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    Clinical Trial Results:
    A Phase III, Open-label, Randomized Study of Atezolizumab in Combination With Bevacizumab Compared With sorafenib in Patients With Untreated Locally Advanced or Metastatic Hepatocellular Carcinoma

    Summary
    EudraCT number
    		 2017-003691-31
    Trial protocol
    		 PL   DE   GB   CZ   ES   IT  
    Global end of trial date
    17 Nov 2022

    Results information
    Results version number
    		 v2(current)
    This version publication date
    21 Oct 2023
    First version publication date
    01 Sep 2021
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    YO40245
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03434379
    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
    Final
    Date of interim/final analysis
    17 Nov 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Nov 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the study is to evaluate the efficacy and safety of atezolizumab in combination with bevacizumab compared with sorafenib in participants with locally advanced or metastatic Hepatocellular Carcinoma (HCC) who had received no prior systemic treatment.
    Protection of trial subjects
    All study participants were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Mar 2018
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 3 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 9
    Country: Number of subjects enrolled
    Canada: 5
    Country: Number of subjects enrolled
    China: 135
    Country: Number of subjects enrolled
    Czechia: 5
    Country: Number of subjects enrolled
    Germany: 16
    Country: Number of subjects enrolled
    Spain: 11
    Country: Number of subjects enrolled
    France: 42
    Country: Number of subjects enrolled
    United Kingdom: 13
    Country: Number of subjects enrolled
    Hong Kong: 18
    Country: Number of subjects enrolled
    Italy: 17
    Country: Number of subjects enrolled
    Japan: 61
    Country: Number of subjects enrolled
    Korea, Republic of: 47
    Country: Number of subjects enrolled
    Poland: 23
    Country: Number of subjects enrolled
    Russian Federation: 24
    Country: Number of subjects enrolled
    Singapore: 17
    Country: Number of subjects enrolled
    Taiwan: 41
    Country: Number of subjects enrolled
    United States: 74
    Worldwide total number of subjects
    558
    EEA total number of subjects
    114
    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)
    300
    From 65 to 84 years
    250
    85 years and over
    8

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled at 117 sites in 17 countries: Australia, Canada, China, Czech Republic, Germany, Spain, France, United Kingdom, Hong Kong, Italy, Japan, Republic of Korea, Poland, Russian Federation, Singapore, Taiwan, United States.

    Pre-assignment
    Screening details
    		 The study included 558 participants with 501 in the Global population. An additional 57 participants enrolled during the China Extension. The total China population included 137 Chinese participants from the Global population plus 57 participants from the China extension. The Global population and the China population were analysed separately.

    Period 1
    Period 1 title
    Overall Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Sorafenib - Global
    Arm description
    		 Participants in the Global population received sorafenib until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Sorafenib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Sorafenib was administered by mouth, 400 mg twice per day, on Days 1-21 of each 21-day cycle.

    Arm title
    		 Atezolizumab + Bevacizumab - Global
    Arm description
    		 Participants in the Global population received Atezolizumab + Bevacizumab until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Bevacizumab was administered by IV, 15 mg/kg on Day 1 of each 21- day cycle.

    Investigational medicinal product name
    Atezolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Atezolizumab was administered by IV, 1200 mg on Day 1 of each 21-day cycle.

    Arm title
    		 Sorafenib - China
    Arm description
    		 Participants in the China population received sorafenib until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Sorafenib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Sorafenib was administered by mouth, 400 mg twice per day, on Days 1-21 of each 21-day cycle.

    Arm title
    		 Atezolizumab + Bevacizumab - China
    Arm description
    		 Participants in the China population received Atezolizumab + Bevacizumab until unacceptable toxicity or loss of clinical benefit as determined by the investigator.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Bevacizumab was administered by IV, 15 mg/kg on Day 1 of each 21- day cycle.

    Investigational medicinal product name
    Atezolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Atezolizumab was administered by IV, 1200 mg on Day 1 of each 21-day cycle.

    Number of subjects in period 1
    		Sorafenib - Global Atezolizumab + Bevacizumab - Global Sorafenib - China Atezolizumab + Bevacizumab - China
    Started
    165
    336
    61
    133
    Completed
    0
    0
    0
    0
    Not completed
    165
    336
    61
    133
         Consent withdrawn by subject
    20
    21
    8
    6
         Physician decision
    1
    -
    -
    -
         Study Ended by Sponsor
    26
    80
    5
    36
         Death
    115
    228
    46
    88
         Lost to follow-up
    3
    6
    2
    3
         Reason Unspecified
    -
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Period
    Reporting group description
    		 -

    Reporting group values
    		 Overall Period Total
    Number of subjects
    		 558 558
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 300 300
        From 65-84 years
    		 250 250
        85 years and over
    		 8 8
    Sex/Gender, Customized
    Global population
    Units: participants
        Female
    		 92 92
        Male
    		 466 466

    End points

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    End points reporting groups
    Reporting group title
    Sorafenib - Global
    Reporting group description
    		 Participants in the Global population received sorafenib until unacceptable toxicity or loss of clinical benefit as determined by the investigator.

    Reporting group title
    Atezolizumab + Bevacizumab - Global
    Reporting group description
    		 Participants in the Global population received Atezolizumab + Bevacizumab until unacceptable toxicity or loss of clinical benefit as determined by the investigator.

    Reporting group title
    Sorafenib - China
    Reporting group description
    		 Participants in the China population received sorafenib until unacceptable toxicity or loss of clinical benefit as determined by the investigator.

    Reporting group title
    Atezolizumab + Bevacizumab - China
    Reporting group description
    		 Participants in the China population received Atezolizumab + Bevacizumab until unacceptable toxicity or loss of clinical benefit as determined by the investigator.

    Primary: Overall Survival (OS) in the Global Population

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    End point title
    		 Overall Survival (OS) in the Global Population [1]
    End point description
    OS was defined as the time from randomization to death from any cause. Global ITT population consisted of all randomized participants in the Global population, whether or not the participant had received the assigned study treatment. 9999/99999 = not estimable due to the limited number of events observed
    End point type
    Primary
    End point timeframe
    From randomization to death from any cause up to the clinical cut off date (CCOD) of 29Aug2019 (up to approximately 18 months) and 31Aug2020 (up to approximately 30 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: This Endpoint is only reporting the data for the Global population.
    End point values
    		 Sorafenib - Global Atezolizumab + Bevacizumab - Global
    Number of subjects analysed
    165
    336
    Units: months
    median (confidence interval 95%)
        At CCOD 18 months
    13.24 (10.41 to 99999)
    9999 (9999 to 99999)
        At CCOD 30 months
    13.40 (11.37 to 16.85)
    19.22 (17.02 to 23.66)
    Statistical analysis title
    		 OS at CCOD 30 months - Global
    Statistical analysis description
    Stratified by geographic region (Asia [excluding Japan] vs. rest of world), macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline alpha-fetoprotein (AFP: <400 vs. >/= 400 ng/mL).
    Comparison groups
    Sorafenib - Global v Atezolizumab + Bevacizumab - Global
    Number of subjects included in analysis
    501
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0009
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.52
         upper limit
    		 0.85
    Statistical analysis title
    		 OS at CCOD 18 months- Global
    Statistical analysis description
    Stratified by geographic region (Asia [excluding Japan] vs. rest of world), macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline alpha-fetoprotein (AFP: <400 vs. >/= 400 ng/mL).
    Comparison groups
    Sorafenib - Global v Atezolizumab + Bevacizumab - Global
    Number of subjects included in analysis
    501
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0006
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.42
         upper limit
    		 0.79

    Primary: Progression Free Survival by Independent Review Facility-Assessment (PFS-IRF) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 in the Global Population

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    End point title
    		 Progression Free Survival by Independent Review Facility-Assessment (PFS-IRF) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 in the Global Population [2]
    End point description
    PFS was defined as the time from randomization to the first occurrence of progressive disease (PD) or death from any cause whichever occurs first as determined by an IRF according to RECIST v1.1. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of >/= 5 millimeters (mm). Global ITT population consisted of all randomized participants in the Global population, whether or not the participant had received the assigned study treatment.
    End point type
    Primary
    End point timeframe
    Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months)
    Notes
    [2] - 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: This Endpoint is only reporting the data for the Global population.
    End point values
    		 Sorafenib - Global Atezolizumab + Bevacizumab - Global
    Number of subjects analysed
    165
    336
    Units: months
        median (confidence interval 95%)
    4.27 (3.98 to 5.55)
    6.83 (5.75 to 8.28)
    Statistical analysis title
    		 PFS-IRF RECIST v1.1 - Global
    Statistical analysis description
    Stratified by geographic region (Asia [excluding Japan] vs. rest of world), macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (<400 vs. >/= 400 ng/mL).
    Comparison groups
    Sorafenib - Global v Atezolizumab + Bevacizumab - Global
    Number of subjects included in analysis
    501
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.47
         upper limit
    		 0.76

    Primary: Overall Survival (OS) in the China Population

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    End point title
    		 Overall Survival (OS) in the China Population [3]
    End point description
    OS was defined as the time from randomization to death from any cause. China ITT population consisted of all randomized participants in the China population, whether or not the participant had received the assigned study treatment. 9999/99999 = not estimable due to the limited number of events observed
    End point type
    Primary
    End point timeframe
    From randomization to death from any cause up to the clinical cut off date (CCOD) of 29Aug2019 (up to approximately 18 months) and 31Aug2020 (up to approximately 30 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: This Endpoint is only reporting the data for the China population.
    End point values
    		 Sorafenib - China Atezolizumab + Bevacizumab - China
    Number of subjects analysed
    61
    133
    Units: months
    median (confidence interval 95%)
        At CCOD 18 months
    11.37 (6.74 to 99999)
    9999 (13.50 to 99999)
        At CCOD 30 months
    11.37 (6.74 to 16.07)
    24.05 (17.12 to 99999)
    Statistical analysis title
    		 OS at CCOD 30 months - China
    Statistical analysis description
    Stratified by macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (<400 vs. >/= 400 ng/mL).
    Comparison groups
    Sorafenib - China v Atezolizumab + Bevacizumab - China
    Number of subjects included in analysis
    194
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0019
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.35
         upper limit
    		 0.8
    Statistical analysis title
    		 OS at CCOD 18 months - China
    Statistical analysis description
    Stratified by macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (<400 vs. >/= 400 ng/mL).
    Comparison groups
    Sorafenib - China v Atezolizumab + Bevacizumab - China
    Number of subjects included in analysis
    194
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0026
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.25
         upper limit
    		 0.76

    Primary: PFS-IRF per RECIST v1.1 in the China Population

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    End point title
    		 PFS-IRF per RECIST v1.1 in the China Population [4]
    End point description
    PFS was defined as the time from randomization to the first occurrence of progressive disease (PD) or death from any cause whichever occurs first as determined by an IRF according to RECIST v1.1. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of >/= 5 millimeters (mm). China ITT population consisted of all randomized participants in the China population, whether or not the participant had received the assigned study treatment.
    End point type
    Primary
    End point timeframe
    Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months)
    Notes
    [4] - 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: This Endpoint is only reporting the data for the China population.
    End point values
    		 Sorafenib - China Atezolizumab + Bevacizumab - China
    Number of subjects analysed
    61
    133
    Units: months
        median (confidence interval 95%)
    3.19 (2.56 to 4.76)
    5.72 (4.17 to 8.28)
    Statistical analysis title
    		 PFS-IRF RECIST v1.1 - China
    Statistical analysis description
    Stratified by macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (<400 vs. >/= 400 ng/mL).
    Comparison groups
    Sorafenib - China v Atezolizumab + Bevacizumab - China
    Number of subjects included in analysis
    194
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0117
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4
         upper limit
    		 0.9

    Secondary: Objective Response Rate by IRF-Assessment (ORR-IRF) per RECIST v1.1 in the Global Population

