389 (8.74%)
    24 / 354 (6.78%)
    42 / 454 (9.25%)
         occurrences all number
    43
    35
    65
    Dizziness
         subjects affected / exposed
    39 / 389 (10.03%)
    18 / 354 (5.08%)
    45 / 454 (9.91%)
         occurrences all number
    51
    19
    59
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    117 / 389 (30.08%)
    12 / 354 (3.39%)
    183 / 454 (40.31%)
         occurrences all number
    297
    13
    378
    Anaemia
         subjects affected / exposed
    257 / 389 (66.07%)
    67 / 354 (18.93%)
    308 / 454 (67.84%)
         occurrences all number
    481
    81
    488
    Leukopenia
         subjects affected / exposed
    64 / 389 (16.45%)
    0 / 354 (0.00%)
    63 / 454 (13.88%)
         occurrences all number
    192
    0
    131
    Neutropenia
         subjects affected / exposed
    148 / 389 (38.05%)
    2 / 354 (0.56%)
    215 / 454 (47.36%)
         occurrences all number
    421
    2
    509
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    106 / 389 (27.25%)
    33 / 354 (9.32%)
    122 / 454 (26.87%)
         occurrences all number
    175
    41
    178
    Nausea
         subjects affected / exposed
    181 / 389 (46.53%)
    43 / 354 (12.15%)
    202 / 454 (44.49%)
         occurrences all number
    317
    53
    329
    Dyspepsia
         subjects affected / exposed
    22 / 389 (5.66%)
    5 / 354 (1.41%)
    20 / 454 (4.41%)
         occurrences all number
    28
    10
    21
    Diarrhoea
         subjects affected / exposed
    73 / 389 (18.77%)
    42 / 354 (11.86%)
    94 / 454 (20.70%)
         occurrences all number
    96
    57
    142
    Constipation
         subjects affected / exposed
    111 / 389 (28.53%)
    67 / 354 (18.93%)
    140 / 454 (30.84%)
         occurrences all number
    149
    74
    186
    Abdominal pain
         subjects affected / exposed
    37 / 389 (9.51%)
    22 / 354 (6.21%)
    44 / 454 (9.69%)
         occurrences all number
    54
    27
    54
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    49 / 389 (12.60%)
    2 / 354 (0.56%)
    33 / 454 (7.27%)
         occurrences all number
    50
    2
    35
    Pruritus
         subjects affected / exposed
    33 / 389 (8.48%)
    41 / 354 (11.58%)
    84 / 454 (18.50%)
         occurrences all number
    38
    65
    122
    Rash
         subjects affected / exposed
    43 / 389 (11.05%)
    27 / 354 (7.63%)
    91 / 454 (20.04%)
         occurrences all number
    52
    32
    117
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    51 / 389 (13.11%)
    47 / 354 (13.28%)
    73 / 454 (16.08%)
         occurrences all number
    65
    55
    102
    Dysuria
         subjects affected / exposed
    20 / 389 (5.14%)
    20 / 354 (5.65%)
    29 / 454 (6.39%)
         occurrences all number
    26
    23
    41
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    12 / 389 (3.08%)
    30 / 354 (8.47%)
    44 / 454 (9.69%)
         occurrences all number
    12
    31
    47
    Hyperthyroidism
         subjects affected / exposed
    6 / 389 (1.54%)
    18 / 354 (5.08%)
    35 / 454 (7.71%)
         occurrences all number
    6
    20
    39
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    30 / 389 (7.71%)
    21 / 354 (5.93%)
    35 / 454 (7.71%)
         occurrences all number
    37
    24
    43
    Myalgia
         subjects affected / exposed
    23 / 389 (5.91%)
    23 / 354 (6.50%)
    27 / 454 (5.95%)
         occurrences all number
    35
    30
    29
    Back pain
         subjects affected / exposed
    45 / 389 (11.57%)
    33 / 354 (9.32%)
    56 / 454 (12.33%)
         occurrences all number
    56
    39
    66
    Arthralgia
         subjects affected / exposed
    44 / 389 (11.31%)
    39 / 354 (11.02%)
    57 / 454 (12.56%)
         occurrences all number
    56
    55
    79
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    61 / 389 (15.68%)
    58 / 354 (16.38%)
    89 / 454 (19.60%)
         occurrences all number
    91
    101
    134
    Upper respiratory tract infection
         subjects affected / exposed
    19 / 389 (4.88%)
    18 / 354 (5.08%)
    30 / 454 (6.61%)
         occurrences all number
    26
    22
    36
    Nasopharyngitis
         subjects affected / exposed
    20 / 389 (5.14%)
    18 / 354 (5.08%)
    33 / 454 (7.27%)
         occurrences all number
    25
    26
    44
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    12 / 389 (3.08%)
    14 / 354 (3.95%)
    26 / 454 (5.73%)
         occurrences all number
    21
    33
    30
    Hyponatraemia
         subjects affected / exposed
    16 / 389 (4.11%)
    9 / 354 (2.54%)
    30 / 454 (6.61%)
         occurrences all number
    21
    10
    37
    Hypomagnesaemia
         subjects affected / exposed
    22 / 389 (5.66%)
    8 / 354 (2.26%)
    26 / 454 (5.73%)
         occurrences all number
    27
    11
    31
    Hypoalbuminaemia
         subjects affected / exposed
    15 / 389 (3.86%)
    19 / 354 (5.37%)
    21 / 454 (4.63%)
         occurrences all number
    24
    20
    27
    Hyperkalaemia
         subjects affected / exposed
    29 / 389 (7.46%)
    13 / 354 (3.67%)
    24 / 454 (5.29%)
         occurrences all number
    39
    17
    39
    Decreased appetite
         subjects affected / exposed
    119 / 389 (30.59%)
    69 / 354 (19.49%)
    143 / 454 (31.50%)
         occurrences all number
    165
    72
    212

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Sep 2016
    Protocol has been amended to include the addition of a third treatment arm to the study of atezolizumab as monotherapy. The study design was modified to include participants who were eligible for a cisplatin-containing regimen. Participants who were ineligible for cisplatin were continued to be enrolled. A primary efficacy objective was added: To evaluate the efficacy of atezolizumab monotherapy compared with placebo plus platinum-based chemotherapy on the basis of OS. A secondary efficacy objective was added: Investigator-assessed PFS in participants treated with atezolizumab monotherapy compared with participants treated with placebo plus platinum-based chemotherapy.
    30 Apr 2018
    Protocol has been amended to reflect that randomization of new participants to all three arms will continue in a 1:1:1 manner regardless of PD-L1 expression status; however, for participants randomized to Atezolizumab monotherapy arm, PD-L1 expression status will be unblinded to the investigator and participants at the time of randomization. The protocol has been updated to reflect the following treatment options for new participants randomized to Atezolizumab Monotherapy arm: PD-L1 status will be unblinded to the investigator and participant at the time of randomization. Participants with a PD-L1 expression status of IC2/3 will receive atezolizumab monotherapy. Participants with a PD-L1 expression status of IC0 or IC1 will receive open-label atezolizumab plus platinum (carboplatin or cisplatin) and gemcitabine chemotherapy instead of atezolizumab monotherapy. Participants with PD-L1 expression status of IC0 or IC1 are recommended to continue with atezolizumab monotherapy and participants with PD-L1 expression status of IC2/3 will continue receiving atezolizumab monotherapy. Secondary Efficacy Objective has been updated to reflect the addition of an Independent Review Facility-progression-free survival (PFS) endpoint, defined as the time from randomization to the first documented disease progression as determined by blinded independent central review with use of RECIST v1.1, or death due to any cause, whichever occurs first.

    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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