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    End point title
    		 Objective Response Rate by IRF-Assessment (ORR-IRF) per RECIST v1.1 in the Global Population [5]
    End point description
    ORR was defined as the percentage of participants with a complete response (CR) or a partial response (PR) as determined by the IRF according to RECIST v1.1. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. OR=CR+PR Global ITT population with measurable disease at baseline consisted of all randomized participants in the Global population, whether or not the participant had received the assigned study treatment, and had measurable disease at baseline.
    End point type
    Secondary
    End point timeframe
    Randomization up to CCOD of 29Aug2019 (up to approximately 18 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: This Endpoint is only reporting the data for the Global population.
    End point values
    		 Sorafenib - Global Atezolizumab + Bevacizumab - Global
    Number of subjects analysed
    159
    326
    Units: percentage of participants
        number (confidence interval 95%)
    11.9 (7.35 to 18.03)
    27.3 (22.54 to 32.48)
    Statistical analysis title
    		 ORR-IRF RECIST v1.1 - Global
    Statistical analysis description
    Stratified by geographic region (Asia [excluding Japan] vs. rest of world), macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (<400 vs. >/= 400 ng/mL).
    Comparison groups
    Sorafenib - Global v Atezolizumab + Bevacizumab - Global
    Number of subjects included in analysis
    485
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.68
         upper limit
    		 5.01

    Secondary: Objective Response Rate by IRF-Assessment (ORR-IRF) per Hepatocellular Carcinoma (HCC) modified RECIST (mRECIST) in the Global Population

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    End point title
    		 Objective Response Rate by IRF-Assessment (ORR-IRF) per Hepatocellular Carcinoma (HCC) modified RECIST (mRECIST) in the Global Population [6]
    End point description
    ORR was defined as the percentage of participants with CR or PR as determined by the IRF according to HCC mRECIST. HCC mRECIST differentiates between vital tumor and necrotic areas in the liver measuring only the residual vital tumor mass in the liver. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. OR=CR+PR Global ITT population with measurable disease at baseline consisted of all randomized participants in the Global population, whether or not the participant had received the assigned study treatment, and had measurable disease at baseline.
    End point type
    Secondary
    End point timeframe
    Randomization up to CCOD of 29Aug2019 (up to approximately 18 months)
    Notes
    [6] - 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: This Endpoint is only reporting the data for the Global population.
    End point values
    		 Sorafenib - Global Atezolizumab + Bevacizumab - Global
    Number of subjects analysed
    158
    325
    Units: percentage of participants
        number (confidence interval 95%)
    13.3 (8.42 to 19.60)
    33.2 (28.13 to 38.64)
    Statistical analysis title
    		 ORR-IRF HCC mRECIST - Global
    Statistical analysis description
    Stratified by geographic region (Asia [excluding Japan] vs. rest of world), macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (<400 vs. >/= 400 ng/mL).
    Comparison groups
    Sorafenib - Global v Atezolizumab + Bevacizumab - Global
    Number of subjects included in analysis
    483
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.02
         upper limit
    		 5.71

    Secondary: ORR by Investigator-Assessment (ORR-INV) per RECIST v1.1 in the Global Population

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    End point title
    		 ORR by Investigator-Assessment (ORR-INV) per RECIST v1.1 in the Global Population [7]
    End point description
    ORR was defined as the percentage of participants with CR or PR as determined by the investigator according to RECIST v1.1. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. OR=CR+PR Global ITT population with measurable disease at baseline consisted of all randomized participants in the Global population, whether or not the participant had received the assigned study treatment, and had measurable disease at baseline.
    End point type
    Secondary
    End point timeframe
    Randomization up to CCOD of 29Aug2019 (up to approximately 18 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: This Endpoint is only reporting the data for the Global population.
    End point values
    		 Sorafenib - Global Atezolizumab + Bevacizumab - Global
    Number of subjects analysed
    164
    336
    Units: percentage of participants
        number (confidence interval 95%)
    5.5 (2.54 to 10.16)
    25.6 (21.01 to 30.61)
    Statistical analysis title
    		 ORR-INV RECIST v1.1 - Global
    Statistical analysis description
    Stratified by geographic region (Asia [excluding Japan] vs. rest of world), macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (<400 vs. >/= 400 ng/mL).
    Comparison groups
    Sorafenib - Global v Atezolizumab + Bevacizumab - Global
    Number of subjects included in analysis
    500
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    6.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.99
         upper limit
    		 12.66

    Secondary: Duration of Response by IRF Assessment (DOR-IRF) per HCC mRECIST in the Global Population

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    End point title
    		 Duration of Response by IRF Assessment (DOR-IRF) per HCC mRECIST in the Global Population [8]
    End point description
    DOR: the time interval from the date of first occurrence of a documented objective response (CR or PR, whichever status is recorded first) until the first date that disease progression (PD) or death was documented, whichever occurs first as determined by the IRF according to HCC mRECIST. HCC mRECIST differentiates between vital tumor and necrotic areas in the liver, measuring only the residual vital tumor mass in the liver CR: disappearance of all target lesions. PR: At least 30% decrease in the sum of diameters of all target lesions compared to baseline, in the absence of CR. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition, the sum of diameters must also demonstrate an absolute increase of >/= 5 mm. The analysis population included Global participants with a confirmed response (CR or PR). 9999/99999 = not estimable due to the limited number of events observed
    End point type
    Secondary
    End point timeframe
    Randomization up to CCOD of 29Aug2019 (up to approximately 18 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: This Endpoint is only reporting the data for the Global population.
    End point values
    		 Sorafenib - Global Atezolizumab + Bevacizumab - Global
    Number of subjects analysed
    21
    108
    Units: months
        median (confidence interval 95%)
    6.28 (4.86 to 99999)
    9999 (9999 to 99999)
    Statistical analysis title
    		 DOR-IRF HCC mRECIST - Global
    Statistical analysis description
    Stratified by geographic region (Asia [excluding Japan] vs. rest of world), macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (<400 vs. >/= 400 ng/mL).
    Comparison groups
    Sorafenib - Global v Atezolizumab + Bevacizumab - Global
    Number of subjects included in analysis
    129
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0048
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.12
         upper limit
    		 0.73

    Secondary: Duration of Response by IRF-Assessment (DOR-IRF) per RECIST v1.1 in the Global Population

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    End point title
    		 Duration of Response by IRF-Assessment (DOR-IRF) per RECIST v1.1 in the Global Population [9]
    End point description
    DOR was defined as the time interval from the date of first occurrence of a documented objective response (CR or PR, whichever status is recorded first) until the first date that disease progression (PD) or death was documented, whichever occurs first as determined by the IRF according to RECIST v1.1. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of >/= 5 mm. The analysis population included Global participants with a confirmed response (CR or PR). 9999/99999 = not estimable due to the limited number of events observed
    End point type
    Secondary
    End point timeframe
    Randomization up to CCOD of 29Aug2019 (up to approximately 18 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: This Endpoint is only reporting the data for the Global population.
    End point values
    		 Sorafenib - Global Atezolizumab + Bevacizumab - Global
    Number of subjects analysed
    19
    89
    Units: months
        median (confidence interval 95%)
    6.28 (4.67 to 99999)
    9999 (9999 to 99999)
    Statistical analysis title
    		 DOR-IRF RECIST v1.1 - Global
    Statistical analysis description
    Stratified by geographic region (Asia [excluding Japan] vs. rest of world), macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (<400 vs. >/= 400 ng/mL).
    Comparison groups
    Sorafenib - Global v Atezolizumab + Bevacizumab - Global
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0051
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.08
         upper limit
    		 0.7

    Secondary: Duration of Response by Investigator Assessment (DOR-INV) per RECIST v1.1 in the Global Population

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    End point title
    		 Duration of Response by Investigator Assessment (DOR-INV) per RECIST v1.1 in the Global Population [10]
    End point description
    DOR was defined as the time interval from the date of first occurrence of a documented objective response (CR or PR, whichever status is recorded first) until the first date that disease progression (PD) or death was documented, whichever occurs first as determined by the investigator according to RECIST v1.1. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of >/= 5 mm. The analysis population included Global participants with a confirmed response (CR or PR). 9999/99999 = not estimable due to the limited number of events observed
    End point type
    Secondary
    End point timeframe
    Randomization up to CCOD of 29Aug2019 (up to approximately 18 months)
    Notes
    [10] - 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: This Endpoint is only reporting the data for the Global population.
    End point values
    		 Sorafenib - Global Atezolizumab + Bevacizumab - Global
    Number of subjects analysed
    9
    86
    Units: months
        median (confidence interval 95%)
    9999 (5.39 to 99999)
    13.08 (13.08 to 99999)
    Statistical analysis title
    		 DOR-INV RECIST v1.1 - Global
    Statistical analysis description
    Stratified by geographic region (Asia [excluding Japan] vs. rest of world), macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (<400 vs. >/= 400 ng/mL).
    Comparison groups
    Sorafenib - Global v Atezolizumab + Bevacizumab - Global
    Number of subjects included in analysis
    95
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4187
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.16
         upper limit
    		 2.15

    Secondary: PFS-IRF per HCC mRECIST in the Global Population

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    End point title
    		 PFS-IRF per HCC mRECIST in the Global Population [11]
    End point description
    PFS was defined as the time from randomization to the first occurrence of progressive disease or death from any cause whichever occurs first as determined by the IRF according to HCC mRECIST. HCC mRECIST differentiates between vital tumor and necrotic areas in the liver, measuring only the residual vital tumor mass in the liver. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of >/= 5 millimeters (mm). Global ITT population consisted of all randomized participants in the Global population, whether or not the participant had received the assigned study treatment.
    End point type
    Secondary
    End point timeframe
    Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months)
    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: This Endpoint is only reporting the data for the Global population.
    End point values
    		 Sorafenib - Global Atezolizumab + Bevacizumab - Global
    Number of subjects analysed
    165
    336
    Units: months
        median (confidence interval 95%)
    4.24 (3.98 to 5.45)
    6.83 (5.72 to 7.69)
    Statistical analysis title
    		 PFS-IRF HCC mRECIST - Global
    Statistical analysis description
    Stratified by geographic region (Asia [excluding Japan] vs. rest of world), macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (<400 vs. >/= 400 ng/mL).
    Comparison groups
    Sorafenib - Global v Atezolizumab + Bevacizumab - Global
    Number of subjects included in analysis
    501
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.46
         upper limit
    		 0.74

    Secondary: PFS by Investigator Assessment (PFS-INV) per RECIST v1.1 in the Global Population

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    End point title
    		 PFS by Investigator Assessment (PFS-INV) per RECIST v1.1 in the Global Population [12]
    End point description
    PFS was defined as the time from randomization to the first occurrence of progressive disease or death from any cause whichever occurs first as determined by the investigator according to RECIST v1.1. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of >/= 5 millimeters (mm). Global ITT population consisted of all randomized participants in the Global population, whether or not the participant had received the assigned study treatment.
    End point type
    Secondary
    End point timeframe
    Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months)
    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: This Endpoint is only reporting the data for the Global population.
    End point values
    		 Sorafenib - Global Atezolizumab + Bevacizumab - Global
    Number of subjects analysed
    165
    336
    Units: months
        median (confidence interval 95%)
    2.89 (2.76 to 4.17)
    7.06 (5.68 to 8.44)
    Statistical analysis title
    		 PFS-INV RECIST v1.1 - Global
    Statistical analysis description
    Stratified by geographic region (Asia [excluding Japan] vs. rest of world), macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (<400 vs. >/= 400 ng/mL).
    Comparison groups
    Sorafenib - Global v Atezolizumab + Bevacizumab - Global
    Number of subjects included in analysis
    501
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.36
         upper limit
    		 0.57

    Secondary: Time to Progression (TTP) by IRF Assessment (TTP-IRF) per RECIST v1.1 in the Global Population

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    End point title
    		 Time to Progression (TTP) by IRF Assessment (TTP-IRF) per RECIST v1.1 in the Global Population [13]
    End point description
    Time to progression was defined as the time from the date of randomization to the date of the first documented tumor progression as determined by the IRF according to RECIST v1.1. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of >/= 5 millimeters (mm). Global ITT population consisted of all randomized participants in the Global population, whether or not the participant had received the assigned study treatment.
    End point type
    Secondary
    End point timeframe
    Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 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: This Endpoint is only reporting the data for the Global population.
    End point values
    		 Sorafenib - Global Atezolizumab + Bevacizumab - Global
    Number of subjects analysed
    165
    336
    Units: months
        median (confidence interval 95%)
    5.59 (4.21 to 7.72)
    8.57 (6.83 to 9.86)
    Statistical analysis title
    		 TTP-IRF RECIST v1.1 - Global
    Statistical analysis description
    Stratified by geographic region (Asia [excluding Japan] vs. rest of world), macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (<400 vs. >/= 400 ng/mL).
    Comparison groups
    Sorafenib - Global v Atezolizumab + Bevacizumab - Global
    Number of subjects included in analysis
    501
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0105
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.53
         upper limit
    		 0.92

    Secondary: TTP-IRF per HCC mRECIST in the Global Population

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    End point title
    		 TTP-IRF per HCC mRECIST in the Global Population [14]
    End point description
    Time to progression was defined as the time from the date of randomization to the date of the first documented tumor progression as determined by the IRF according to HCC mRECIST. HCC mRECIST differentiates between vital tumor and necrotic areas in the liver, measuring only the residual vital tumor mass in the liver. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of >/= 5 millimeters (mm). Global ITT population consisted of all randomized participants in the Global population, whether or not the participant had received the assigned study treatment.
    End point type
    Secondary
    End point timeframe
    Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 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: This Endpoint is only reporting the data for the Global population.
    End point values
    		 Sorafenib - Global Atezolizumab + Bevacizumab - Global
    Number of subjects analysed
    165
    336
    Units: months
        median (confidence interval 95%)
    5.55 (4.21 to 7.69)
    8.28 (6.80 to 9.86)
    Statistical analysis title
    		 TTP-IRF HCC mRECIST - Global
    Statistical analysis description
    Stratified by geographic region (Asia [excluding Japan] vs. rest of world), macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (<400 vs. >/= 400 ng/mL).
    Comparison groups
    Sorafenib - Global v Atezolizumab + Bevacizumab - Global
    Number of subjects included in analysis
    501
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0063
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.69
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.52
         upper limit
    		 0.9

    Secondary: TTP by Investigator Assessment (TTP-INV) per RECIST v1.1 in the Global Population

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    End point title
    		 TTP by Investigator Assessment (TTP-INV) per RECIST v1.1 in the Global Population [15]
    End point description
    Time to progression was defined as the time from the date of randomization to the date of the first documented tumor progression as determined by the investigator according to RECIST v1.1. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of >/= 5 millimeters (mm). Global ITT population consisted of all randomized participants in the Global population, whether or not the participant had received the assigned study treatment.
    End point type
    Secondary
    End point timeframe
    Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 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: This Endpoint is only reporting the data for the Global population.
    End point values
    		 Sorafenib - Global Atezolizumab + Bevacizumab - Global
    Number of subjects analysed
    165
    336
    Units: months
        median (confidence interval 95%)
    3.98 (2.83 to 4.30)
    8.54 (6.93 to 9.92)
    Statistical analysis title
    		 TTP-INV RECIST v1.1 - Global
    Statistical analysis description
    Stratified by geographic region (Asia [excluding Japan] vs. rest of world), macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (<400 vs. >/= 400 ng/mL).
    Comparison groups
    Sorafenib - Global v Atezolizumab + Bevacizumab - Global
    Number of subjects included in analysis
    501
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.35
         upper limit
    		 0.57

    Secondary: Overall Survival by Baseline AFP in the Global Population

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    End point title
    		 Overall Survival by Baseline AFP in the Global Population [16]
    End point description
    OS was defined as the time from randomization to death from any cause. Global ITT population consisted of all randomized participants in the Global population, whether or not the participant had received the assigned study treatment. Subpopulations with baseline AFP <400 ng/mL and AFP>/= 400 ng/mL were analyzed. 9999/99999 = not estimable due to the limited number of events observed
    End point type
    Secondary
    End point timeframe
    From randomization to death from any cause up to CCOD of 29Aug2019 (up to approximately 18 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: This Endpoint is only reporting the data for the Global population.
    End point values
    		 Sorafenib - Global Atezolizumab + Bevacizumab - Global
    Number of subjects analysed
    165
    336
    Units: months
    arithmetic mean (confidence interval 95%)
        AFP <400 ng/mL; n=104, 210
    13.93 (11.73 to 99999)
    9999 (9999 to 99999)
        AFP >/=400 ng/mL; n=61, 126
    9.10 (5.75 to 99999)
    12.78 (10.15 to 99999)
    Statistical analysis title
    		 OS AFP >/=400 ng/mL - Global
    Statistical analysis description
    AFP >/= 400 ng/mL and stratified by geographic region (Asia [excluding Japan] vs. rest of world), macrovascular invasion and/or extrahepatic spread (presence vs. absence).
    Comparison groups
    Sorafenib - Global v Atezolizumab + Bevacizumab - Global
    Number of subjects included in analysis
    501
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0879
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.42
         upper limit
    		 1.06
    Statistical analysis title
    		 OS AFP <400 ng/mL - Global
    Statistical analysis description
    AFP <400 ng/mL and stratified by geographic region (Asia [excluding Japan] vs. rest of world), macrovascular invasion and/or extrahepatic spread (presence vs. absence).
    Comparison groups
    Sorafenib - Global v Atezolizumab + Bevacizumab - Global
    Number of subjects included in analysis
    501
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0019
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.32
         upper limit
    		 0.78

    Secondary: PFS-IRF per RECIST v1.1 by Baseline AFP in the Global Population

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    End point title
    		 PFS-IRF per RECIST v1.1 by Baseline AFP in the Global Population [17]
    End point description
    PFS was defined as the time from randomization to the first occurrence of progressive disease or death from any cause whichever occurs first as determined by the IRF according to RECIST v1.1. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of >/= 5 millimeters (mm). Global ITT population consisted of all randomized participants in the Global population, whether or not the participant had received the assigned study treatment. Subpopulations with baseline AFP <400 ng/mL and AFP>/= 400 ng/mL were analyzed.
    End point type
    Secondary
    End point timeframe
    Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months)
    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: This Endpoint is only reporting the data for the Global population.
    End point values
    		 Sorafenib - Global Atezolizumab + Bevacizumab - Global
    Number of subjects analysed
    165
    336
    Units: months
    median (confidence interval 95%)
        AFP <400 ng/mL; n=104, 210
    4.40 (4.01 to 6.21)
    8.28 (6.83 to 11.04)
        AFP >/=400 ng/mL; n=61, 126
    4.14 (2.76 to 5.26)
    5.19 (3.94 to 6.77)
    Statistical analysis title
    		 PFS-IRF RECIST v1,1 AFP>/=400 ng/mL - Global
    Statistical analysis description
    AFP >/=400 ng/mL and stratified by geographic region (Asia [excluding Japan] vs. rest of world), macrovascular invasion and/or extrahepatic spread (presence vs. absence).
    Comparison groups
    Sorafenib - Global v Atezolizumab + Bevacizumab - Global
    Number of subjects included in analysis
    501
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2159
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.53
         upper limit
    		 1.15
    Statistical analysis title
    		 PFS-IRF RECIST v1,1 AFP<400 ng/mL - Global
    Statistical analysis description
    AFP<400 ng/mL and stratified by geographic region (Asia [excluding Japan] vs. rest of world), macrovascular invasion and/or extrahepatic spread (presence vs. absence).
    Comparison groups
    Sorafenib - Global v Atezolizumab + Bevacizumab - Global
    Number of subjects included in analysis
    501
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.37
         upper limit
    		 0.68

    Secondary: PFS-INV per RECIST v1.1 by Baseline AFP in the Global Population

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    End point title
    		 PFS-INV per RECIST v1.1 by Baseline AFP in the Global Population [18]
    End point description
    PFS was defined as the time from randomization to the first occurrence of progressive disease or death from any cause whichever occurs first as determined by the investigator according to RECIST v1.1. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of >/= 5 millimeters (mm). Global ITT population consisted of all randomized participants in the Global population, whether or not the participant had received the assigned study treatment. Subpopulations with baseline AFP <400 ng/mL and AFP>/= 400 ng/mL were analyzed.
    End point type
    Secondary
    End point timeframe
    Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months)
    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: This Endpoint is only reporting the data for the Global population.
    End point values
    		 Sorafenib - Global Atezolizumab + Bevacizumab - Global
    Number of subjects analysed
    165
    336
    Units: months
    median (confidence interval 95%)
        AFP <400 ng/mL; n=104, 210
    3.98 (2.79 to 5.62)
    8.41 (7.06 to 9.66)
        AFP >/=400 ng/mL; n=61, 126
    2.79 (1.58 to 3.98)
    5.42 (4.17 to 6.90)
    Statistical analysis title
    		 PFS-INV RECIST v1.1 AFP>/=400 ng/mL - Global
    Statistical analysis description
    AFP >/=400 ng/mL and stratified by geographic region (Asia [excluding Japan] vs. rest of world), macrovascular invasion and/or extrahepatic spread (presence vs. absence).
    Comparison groups
    Sorafenib - Global v Atezolizumab + Bevacizumab - Global
    Number of subjects included in analysis
    501
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0002
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.35
         upper limit
    		 0.73
    Statistical analysis title
    		 PFS-INV RECIST v1.1 AFP<400 ng/mL - Global
    Statistical analysis description
    AFP <400 ng/mL and stratified by geographic region (Asia [excluding Japan] vs. rest of world), macrovascular invasion and/or extrahepatic spread (presence vs. absence).
    Comparison groups
    Sorafenib - Global v Atezolizumab + Bevacizumab - Global
    Number of subjects included in analysis
    501
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.31
         upper limit
    		 0.57

    Secondary: Time to Deterioration (TTD) in the Global Population

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    End point title
    		 Time to Deterioration (TTD) in the Global Population [19]
    End point description
    TTD was defined as the time from randomization to the first deterioration (decrease from baseline of >/= 10 points) in the patient-reported health-related global health status/quality of life (GHS /HRQoL), physical function or role function scales of the European Organization for Research and Treatment of Cancer quality-of-life questionnaire for cancer (EORTC) QLQ-C30, maintained for two consecutive assessments, or one assessment followed by death from any cause within 3 weeks. Global ITT population consisted of all randomized participants in the Global population, whether or not the participant had received the assigned study treatment. 99999 = not estimable due to the limited number of events observed
    End point type
    Secondary
    End point timeframe
    Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 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: This Endpoint is only reporting the data for the Global population.
    End point values
    		 Sorafenib - Global Atezolizumab + Bevacizumab - Global
    Number of subjects analysed
    165
    336
    Units: months
    median (confidence interval 95%)
        Physical Functioning
    4.86 (3.48 to 6.24)
    13.14 (9.69 to 99999)
        Role Functioning
    3.58 (2.20 to 5.98)
    9.13 (6.51 to 99999)
        GHS/QoL
    3.58 (3.02 to 6.97)
    11.24 (5.98 to 99999)
    Statistical analysis title
    		 TTD Physical Functioning - Global
    Statistical analysis description
    Physical Functioning: Stratified by geographic region (Asia [excluding Japan] vs. rest of world), macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (<400 vs. >/= 400 ng/mL).
    Comparison groups
    Sorafenib - Global v Atezolizumab + Bevacizumab - Global
    Number of subjects included in analysis
    501
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.39
         upper limit
    		 0.73
    Statistical analysis title
    		 TTD Role Functioning - Global
    Statistical analysis description
    Role Functioning: Stratified by geographic region (Asia [excluding Japan] vs. rest of world), macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (<400 vs. >/= 400 ng/mL).
    Comparison groups
    Sorafenib - Global v Atezolizumab + Bevacizumab - Global
    Number of subjects included in analysis
    501
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0019
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.46
         upper limit
    		 0.84
    Statistical analysis title
    		 TTD GHS/QoL - Global
    Statistical analysis description
    GHS/QoL: Stratified by geographic region (Asia [excluding Japan] vs. rest of world), macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (<400 vs. >/= 400 ng/mL).
    Comparison groups
    Sorafenib - Global v Atezolizumab + Bevacizumab - Global
    Number of subjects included in analysis
    501
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0028
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.46
         upper limit
    		 0.85

    Secondary: Percentage of Participants With Adverse Events (AEs) in the Global Population

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    End point title
    		 Percentage of Participants With Adverse Events (AEs) in the Global Population [20]
    End point description
    An adverse event is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. Global safety population included all randomized Global participants who received any amount of study drug with participants grouped according to the treatment the participant actually received.
    End point type
    Secondary
    End point timeframe
    Up to end of study (up to approximately 40 months)
    Notes
    [20] - 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: This Endpoint is only reporting the data for the Global population.
    End point values
    		 Sorafenib - Global Atezolizumab + Bevacizumab - Global
    Number of subjects analysed
    156
    329
    Units: percentage of participants
    154
    322
    No statistical analyses for this end point

    Secondary: Trough Serum Concentration (Cmin) of Atezolizumab in the Global Population

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    End point title
    		 Trough Serum Concentration (Cmin) of Atezolizumab in the Global Population [21]
    End point description
    The pharmacokinetic (PK)-evaluable population was defined as all participants in the Global population who received any dose of study treatment and who had at least one post-baseline PK sample available.
    End point type
    Secondary
    End point timeframe
    Pre-dose on Day 1 of Cycles 2, 3, 4, 8, 12 and 16
    Notes
    [21] - 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: This Endpoint is only reporting the data for the Global population.
    End point values
    		 Atezolizumab + Bevacizumab - Global
    Number of subjects analysed
    329
    Units: mcg/mL
    arithmetic mean (standard deviation)
        Pre-dose Cycle 2, Day 1; n=298
    79.2 ( 50.2 )
        Pre-dose Cycle 3, Day 1; n=41
    101 ( 55.4 )
        Pre-dose Cycle 4, Day 1; n=263
    131 ( 63.7 )
        Pre-dose Cycle 8, Day 1; n=134
    145 ( 61.7 )
        Pre-dose Cycle 12, Day 1; n=153
    168 ( 82.9 )
        Pre-dose Cycle 16, Day 1; n=124
    167 ( 65.0 )
    No statistical analyses for this end point

    Secondary: Maximum Serum Concentration (Cmax) of Atezolizumab at Cycle 1 in the Global Population

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    End point title
    		 Maximum Serum Concentration (Cmax) of Atezolizumab at Cycle 1 in the Global Population [22]
    End point description
    The pharmacokinetic (PK)-evaluable population was defined as all participants in the Global population who received any dose of study treatment and who had at least one post-baseline PK sample available.
    End point type
    Secondary
    End point timeframe
    Post-dose on Day 1 of Cycle 1
    Notes
    [22] - 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: This Endpoint is only reporting the data for the Global population.
    End point values
    		 Atezolizumab + Bevacizumab - Global
    Number of subjects analysed
    309
    Units: micrograms/milliliter (mcg/mL)
        arithmetic mean (standard deviation)
    398 ( 132 )
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Anti-Drug Antibodies (ADAs) to Atezolizumab in the Global Population

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    End point title
    		 Percentage of Participants With Anti-Drug Antibodies (ADAs) to Atezolizumab in the Global Population [23]
    End point description
    The Global ADA-evaluable population was defined as all participants in the Global population who received any dose of atezolizumab and who had at least one post-baseline ADA assessment.
    End point type
    Secondary
    End point timeframe
    Baseline and post-baseline on Day 1 (pre-dose) of Cycles 2, 3, 4, 8, 12, 16 (cycle length = 21 days) and treatment discontinuation visit (up to approximately 30 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: This Endpoint is only reporting the data for the Global population.
    End point values
    		 Atezolizumab + Bevacizumab - Global
    Number of subjects analysed
    329
    Units: percentage of participants
    number (not applicable)
        Baseline; n=316
    2.2
        Post-baseline; n=318
    29.6
    No statistical analyses for this end point

    Secondary: Objective Response Rate by IRF-Assessment (ORR-IRF) per RECIST v1.1 in the China Population

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    End point title
    		 Objective Response Rate by IRF-Assessment (ORR-IRF) per RECIST v1.1 in the China Population [24]
    End point description
    ORR was defined as the percentage of participants with a complete response (CR) or a partial response (PR) as determined by the IRF according to RECIST v1.1. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. OR=CR+PR China ITT population with measurable disease at baseline consisted of all randomized participants in the China population, whether or not the participant had received the assigned study treatment, and had measurable disease at baseline.
    End point type
    Secondary
    End point timeframe
    Randomization up to CCOD of 29Aug2019 (up to approximately 18 months)
    Notes
    [24] - 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: This Endpoint is only reporting the data for the China population.
    End point values
    		 Sorafenib - China Atezolizumab + Bevacizumab - China
    Number of subjects analysed
    60
    130
    Units: percentage of participants
        number (confidence interval 95%)
    6.7 (1.85 to 16.20)
    24.6 (17.49 to 32.94)
    Statistical analysis title
    		 ORR-IRF RECIST v1,1 - China
    Statistical analysis description
    Stratified by macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (<400 vs. >/= 400 ng/mL).
    Comparison groups
    Sorafenib - China v Atezolizumab + Bevacizumab - China
    Number of subjects included in analysis
    190
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0036
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    4.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.53
         upper limit
    		 13.86

    Secondary: Objective Response Rate by IRF-Assessment (ORR-IRF) per Hepatocellular Carcinoma (HCC) modified RECIST (mRECIST) in the China Population

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    End point title
    		 Objective Response Rate by IRF-Assessment (ORR-IRF) per Hepatocellular Carcinoma (HCC) modified RECIST (mRECIST) in the China Population [25]
    End point description
    ORR was defined as the percentage of participants with CR or PR as determined by the IRF according to HCC mRECIST. HCC mRECIST differentiates between vital tumor and necrotic areas in the liver measuring only the residual vital tumor mass in the liver. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. OR=CR+PR China ITT population with measurable disease at baseline consisted of all randomized participants in the China population, whether or not the participant had received the assigned study treatment, and had measurable disease at baseline.
    End point type
    Secondary
    End point timeframe
    Randomization up to CCOD of 29Aug2019 (up to approximately 18 months)
    Notes
    [25] - 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: This Endpoint is only reporting the data for the China population.
    End point values
    		 Sorafenib - China Atezolizumab + Bevacizumab - China
    Number of subjects analysed
    59
    128
    Units: percentage of participants
        number (confidence interval 95%)
    8.5 (2.81 to 18.68)
    29.7 (21.94 to 38.40)
    Statistical analysis title
    		 ORR-IRF HCC mRECIST - China
    Statistical analysis description
    Stratified by macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (<400 vs. >/= 400 ng/mL).
    Comparison groups
    Sorafenib - China v Atezolizumab + Bevacizumab - China
    Number of subjects included in analysis
    187
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0013
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    4.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.72
         upper limit
    		 12.87

    Secondary: ORR by Investigator-Assessment (ORR-INV) per RECIST v1.1 in the China Population

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    End point title
    		 ORR by Investigator-Assessment (ORR-INV) per RECIST v1.1 in the China Population [26]
    End point description
    ORR was defined as the percentage of participants with CR or PR as determined by the investigator according to RECIST v1.1. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. OR=CR+PR China ITT population with measurable disease at baseline consisted of all randomized participants in the China population, whether or not the participant had received the assigned study treatment, and had measurable disease at baseline.
    End point type
    Secondary
    End point timeframe
    Randomization up to CCOD of 29Aug2019 (up to approximately 18 months)
    Notes
    [26] - 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: This Endpoint is only reporting the data for the China population.
    End point values
    		 Sorafenib - China Atezolizumab + Bevacizumab - China
    Number of subjects analysed
    61
    133
    Units: percentage of participants
        number (confidence interval 95%)
    4.9 (1.03 to 13.71)
    21.1 (14.47 to 28.97)
    Statistical analysis title
    		 ORR-INV RECIST v1.1 - China
    Statistical analysis description
    Stratified by macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (<400 vs. >/= 400 ng/mL).
    Comparison groups
    Sorafenib - China v Atezolizumab + Bevacizumab - China
    Number of subjects included in analysis
    194
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0052
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    5.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.47
         upper limit
    		 17.39

    Secondary: Duration of Response by IRF-Assessment (DOR-IRF) per RECIST v1.1 in the China Population

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    End point title
    		 Duration of Response by IRF-Assessment (DOR-IRF) per RECIST v1.1 in the China Population [27]
    End point description
    DOR was defined as the time interval from the date of first occurrence of a documented objective response (CR or PR, whichever status is recorded first) until the first date that disease progression (PD) or death was documented, whichever occurs first as determined by the IRF according to RECIST v1.1. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of >/= 5 mm. The analysis population included China participants with a confirmed response (CR or PR). 9999/99999 = not estimable due to the limited number of events observed
    End point type
    Secondary
    End point timeframe
    Randomization up to CCOD of 29Aug2019 (up to approximately 18 months)
    Notes
    [27] - 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: This Endpoint is only reporting the data for the China population.
    End point values
    		 Sorafenib - China Atezolizumab + Bevacizumab - China
    Number of subjects analysed
    4
    32
    Units: months
        median (confidence interval 95%)
    9999 (4.86 to 99999)
    9999 (8.15 to 99999)
    Statistical analysis title
    		 DOR-IRF RECIST v1.1 - China
    Statistical analysis description
    Stratified by macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (<400 vs. >/= 400 ng/mL).
    Comparison groups
    Sorafenib - China v Atezolizumab + Bevacizumab - China
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4581
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.02
         upper limit
    		 5.85

    Secondary: Duration of Response by IRF Assessment (DOR-IRF) per HCC mRECIST in the China Population

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    End point title
    		 Duration of Response by IRF Assessment (DOR-IRF) per HCC mRECIST in the China Population [28]
    End point description
    DOR: the time interval from the date of first occurrence of a documented objective response (CR or PR, whichever status is recorded first) until the first date that disease progression (PD) or death was documented, whichever occurs first as determined by the IRF according to HCC mRECIST. HCC mRECIST differentiates between vital tumor and necrotic areas in the liver, measuring only the residual vital tumor mass in the liver CR: disappearance of all target lesions. PR: At least 30% decrease in the sum of diameters of all target lesions compared to baseline, in the absence of CR. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition, the sum of diameters must also demonstrate an absolute increase of >/= 5 mm. The analysis population included Global participants with a confirmed response (CR or PR). 9999/99999 = not estimable due to the limited number of events observed
    End point type
    Secondary
    End point timeframe
    Randomization up to CCOD of 29Aug2019 (up to approximately 18 months)
    Notes
    [28] - 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: This Endpoint is only reporting the data for the China population.
    End point values
    		 Sorafenib - China Atezolizumab + Bevacizumab - China
    Number of subjects analysed
    5
    38
    Units: months
        median (confidence interval 95%)
    4.86 (4.47 to 99999)
    9999 (8.15 to 99999)
    Statistical analysis title
    		 DOR-IRF HCC mRECIST - China
    Statistical analysis description
    Stratified by macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (<400 vs. >/= 400 ng/mL).
    Comparison groups
    Sorafenib - China v Atezolizumab + Bevacizumab - China
    Number of subjects included in analysis
    43
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.01
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.01
         upper limit
    		 0.91

    Secondary: Duration of Response by Investigator Assessment (DOR-INV) per RECIST v1.1 in the China Population

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    End point title
    		 Duration of Response by Investigator Assessment (DOR-INV) per RECIST v1.1 in the China Population [29]
    End point description
    DOR was defined as the time interval from the date of first occurrence of a documented objective response (CR or PR, whichever status is recorded first) until the first date that disease progression (PD) or death was documented, whichever occurs first as determined by the investigator according to RECIST v1.1. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of >/= 5 mm. The analysis population included China participants with a confirmed response (CR or PR). 9999/99999 = not estimable due to the limited number of events observed
    End point type
    Secondary
    End point timeframe
    Randomization up to CCOD of 29Aug2019 (up to approximately 18 months)
    Notes
    [29] - 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: This Endpoint is only reporting the data for the China population.
    End point values
    		 Sorafenib - China Atezolizumab + Bevacizumab - China
    Number of subjects analysed
    3
    28
    Units: months
        median (confidence interval 95%)
    5.55 (4.17 to 99999)
    9999 (9999 to 99999)
    Statistical analysis title
    		 DOR-INV RECIST v1.1 - China
    Statistical analysis description
    Stratified by macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (<400 vs. >/= 400 ng/mL).
    Comparison groups
    Sorafenib - China v Atezolizumab + Bevacizumab - China
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3477
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.03
         upper limit
    		 3.69

    Secondary: PFS-IRF per HCC mRECIST in the China Population

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    End point title
    		 PFS-IRF per HCC mRECIST in the China Population [30]
    End point description
    PFS was defined as the time from randomization to the first occurrence of progressive disease or death from any cause whichever occurs first as determined by the IRF according to HCC mRECIST. HCC mRECIST differentiates between vital tumor and necrotic areas in the liver, measuring only the residual vital tumor mass in the liver. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of >/= 5 millimeters (mm). China ITT population consisted of all randomized participants in the China population, whether or not the participant had received the assigned study treatment.
    End point type
    Secondary
    End point timeframe
    Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months)
    Notes
    [30] - 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: This Endpoint is only reporting the data for the China population.
    End point values
    		 Sorafenib - China Atezolizumab + Bevacizumab - China
    Number of subjects analysed
    61
    133
    Units: months
        median (confidence interval 95%)
    3.19 (2.56 to 4.76)
    5.72 (4.17 to 8.11)
    Statistical analysis title
    		 PFS-IRF HCC mRECIST - China
    Statistical analysis description
    Stratified by macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (<400 vs. >/= 400 ng/mL).
    Comparison groups
    Sorafenib - China v Atezolizumab + Bevacizumab - China
    Number of subjects included in analysis
    194
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0103
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4
         upper limit
    		 0.89

    Secondary: PFS by Investigator Assessment (PFS-INV) per RECIST v1.1 in the China Population

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    End point title
    		 PFS by Investigator Assessment (PFS-INV) per RECIST v1.1 in the China Population [31]
    End point description
    PFS was defined as the time from randomization to the first occurrence of progressive disease or death from any cause whichever occurs first as determined by the investigator according to RECIST v1.1. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of >/= 5 millimeters (mm). China ITT population consisted of all randomized participants in the China population, whether or not the participant had received the assigned study treatment.
    End point type
    Secondary
    End point timeframe
    Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months)
    Notes
    [31] - 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: This Endpoint is only reporting the data for the China population.
    End point values
    		 Sorafenib - China Atezolizumab + Bevacizumab - China
    Number of subjects analysed
    61
    133
    Units: months
        median (confidence interval 95%)
    2.83 (2.73 to 3.98)
    5.55 (4.21 to 8.34)
    Statistical analysis title
    		 PFS-INV RECIST v1.1 - China
    Statistical analysis description
    Stratified by macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (<400 vs. >/= 400 ng/mL).
    Comparison groups
    Sorafenib - China v Atezolizumab + Bevacizumab - China
    Number of subjects included in analysis
    194
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0002
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.33
         upper limit
    		 0.71

    Secondary: Time to Progression (TTP) by IRF Assessment (TTP-IRF) per RECIST v1.1 in the China Population

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    End point title
    		 Time to Progression (TTP) by IRF Assessment (TTP-IRF) per RECIST v1.1 in the China Population [32]
    End point description
    Time to progression was defined as the time from the date of randomization to the date of the first documented tumor progression as determined by the IRF according to RECIST v1.1. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of >/= 5 millimeters (mm). China ITT population consisted of all randomized participants in the China population, whether or not the participant had received the assigned study treatment.
    End point type
    Secondary
    End point timeframe
    Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months)
    Notes
    [32] - 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: This Endpoint is only reporting the data for the China population.
    End point values
    		 Sorafenib - China Atezolizumab + Bevacizumab - China
    Number of subjects analysed
    61
    133
    Units: months
        median (confidence interval 95%)
    4.14 (2.76 to 10.15)
    7.00 (5.45 to 9.49)
    Statistical analysis title
    		 TTP-IRF RECIST v1.1 - China
    Statistical analysis description
    Stratified by macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (<400 vs. >/= 400 ng/mL).
    Comparison groups
    Sorafenib - China v Atezolizumab + Bevacizumab - China
    Number of subjects included in analysis
    194
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0927
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.43
         upper limit
    		 1.07

    Secondary: TTP-IRF per HCC mRECIST in the China Population

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    End point title
    		 TTP-IRF per HCC mRECIST in the China Population [33]
    End point description
    Time to progression was defined as the time from the date of randomization to the date of the first documented tumor progression as determined by the IRF according to HCC mRECIST. HCC mRECIST differentiates between vital tumor and necrotic areas in the liver, measuring only the residual vital tumor mass in the liver. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of >/= 5 millimeters (mm). China ITT population consisted of all randomized participants in the China population, whether or not the participant had received the assigned study treatment.
    End point type
    Secondary
    End point timeframe
    Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months)
    Notes
    [33] - 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: This Endpoint is only reporting the data for the China population.
    End point values
    		 Sorafenib - China Atezolizumab + Bevacizumab - China
    Number of subjects analysed
    61
    133
    Units: months
        median (confidence interval 95%)
    4.14 (2.76 to 10.15)
    7.00 (5.45 to 9.49)
    Statistical analysis title
    		 TTP-IRF HCC mRECIST - China
    Statistical analysis description
    Stratified by macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (<400 vs. >/= 400 ng/mL).
    Comparison groups
    Sorafenib - China v Atezolizumab + Bevacizumab - China
    Number of subjects included in analysis
    194
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0861
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.43
         upper limit
    		 1.06

    Secondary: TTP by Investigator Assessment (TTP-INV) per RECIST v1.1 in the China Population

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    End point title
    		 TTP by Investigator Assessment (TTP-INV) per RECIST v1.1 in the China Population [34]
    End point description
    Time to progression was defined as the time from the date of randomization to the date of the first documented tumor progression as determined by the investigator according to RECIST v1.1. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of >/= 5 millimeters (mm). China ITT population consisted of all randomized participants in the China population, whether or not the participant had received the assigned study treatment.
    End point type
    Secondary
    End point timeframe
    Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months)
    Notes
    [34] - 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: This Endpoint is only reporting the data for the China population.
    End point values
    		 Sorafenib - China Atezolizumab + Bevacizumab - China
    Number of subjects analysed
    61
    133
    Units: months
        median (confidence interval 95%)
    2.83 (2.79 to 4.17)
    6.83 (5.32 to 9.33)
    Statistical analysis title
    		 TTP-INV RECIST v1.1 - China
    Statistical analysis description
    Stratified by macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (<400 vs. >/= 400 ng/mL).
    Comparison groups
    Sorafenib - China v Atezolizumab + Bevacizumab - China
    Number of subjects included in analysis
    194
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0004
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.33
         upper limit
    		 0.74

    Secondary: Time to Deterioration (TTD) in the China Population

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    End point title
    		 Time to Deterioration (TTD) in the China Population [35]
    End point description
    TTD was defined as the time from randomization to the first deterioration (decrease from baseline of >/= 10 points) in the patient-reported health-related global health status/quality of life (GHS /HRQoL), physical function or role function scales of the European Organization for Research and Treatment of Cancer quality-of-life questionnaire for cancer (EORTC) QLQ-C30, maintained for two consecutive assessments, or one assessment followed by death from any cause within 3 weeks. China ITT population consisted of all randomized participants in the China population, whether or not the participant had received the assigned study treatment. 9999/99999 = not estimable due to the limited number of events observed
    End point type
    Secondary
    End point timeframe
    Randomization to the first occurrence of disease progression or death from any cause up to CCOD of 29Aug2019 (up to approximately 18 months)
    Notes
    [35] - 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: This Endpoint is only reporting the data for the China population.
    End point values
    		 Sorafenib - China Atezolizumab + Bevacizumab - China
    Number of subjects analysed
    61
    133
    Units: months
    median (confidence interval 95%)
        Physical Functioning
    5.62 (2.10 to 99999)
    13.14 (9.69 to 99999)
        Role Functioning
    9999 (2.14 to 99999)
    9999 (7.20 to 99999)
        GHS/QoL
    3.58 (1.48 to 9.82)
    9.76 (6.24 to 99999)
    Statistical analysis title
    		 TTD Physical Functioning - China
    Statistical analysis description
    Physical Functioning: Stratified by macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (<400 vs. >/= 400 ng/mL).
    Comparison groups
    Sorafenib - China v Atezolizumab + Bevacizumab - China
    Number of subjects included in analysis
    194
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0035
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.26
         upper limit
    		 0.78
    Statistical analysis title
    		 TTD GHS/QoL - China
    Statistical analysis description
    GHS/QoL: Stratified by macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (<400 vs. >/= 400 ng/mL).
    Comparison groups
    Sorafenib - China v Atezolizumab + Bevacizumab - China
    Number of subjects included in analysis
    194
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0135
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.32
         upper limit
    		 0.88
    Statistical analysis title
    		 TTD Role Functioning - China
    Statistical analysis description
    Role Functioning: Stratified by macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (<400 vs. >/= 400 ng/mL).
    Comparison groups
    Sorafenib - China v Atezolizumab + Bevacizumab - China
    Number of subjects included in analysis
    194
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.2214
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.42
         upper limit
    		 1.23

    Secondary: Percentage of Participants With Adverse Events (AEs) in the China Population

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    End point title
    		 Percentage of Participants With Adverse Events (AEs) in the China Population [36]
    End point description
    An adverse event is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. China safety population included all randomized China participants who received any amount of study drug with participants grouped according to the treatment the participant actually received.
    End point type
    Secondary
    End point timeframe
    Up to end of study (up to approximately 40 months)
    Notes
    [36] - 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: This Endpoint is only reporting the data for the China population.
    End point values
    		 Sorafenib - China Atezolizumab + Bevacizumab - China
    Number of subjects analysed
    58
    132
    Units: percentage of participants
    56
    131
    No statistical analyses for this end point

    Secondary: Trough Serum Concentration (Cmin) of Atezolizumab in the China Population

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    End point title
    		 Trough Serum Concentration (Cmin) of Atezolizumab in the China Population [37]
    End point description
    The pharmacokinetic (PK)-evaluable population was defined as all participants in the China population who received any dose of study treatment and who had at least one post-baseline PK sample available.
    End point type
    Secondary
    End point timeframe
    Pre-dose on Day 1 of Cycles 2, 3, 4, 8, 12 and 16
    Notes
    [37] - 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: This Endpoint is only reporting the data for the China population.
    End point values
    		 Atezolizumab + Bevacizumab - China
    Number of subjects analysed
    132
    Units: mcg/mL
    arithmetic mean (standard deviation)
        Pre-dose Cycle 2, Day 1; n=87
    92.6 ( 65.7 )
        Pre-dose Cycle 3, Day 1; n=4
    105 ( 36.8 )
        Pre-dose Cycle 4, Day 1; n=80
    143 ( 61.4 )
        Pre-dose Cycle 8, Day 1; n=11
    177 ( 61.9 )
        Pre-dose Cycle 12, Day 1; n=20
    201 ( 97.6 )
        Pre-dose Cycle 16, Day 1; n=13
    208 ( 79.4 )
    No statistical analyses for this end point

    Secondary: Maximum Serum Concentration (Cmax) of Atezolizumab in the China Population

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    End point title
    		 Maximum Serum Concentration (Cmax) of Atezolizumab in the China Population [38]
    End point description
    The pharmacokinetic (PK)-evaluable population was defined as all participants in the China population who received any dose of study treatment and who had at least one post-baseline PK sample available.
    End point type
    Secondary
    End point timeframe
    Post-dose on Day 1 of Cycle 1
    Notes
    [38] - 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: This Endpoint is only reporting the data for the China population.
    End point values
    		 Atezolizumab + Bevacizumab - China
    Number of subjects analysed
    85
    Units: mcg/mL
        arithmetic mean (standard deviation)
    456 ( 153 )
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Anti-Drug Antibodies (ADAs) to Atezolizumab in the China Population

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    End point title
    		 Percentage of Participants With Anti-Drug Antibodies (ADAs) to Atezolizumab in the China Population [39]
    End point description
    The China ADA-evaluable population was defined as all participants in the China population who received any dose of atezolizumab and who had at least one post-baseline ADA assessment.
    End point type
    Secondary
    End point timeframe
    Baseline and post-baseline on Day 1 (pre-dose) of Cycles 2, 3, 4, 8, 12, 16 (cycle length = 21 days) and treatment discontinuation visit (up to approximately 18 months)
    Notes
    [39] - 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: This Endpoint is only reporting the data for the China population.
    End point values
    		 Atezolizumab + Bevacizumab - China
    Number of subjects analysed
    132
    Units: percentage of participants
    number (not applicable)
        Baseline; n=90
    1.1
        Post-baseline; n=89
    20.2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to end of study (up to approximately 56 months)
    Adverse event reporting additional description
    Safety population: all randomized participants who received any amount of study drug with participants grouped according to the treatment the participant actually received. Reported here are the analyses of the Global and China safety populations.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    Atezolizumab + Bevacizumab - Global
    Reporting group description
    		 Participants in the Global population received Atezolizumab + Bevacizumab until unacceptable toxicity or loss of clinical benefit as determined by the investigator.

    Reporting group title
    Atezolizumab + Bevacizumab - China
    Reporting group description
    		 Participants in the China population received Atezolizumab + Bevacizumab until unacceptable toxicity or loss of clinical benefit as determined by the investigator.

    Reporting group title
    Sorafenib - China
    Reporting group description
    		 Participants in the China population received sorafenib until unacceptable toxicity or loss of clinical benefit as determined by the investigator.

    Reporting group title
    Sorafenib - Global
    Reporting group description
    		 Participants in the Global population received sorafenib until unacceptable toxicity or loss of clinical benefit as determined by the investigator.

    Serious adverse events
    		 Atezolizumab + Bevacizumab - Global Atezolizumab + Bevacizumab - China Sorafenib - China Sorafenib - Global
    Total subjects affected by serious adverse events
         subjects affected / exposed
    171 / 329 (51.98%)
    54 / 132 (40.91%)
    12 / 58 (20.69%)
    51 / 156 (32.69%)
         number of deaths (all causes)
    227
    88
    45
    114
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Oesophageal squamous cell carcinoma
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasm
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic myeloid leukaemia
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric cancer
         subjects affected / exposed
    0 / 329 (0.00%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour rupture
         subjects affected / exposed
    1 / 329 (0.30%)
    1 / 132 (0.76%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Bleeding varicose vein
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    2 / 329 (0.61%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    1 / 329 (0.30%)
    1 / 132 (0.76%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    3 / 329 (0.91%)
    1 / 132 (0.76%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Phlebitis
         subjects affected / exposed
    0 / 329 (0.00%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral vascular disorder
         subjects affected / exposed
    1 / 329 (0.30%)
    1 / 132 (0.76%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    1 / 329 (0.30%)
    1 / 132 (0.76%)
    1 / 58 (1.72%)
    2 / 156 (1.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 2
    Fatigue
         subjects affected / exposed
    2 / 329 (0.61%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 329 (0.00%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    2 / 329 (0.61%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    11 / 329 (3.34%)
    4 / 132 (3.03%)
    1 / 58 (1.72%)
    2 / 156 (1.28%)
         occurrences causally related to treatment / all
    3 / 15
    2 / 7
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 329 (0.30%)
    1 / 132 (0.76%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cytokine release syndrome
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    1 / 329 (0.30%)
    1 / 132 (0.76%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Scrotal dermatitis
         subjects affected / exposed
    1 / 329 (0.30%)
    1 / 132 (0.76%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 329 (0.00%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    3 / 329 (0.91%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    2 / 156 (1.28%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 329 (0.30%)
    1 / 132 (0.76%)
    0 / 58 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    3 / 329 (0.91%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    2 / 156 (1.28%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    2 / 329 (0.61%)
    1 / 132 (0.76%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    3 / 329 (0.91%)
    1 / 132 (0.76%)
    0 / 58 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    4 / 5
    2 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hiccups
         subjects affected / exposed
    0 / 329 (0.00%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    0 / 329 (0.00%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Acute pulmonary oedema
         subjects affected / exposed
    1 / 329 (0.30%)
    1 / 132 (0.76%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Orthopnoea
         subjects affected / exposed
    1 / 329 (0.30%)
    1 / 132 (0.76%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    2 / 329 (0.61%)
    1 / 132 (0.76%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    2 / 329 (0.61%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 329 (0.30%)
    1 / 132 (0.76%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Amylase increased
         subjects affected / exposed
    0 / 329 (0.00%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    4 / 329 (1.22%)
    1 / 132 (0.76%)
    0 / 58 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    2 / 4
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    7 / 329 (2.13%)
    2 / 132 (1.52%)
    1 / 58 (1.72%)
    2 / 156 (1.28%)
         occurrences causally related to treatment / all
    2 / 7
    2 / 2
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General physical condition abnormal
         subjects affected / exposed
    0 / 329 (0.00%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Granulocyte count decreased
         subjects affected / exposed
    1 / 329 (0.30%)
    1 / 132 (0.76%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lipase increased
         subjects affected / exposed
    0 / 329 (0.00%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    2 / 329 (0.61%)
    2 / 132 (1.52%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Liver function test increased
         subjects affected / exposed
    0 / 329 (0.00%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 329 (0.00%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acetabulum fracture
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Compression fracture
         subjects affected / exposed
    0 / 329 (0.00%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    2 / 329 (0.61%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 329 (0.00%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    4 / 329 (1.22%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    6 / 6
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    0 / 329 (0.00%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    2 / 329 (0.61%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Hydrocele
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Atrial fibrillation
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Acute myocardial infarction
         subjects affected / exposed
    2 / 329 (0.61%)
    1 / 132 (0.76%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    4 / 329 (1.22%)
    2 / 132 (1.52%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 329 (0.30%)
    1 / 132 (0.76%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 329 (0.30%)
    1 / 132 (0.76%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic encephalopathy
         subjects affected / exposed
    5 / 329 (1.52%)
    1 / 132 (0.76%)
    0 / 58 (0.00%)
    3 / 156 (1.92%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 2
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    2 / 329 (0.61%)
    2 / 132 (1.52%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 329 (0.00%)
    0 / 132 (0.00%)
    1 / 58 (1.72%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Altered state of consciousness
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    2 / 329 (0.61%)
    2 / 132 (1.52%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    VIth nerve paralysis
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    VIth nerve disorder
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural hygroma
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Metabolic encephalopathy
         subjects affected / exposed
    0 / 329 (0.00%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    5 / 329 (1.52%)
    3 / 132 (2.27%)
    1 / 58 (1.72%)
    2 / 156 (1.28%)
         occurrences causally related to treatment / all
    1 / 7
    0 / 3
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune thrombocytopenia
         subjects affected / exposed
    1 / 329 (0.30%)
    1 / 132 (0.76%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    2 / 329 (0.61%)
    1 / 132 (0.76%)
    2 / 58 (3.45%)
    2 / 156 (1.28%)
         occurrences causally related to treatment / all
    3 / 4
    3 / 3
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypersplenism
         subjects affected / exposed
    1 / 329 (0.30%)
    1 / 132 (0.76%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Hypoacusis
         subjects affected / exposed
    1 / 329 (0.30%)
    1 / 132 (0.76%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Blindness unilateral
         subjects affected / exposed
    1 / 329 (0.30%)
    1 / 132 (0.76%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cataract
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    2 / 329 (0.61%)
    2 / 132 (1.52%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    2 / 329 (0.61%)
    1 / 132 (0.76%)
    1 / 58 (1.72%)
    2 / 156 (1.28%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 329 (0.30%)
    2 / 132 (1.52%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    5 / 329 (1.52%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    3 / 5
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    13 / 329 (3.95%)
    6 / 132 (4.55%)
    0 / 58 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    1 / 18
    0 / 9
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    5 / 329 (1.52%)
    1 / 132 (0.76%)
    0 / 58 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    3 / 5
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal fissure
         subjects affected / exposed
    0 / 329 (0.00%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    1 / 329 (0.30%)
    1 / 132 (0.76%)
    0 / 58 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    2 / 329 (0.61%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric mucosal lesion
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    11 / 329 (3.34%)
    3 / 132 (2.27%)
    0 / 58 (0.00%)
    3 / 156 (1.92%)
         occurrences causally related to treatment / all
    4 / 11
    3 / 3
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    1 / 3
    1 / 1
    0 / 0
    0 / 0
    Gastric ulcer perforation
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Gastric varices haemorrhage
         subjects affected / exposed
    4 / 329 (1.22%)
    1 / 132 (0.76%)
    0 / 58 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer haemorrhage
         subjects affected / exposed
    0 / 329 (0.00%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal necrosis
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    2 / 329 (0.61%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemoperitoneum
         subjects affected / exposed
    0 / 329 (0.00%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    2 / 156 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Large intestinal haemorrhage
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune-mediated enterocolitis
         subjects affected / exposed
    1 / 329 (0.30%)
    1 / 132 (0.76%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Incarcerated umbilical hernia
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hiatus hernia
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 329 (0.30%)
    1 / 132 (0.76%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mesenteric vein thrombosis
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mouth haemorrhage
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophageal haemorrhage
         subjects affected / exposed
    3 / 329 (0.91%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophageal stenosis
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Varices oesophageal
         subjects affected / exposed
    3 / 329 (0.91%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    2 / 329 (0.61%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    2 / 156 (1.28%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    3 / 329 (0.91%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    5 / 329 (1.52%)
    5 / 132 (3.79%)
    1 / 58 (1.72%)
    2 / 156 (1.28%)
         occurrences causally related to treatment / all
    3 / 5
    5 / 5
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Oesophageal varices haemorrhage
         subjects affected / exposed
    10 / 329 (3.04%)
    2 / 132 (1.52%)
    0 / 58 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    3 / 12
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 329 (0.61%)
    1 / 132 (0.76%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diaphragmatic hernia
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute hepatic failure
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Autoimmune hepatitis
         subjects affected / exposed
    2 / 329 (0.61%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bile duct stone
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    4 / 329 (1.22%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    0 / 329 (0.00%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic cirrhosis
         subjects affected / exposed
    3 / 329 (0.91%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    2 / 156 (1.28%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    1 / 2
    Hepatic failure
         subjects affected / exposed
    4 / 329 (1.22%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    2 / 156 (1.28%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    1 / 329 (0.30%)
    5 / 132 (3.79%)
    0 / 58 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    1 / 1
    5 / 5
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Hepatic pain
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertransaminasaemia
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disease
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatorenal failure
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatorenal syndrome
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    3 / 329 (0.91%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    2 / 329 (0.61%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    2 / 329 (0.61%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Liver injury
         subjects affected / exposed
    1 / 329 (0.30%)
    1 / 132 (0.76%)
    1 / 58 (1.72%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Toxic skin eruption
         subjects affected / exposed
    0 / 329 (0.00%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    0 / 329 (0.00%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug eruption
         subjects affected / exposed
    0 / 329 (0.00%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cutaneous vasculitis
         subjects affected / exposed
    1 / 329 (0.30%)
    1 / 132 (0.76%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    3 / 329 (0.91%)
    1 / 132 (0.76%)
    1 / 58 (1.72%)
    2 / 156 (1.28%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal haematoma
         subjects affected / exposed
    0 / 329 (0.00%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephritis
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 329 (0.00%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephropathy toxic
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Proteinuria
         subjects affected / exposed
    2 / 329 (0.61%)
    1 / 132 (0.76%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    1 / 329 (0.30%)
    1 / 132 (0.76%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Hypophysitis
         subjects affected / exposed
    2 / 329 (0.61%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Addison's disease
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 329 (0.00%)
    0 / 132 (0.00%)
    1 / 58 (1.72%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Autoimmune arthritis
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    2 / 329 (0.61%)
    1 / 132 (0.76%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Groin pain
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    1 / 329 (0.30%)
    1 / 132 (0.76%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myositis
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tendonitis
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abscess limb
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Burkholderia pseudomallei infection
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 329 (0.30%)
    1 / 132 (0.76%)
    0 / 58 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Empyema
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Biliary tract infection
         subjects affected / exposed
    1 / 329 (0.30%)
    1 / 132 (0.76%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 329 (0.61%)
    1 / 132 (0.76%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemophilus infection
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis E
         subjects affected / exposed
    0 / 329 (0.00%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Herpes simplex encephalitis
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    8 / 329 (2.43%)
    1 / 132 (0.76%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    1 / 9
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritonsillar abscess
         subjects affected / exposed
    0 / 329 (0.00%)
    0 / 132 (0.00%)
    1 / 58 (1.72%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    5 / 329 (1.52%)
    3 / 132 (2.27%)
    0 / 58 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    3 / 5
    2 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    1 / 2
    0 / 1
    0 / 0
    0 / 0
    Post procedural infection
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritoneal abscess
         subjects affected / exposed
    1 / 329 (0.30%)
    1 / 132 (0.76%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    2 / 329 (0.61%)
    1 / 132 (0.76%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    1 / 329 (0.30%)
    1 / 132 (0.76%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tooth infection
         subjects affected / exposed
    1 / 329 (0.30%)
    1 / 132 (0.76%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tuberculosis
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    3 / 329 (0.91%)
    1 / 132 (0.76%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Peritonitis bacterial
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Streptococcal bacteraemia
         subjects affected / exposed
    1 / 329 (0.30%)
    1 / 132 (0.76%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    2 / 329 (0.61%)
    1 / 132 (0.76%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemic hyperosmolar nonketotic syndrome
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    3 / 329 (0.91%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Hyperammonaemia
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    1 / 329 (0.30%)
    1 / 132 (0.76%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lactic acidosis
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    2 / 156 (1.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 329 (0.30%)
    0 / 132 (0.00%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    2 / 329 (0.61%)
    1 / 132 (0.76%)
    0 / 58 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 329 (0.00%)
    0 / 132 (0.00%)
    1 / 58 (1.72%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoproteinaemia
         subjects affected / exposed
    1 / 329 (0.30%)
    1 / 132 (0.76%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Atezolizumab + Bevacizumab - Global Atezolizumab + Bevacizumab - China Sorafenib - China Sorafenib - Global
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    311 / 329 (94.53%)
    129 / 132 (97.73%)
    55 / 58 (94.83%)
    147 / 156 (94.23%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    118 / 329 (35.87%)
    54 / 132 (40.91%)
    12 / 58 (20.69%)
    38 / 156 (24.36%)
         occurrences all number
    191
    90
    15
    43
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    28 / 329 (8.51%)
    11 / 132 (8.33%)
    3 / 58 (5.17%)
    21 / 156 (13.46%)
         occurrences all number
    40
    12
    3
    23
    Fatigue
         subjects affected / exposed
    76 / 329 (23.10%)
    17 / 132 (12.88%)
    6 / 58 (10.34%)
    30 / 156 (19.23%)
         occurrences all number
    92
    22
    6
    32
    Oedema peripheral
         subjects affected / exposed
    45 / 329 (13.68%)
    13 / 132 (9.85%)
    3 / 58 (5.17%)
    6 / 156 (3.85%)
         occurrences all number
    55
    18
    3
    6
    Pyrexia
         subjects affected / exposed
    58 / 329 (17.63%)
    23 / 132 (17.42%)
    6 / 58 (10.34%)
    15 / 156 (9.62%)
         occurrences all number
    83
    32
    9
    22
    Malaise
         subjects affected / exposed
    13 / 329 (3.95%)
    6 / 132 (4.55%)
    3 / 58 (5.17%)
    5 / 156 (3.21%)
         occurrences all number
    13
    6
    3
    5
    Pain
         subjects affected / exposed
    9 / 329 (2.74%)
    9 / 132 (6.82%)
    1 / 58 (1.72%)
    1 / 156 (0.64%)
         occurrences all number
    10
    10
    1
    1
    Respiratory, thoracic and mediastinal disorders
    Dysphonia
         subjects affected / exposed
    31 / 329 (9.42%)
    6 / 132 (4.55%)
    3 / 58 (5.17%)
    11 / 156 (7.05%)
         occurrences all number
    35
    6
    3
    11
    Cough
         subjects affected / exposed
    46 / 329 (13.98%)
    14 / 132 (10.61%)
    5 / 58 (8.62%)
    15 / 156 (9.62%)
         occurrences all number
    56
    19
    6
    18
    Dyspnoea
         subjects affected / exposed
    28 / 329 (8.51%)
    5 / 132 (3.79%)
    2 / 58 (3.45%)
    5 / 156 (3.21%)
         occurrences all number
    29
    5
    2
    5
    Epistaxis
         subjects affected / exposed
    37 / 329 (11.25%)
    12 / 132 (9.09%)
    2 / 58 (3.45%)
    6 / 156 (3.85%)
         occurrences all number
    45
    12
    2
    6
    Haemoptysis
         subjects affected / exposed
    4 / 329 (1.22%)
    1 / 132 (0.76%)
    3 / 58 (5.17%)
    4 / 156 (2.56%)
         occurrences all number
    4
    1
    3
    4
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    39 / 329 (11.85%)
    11 / 132 (8.33%)
    5 / 58 (8.62%)
    11 / 156 (7.05%)
         occurrences all number
    41
    12
    5
    11
    Investigations
    Platelet count decreased
         subjects affected / exposed
    48 / 329 (14.59%)
    27 / 132 (20.45%)
    10 / 58 (17.24%)
    18 / 156 (11.54%)
         occurrences all number
    87
    65
    11
    22
    Alanine aminotransferase increased
         subjects affected / exposed
    56 / 329 (17.02%)
    30 / 132 (22.73%)
    12 / 58 (20.69%)
    14 / 156 (8.97%)
         occurrences all number
    80
    52
    18
    18
    Aspartate aminotransferase increased
         subjects affected / exposed
    77 / 329 (23.40%)
    41 / 132 (31.06%)
    19 / 58 (32.76%)
    28 / 156 (17.95%)
         occurrences all number
    116
    76
    23
    32
    Blood alkaline phosphatase increased
         subjects affected / exposed
    33 / 329 (10.03%)
    19 / 132 (14.39%)
    7 / 58 (12.07%)
    11 / 156 (7.05%)
         occurrences all number
    43
    29
    9
    12
    Blood bilirubin increased
         subjects affected / exposed
    59 / 329 (17.93%)
    35 / 132 (26.52%)
    14 / 58 (24.14%)
    23 / 156 (14.74%)
         occurrences all number
    114
    86
    16
    27
    Blood creatinine increased
         subjects affected / exposed
    20 / 329 (6.08%)
    10 / 132 (7.58%)
    0 / 58 (0.00%)
    1 / 156 (0.64%)
         occurrences all number
    32
    18
    0
    1
    Weight decreased
         subjects affected / exposed
    50 / 329 (15.20%)
    21 / 132 (15.91%)
    6 / 58 (10.34%)
    15 / 156 (9.62%)
         occurrences all number
    55
    23
    9
    18
    White blood cell count decreased
         subjects affected / exposed
    21 / 329 (6.38%)
    23 / 132 (17.42%)
    9 / 58 (15.52%)
    9 / 156 (5.77%)
         occurrences all number
    76
    83
    15
    24
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    11 / 329 (3.34%)
    16 / 132 (12.12%)
    9 / 58 (15.52%)
    7 / 156 (4.49%)
         occurrences all number
    13
    18
    9
    7
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    10 / 329 (3.04%)
    11 / 132 (8.33%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences all number
    16
    15
    0
    0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    10 / 329 (3.04%)
    10 / 132 (7.58%)
    9 / 58 (15.52%)
    7 / 156 (4.49%)
         occurrences all number
    14
    13
    13
    10
    Blood bilirubin unconjugated increased
         subjects affected / exposed
    7 / 329 (2.13%)
    7 / 132 (5.30%)
    2 / 58 (3.45%)
    1 / 156 (0.64%)
         occurrences all number
    19
    19
    2
    1
    Bilirubin conjugated increased
         subjects affected / exposed
    12 / 329 (3.65%)
    13 / 132 (9.85%)
    6 / 58 (10.34%)
    4 / 156 (2.56%)
         occurrences all number
    28
    29
    10
    7
    Lymphocyte count decreased
         subjects affected / exposed
    15 / 329 (4.56%)
    9 / 132 (6.82%)
    3 / 58 (5.17%)
    2 / 156 (1.28%)
         occurrences all number
    25
    17
    5
    4
    Neutrophil count decreased
         subjects affected / exposed
    16 / 329 (4.86%)
    18 / 132 (13.64%)
    5 / 58 (8.62%)
    5 / 156 (3.21%)
         occurrences all number
    46
    56
    6
    15
    Protein urine present
         subjects affected / exposed
    3 / 329 (0.91%)
    5 / 132 (3.79%)
    5 / 58 (8.62%)
    4 / 156 (2.56%)
         occurrences all number
    5
    9
    5
    4
    Prothrombin time prolonged
         subjects affected / exposed
    6 / 329 (1.82%)
    7 / 132 (5.30%)
    1 / 58 (1.72%)
    1 / 156 (0.64%)
         occurrences all number
    7
    10
    1
    1
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    33 / 329 (10.03%)
    13 / 132 (9.85%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences all number
    40
    13
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    35 / 329 (10.64%)
    14 / 132 (10.61%)
    2 / 58 (3.45%)
    11 / 156 (7.05%)
         occurrences all number
    44
    18
    4
    14
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    38 / 329 (11.55%)
    26 / 132 (19.70%)
    8 / 58 (13.79%)
    14 / 156 (8.97%)
         occurrences all number
    56
    44
    9
    15
    Thrombocytopenia
         subjects affected / exposed
    32 / 329 (9.73%)
    22 / 132 (16.67%)
    5 / 58 (8.62%)
    7 / 156 (4.49%)
         occurrences all number
    45
    41
    5
    9
    Neutropenia
         subjects affected / exposed
    20 / 329 (6.08%)
    12 / 132 (9.09%)
    3 / 58 (5.17%)
    4 / 156 (2.56%)
         occurrences all number
    28
    20
    6
    7
    Leukopenia
         subjects affected / exposed
    21 / 329 (6.38%)
    19 / 132 (14.39%)
    4 / 58 (6.90%)
    4 / 156 (2.56%)
         occurrences all number
    33
    32
    6
    6
    Gastrointestinal disorders
    Ascites
         subjects affected / exposed
    31 / 329 (9.42%)
    9 / 132 (6.82%)
    2 / 58 (3.45%)
    8 / 156 (5.13%)
         occurrences all number
    36
    10
    3
    10
    Constipation
         subjects affected / exposed
    58 / 329 (17.63%)
    18 / 132 (13.64%)
    5 / 58 (8.62%)
    25 / 156 (16.03%)
         occurrences all number
    63
    20
    5
    27
    Diarrhoea
         subjects affected / exposed
    75 / 329 (22.80%)
    20 / 132 (15.15%)
    26 / 58 (44.83%)
    79 / 156 (50.64%)
         occurrences all number
    109
    28
    38
    107
    Nausea
         subjects affected / exposed
    49 / 329 (14.89%)
    18 / 132 (13.64%)
    7 / 58 (12.07%)
    25 / 156 (16.03%)
         occurrences all number
    64
    22
    9
    28
    Stomatitis
         subjects affected / exposed
    19 / 329 (5.78%)
    4 / 132 (3.03%)
    2 / 58 (3.45%)
    7 / 156 (4.49%)
         occurrences all number
    21
    4
    2
    7
    Abdominal pain upper
         subjects affected / exposed
    20 / 329 (6.08%)
    7 / 132 (5.30%)
    4 / 58 (6.90%)
    9 / 156 (5.77%)
         occurrences all number
    30
    8
    4
    10
    Abdominal pain
         subjects affected / exposed
    50 / 329 (15.20%)
    19 / 132 (14.39%)
    10 / 58 (17.24%)
    27 / 156 (17.31%)
         occurrences all number
    63
    24
    15
    31
    Abdominal distension
         subjects affected / exposed
    26 / 329 (7.90%)
    16 / 132 (12.12%)
    4 / 58 (6.90%)
    5 / 156 (3.21%)
         occurrences all number
    27
    17
    4
    5
    Vomiting
         subjects affected / exposed
    34 / 329 (10.33%)
    15 / 132 (11.36%)
    5 / 58 (8.62%)
    14 / 156 (8.97%)
         occurrences all number
    49
    25
    5
    14
    Gingival bleeding
         subjects affected / exposed
    11 / 329 (3.34%)
    9 / 132 (6.82%)
    1 / 58 (1.72%)
    0 / 156 (0.00%)
         occurrences all number
    14
    12
    1
    0
    Hepatobiliary disorders
    Hepatic function abnormal
         subjects affected / exposed
    8 / 329 (2.43%)
    8 / 132 (6.06%)
    3 / 58 (5.17%)
    4 / 156 (2.56%)
         occurrences all number
    8
    9
    3
    4
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    71 / 329 (21.58%)
    24 / 132 (18.18%)
    7 / 58 (12.07%)
    15 / 156 (9.62%)
         occurrences all number
    99
    31
    8
    16
    Alopecia
         subjects affected / exposed
    6 / 329 (1.82%)
    2 / 132 (1.52%)
    7 / 58 (12.07%)
    22 / 156 (14.10%)
         occurrences all number
    6
    2
    7
    22
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    6 / 329 (1.82%)
    2 / 132 (1.52%)
    33 / 58 (56.90%)
    76 / 156 (48.72%)
         occurrences all number
    7
    2
    39
    82
    Rash
         subjects affected / exposed
    46 / 329 (13.98%)
    21 / 132 (15.91%)
    7 / 58 (12.07%)
    28 / 156 (17.95%)
         occurrences all number
    51
    24
    7
    28
    Rash maculo-papular
         subjects affected / exposed
    10 / 329 (3.04%)
    3 / 132 (2.27%)
    3 / 58 (5.17%)
    5 / 156 (3.21%)
         occurrences all number
    11
    3
    4
    6
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    107 / 329 (32.52%)
    68 / 132 (51.52%)
    11 / 58 (18.97%)
    13 / 156 (8.33%)
         occurrences all number
    184
    120
    18
    19
    Haematuria
         subjects affected / exposed
    13 / 329 (3.95%)
    8 / 132 (6.06%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences all number
    25
    19
    0
    0
    Cylindruria
         subjects affected / exposed
    7 / 329 (2.13%)
    8 / 132 (6.06%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences all number
    20
    21
    0
    0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    35 / 329 (10.64%)
    15 / 132 (11.36%)
    1 / 58 (1.72%)
    3 / 156 (1.92%)
         occurrences all number
    41
    19
    1
    3
    Hyperthyroidism
         subjects affected / exposed
    17 / 329 (5.17%)
    9 / 132 (6.82%)
    0 / 58 (0.00%)
    0 / 156 (0.00%)
         occurrences all number
    20
    11
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    62 / 329 (18.84%)
    16 / 132 (12.12%)
    1 / 58 (1.72%)
    9 / 156 (5.77%)
         occurrences all number
    73
    18
    1
    10
    Back pain
         subjects affected / exposed
    27 / 329 (8.21%)
    11 / 132 (8.33%)
    5 / 58 (8.62%)
    6 / 156 (3.85%)
         occurrences all number
    30
    11
    7
    6
    Myalgia
         subjects affected / exposed
    20 / 329 (6.08%)
    4 / 132 (3.03%)
    2 / 58 (3.45%)
    5 / 156 (3.21%)
         occurrences all number
    24
    4
    2
    6
    Pain in extremity
         subjects affected / exposed
    10 / 329 (3.04%)
    3 / 132 (2.27%)
    3 / 58 (5.17%)
    6 / 156 (3.85%)
         occurrences all number
    10
    3
    3
    6
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    20 / 329 (6.08%)
    7 / 132 (5.30%)
    1 / 58 (1.72%)
    4 / 156 (2.56%)
         occurrences all number
    26
    10
    1
    4
    Upper respiratory tract infection
         subjects affected / exposed
    24 / 329 (7.29%)
    22 / 132 (16.67%)
    2 / 58 (3.45%)
    2 / 156 (1.28%)
         occurrences all number
    27
    26
    2
    2
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    68 / 329 (20.67%)
    27 / 132 (20.45%)
    12 / 58 (20.69%)
    39 / 156 (25.00%)
         occurrences all number
    78
    32
    15
    50
    Hyperglycaemia
         subjects affected / exposed
    23 / 329 (6.99%)
    13 / 132 (9.85%)
    0 / 58 (0.00%)
    4 / 156 (2.56%)
         occurrences all number
    40
    30
    0
    5
    Hypoalbuminaemia
         subjects affected / exposed
    42 / 329 (12.77%)
    32 / 132 (24.24%)
    5 / 58 (8.62%)
    11 / 156 (7.05%)
         occurrences all number
    53
    44
    8
    13
    Hypokalaemia
         subjects affected / exposed
    13 / 329 (3.95%)
    13 / 132 (9.85%)
    11 / 58 (18.97%)
    11 / 156 (7.05%)
         occurrences all number
    19
    22
    13
    13
    Hyponatraemia
         subjects affected / exposed
    26 / 329 (7.90%)
    9 / 132 (6.82%)
    4 / 58 (6.90%)
    7 / 156 (4.49%)
         occurrences all number
    32
    16
    4
    7
    Hypophosphataemia
         subjects affected / exposed
    9 / 329 (2.74%)
    3 / 132 (2.27%)
    6 / 58 (10.34%)
    11 / 156 (7.05%)
         occurrences all number
    10
    6
    10
    13
    Hypoproteinaemia
         subjects affected / exposed
    4 / 329 (1.22%)
    8 / 132 (6.06%)
    1 / 58 (1.72%)
    1 / 156 (0.64%)
         occurrences all number
    4
    10
    1
    1

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Mar 2018
    Given that sorafenib has been shown to prolong the QT and QTc interval, which could lead to an increased risk of ventricular arrhythmia, two exclusion criteria were added to exclude subjects with a history of congenital long QT syndrome or corrected QT interval >500 ms (calculated through the use of the Fridericia method) at screening and subjects with a history of uncorrectable electrolyte disorder affecting serum levels of potassium, calcium, or magnesium. Under the same rationale, it was specified that caution is recommended when administering sorafenib with certain anti-arrhythmic medicines or other medicinal products that lead to QT prolongation in sorafenib-treated participants. The stratification factors to be used for stratified analyses planned to be conducted for both co-primary efficacy endpoints, overall survival (OS) and overall response rate (ORR), were clarified. The following stratification factors were to be used for the stratified analyses that were planned to be conducted for both co-primary endpoints: geographic region (Asia excluding Japan vs. rest of world), macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline alpha-fetoprotein level (<400 vs. >/=400 ng/mL). Results from unstratified analyses may be provided as sensitivity analyses. Language to describe how the homogeneity of treatment effects across important patient subgroups will be descriptively assessed was added to the statistical details provided for the primary efficacy analyses of OS and ORR. The testing order of the key secondary endpoints was removed as the time to progression was no longer planned to be formally tested. The optional interim analysis was removed.
    15 Sep 2018
    The co-primary endpoint of objective response rate (ORR) was changed to progression-free survival (PFS). ORR by investigator assessment was added as a secondary efficacy endpoint. The eligibility criteria were updated to refine the patient population, with the intent to ensure the safety of participants considering the toxicity profile of the study drugs. The window for assessing ECOG performance status, Child-Pugh Class A, and adequate hematologic and end-organ function lab tests was shortened from 14 days to 7 days prior to randomization to ensure fit participants were enrolled and to exclude subjects who could have progressively deteriorating liver function and overall health status. To ensure the safety of participants who would potentially receive bevacizumab (in combination with atezolizumab), the following eligibility criteria were modified/added: 1) Clarified the type of excluded, untreated or incompletely treated varices with bleeding or high risk for bleeding, esophageal and/or gastric varices in the relevant exclusion criteria; 2) The windows for previous stereotactic radiotherapy (within 7 days) and whole brain radiotherapy (within 14 days) were both extended to 28 days prior to initiation of study treatment; 3) A prior bleeding event due to esophageal and/or gastric varices within 6 months prior to initiation of study treatment was added as an exclusion criterion; 4) Local therapy to liver within 28 days prior to initiation of study treatment or non-recovery from side effects of any such procedure was added as an exclusion criterion. The requirement to hold bevacizumab or sorafenib treatment during palliative radiotherapy treatment and the need to obtain Medical Monitor approval prior to continuation of bevacizumab or sorafenib treatment upon completion of such therapy was added. For participants receiving sorafenib, prohibition of strong CYP3A inducers was removed. Additional atezolizumab anti-drug antibody (ADA) and PK samples were added.
    20 Feb 2019
    The protocol was amended primarily to modify the statistical analysis plan to include a second interim analysis for overall survival (OS), which should be conducted when approximately 243 OS events (78% information fraction) have been observed. Guidelines for managing participants who experience atezolizumab-associated adverse events were revised to include guidelines for immune-related myositis. The secondary endpoint for patient reported outcomes of time to deterioration (TTD) was amended to align with the co-primary endpoints of progression-free survival and OS. The previous TTD endpoint was added as an exploratory endpoint. Modifications were made to the statistical analysis plan to add progression-free survival as the primary endpoint for the China subpopulation analysis to align with the global study analysis. Anaphylaxis Precautions appendix was modified to remove the requirement for use of a tourniquet. The application of a tourniquet is no longer recommended due to the limited therapeutic benefit and risk of losing time for more important measures. Guidelines for managing participants who experience bevacizumab-associated adverse events were revised to update guidelines on proteinuria.
    15 Jan 2020
    The protocol was modified primarily with an update to the risks and management guidelines for atezolizumab to align with the latest atezolizumab Investigator’s Brochure.
    01 Feb 2021
    The descriptive and optional nature of subsequent overall survival (OS) analyses once statistical significance is reached at any of the pre-planned interim analyses of OS was clarified. Severe Cutaneous Adverse Reactions (SCARs) were added as a risk associated with atezolizumab. The Management Guidelines for Dermatologic Events was updated to include updated management guidelines for Grade 3 dermatologic events and new guidelines for Stevens-Johnson syndrome or toxic epidermal necrolysis of any grade were added. COVID-19 Considerations section was added to describe COVID-19-related risks. Exclusion criteria: Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia was updated to include any active infection that, the opinion of the investigator, could impact patient safety. COVID-19 risk language was included in the Safety Plan, to state that patients with an active infection were to be excluded from study participation.The Management Guidelines for Infusion-Related Reactions and Cytokine-Release Syndrome were updated to include COVID-19 risk language.

    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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