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    Clinical Trial Results:
    A Phase III, Multicenter, Randomized, Open-Label Study of Atezolizumab (Anti-PD-L1 Antibody) Plus Bevacizumab Versus Active Surveillance as Adjuvant Therapy in Patients With Hepatocellular Carcinoma at High Risk of Recurrence After Surgical Resection or Ablation

    Summary
    EudraCT number
    		 2019-002491-14
    Trial protocol
    		 DE   CZ   FR   ES   PL   NL   BE   IT  
    Global end of trial date

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

    Trial information

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    Trial identification
    Sponsor protocol code
    WO41535
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04102098
    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
    Medical Communications, F. Hoffmann-La Roche AG, 41 616878333, global.trial_information@roche.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Interim
    Date of interim/final analysis
    21 Oct 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Oct 2022
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    IMbrave050 is an ongoing study designed to evaluate the efficacy and safety of adjuvant therapy with atezolizumab plus bevacizumab compared with active surveillance in participants with completely resected or ablated hepatocellular carcinoma (HCC) who are at high risk for disease recurrence.
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    31 Dec 2019
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy
    Long term follow-up duration
    		 79 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 2
    Country: Number of subjects enrolled
    Austria: 8
    Country: Number of subjects enrolled
    Belgium: 2
    Country: Number of subjects enrolled
    Brazil: 8
    Country: Number of subjects enrolled
    Canada: 2
    Country: Number of subjects enrolled
    China: 294
    Country: Number of subjects enrolled
    Costa Rica: 1
    Country: Number of subjects enrolled
    Czechia: 4
    Country: Number of subjects enrolled
    Germany: 6
    Country: Number of subjects enrolled
    Spain: 4
    Country: Number of subjects enrolled
    France: 37
    Country: Number of subjects enrolled
    Hong Kong: 7
    Country: Number of subjects enrolled
    Italy: 7
    Country: Number of subjects enrolled
    Japan: 61
    Country: Number of subjects enrolled
    Korea, Republic of: 125
    Country: Number of subjects enrolled
    Mexico: 4
    Country: Number of subjects enrolled
    Netherlands: 2
    Country: Number of subjects enrolled
    New Zealand: 5
    Country: Number of subjects enrolled
    Peru: 4
    Country: Number of subjects enrolled
    Poland: 2
    Country: Number of subjects enrolled
    Russian Federation: 14
    Country: Number of subjects enrolled
    Singapore: 6
    Country: Number of subjects enrolled
    Thailand: 15
    Country: Number of subjects enrolled
    Turkey: 1
    Country: Number of subjects enrolled
    Taiwan: 28
    Country: Number of subjects enrolled
    United States: 19
    Worldwide total number of subjects
    668
    EEA total number of subjects
    72
    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)
    427
    From 65 to 84 years
    239
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted at 134 centers in 26 countries/regions.

    Pre-assignment
    Screening details
    		 Participants included completely resected or ablated hepatocellular carcinoma (HCC) who are at high risk for disease recurrence. Participants randomized to Active Surveillance arm were offered the option to crossover to receive treatment with Atezolizumab.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm B (active surveillance)
    Arm description
    		 Active surveillance of participants.
    Arm type
    		 Active surveillance

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Arm A (atezolizumab plus bevacizumab)
    Arm description
    		 Participants received Atezolizumab + Bevacizumab until disease recurrence or unacceptable toxicity.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Avastin
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Bevacizumab will be administered by IV infusion at a dose of 15 mg/kg on Day 1 of each 21-day cycle.

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

    Number of subjects in period 1
    		Arm B (active surveillance) Arm A (atezolizumab plus bevacizumab)
    Started
    334
    334
    Completed
    0
    0
    Not completed
    334
    334
         Physician Decision
    -
    1
         Ongoing in study
    302
    291
         Death
    20
    27
         Withdrawal by Subject
    11
    14
         Lost to follow-up
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm B (active surveillance)
    Reporting group description
    		 Active surveillance of participants.

    Reporting group title
    Arm A (atezolizumab plus bevacizumab)
    Reporting group description
    		 Participants received Atezolizumab + Bevacizumab until disease recurrence or unacceptable toxicity.

    Reporting group values
    		 Arm B (active surveillance) Arm A (atezolizumab plus bevacizumab) Total
    Number of subjects
    		 334 334 668
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 215 212 427
        From 65-84 years
    		 118 121 239
        85 years and over
    		 1 1 2
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 58.9 ( 12.5 ) 59.0 ( 12.1 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 56 57 113
        Male
    		 278 277 555
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 1 3 4
        Asian
    		 269 276 545
        Native Hawaiian or Other Pacific Islander
    		 1 0 1
        Black or African American
    		 1 2 3
        White
    		 41 35 76
        More than one race
    		 0 2 2
        Unknown or Not Reported
    		 21 16 37

    End points

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    End points reporting groups
    Reporting group title
    Arm B (active surveillance)
    Reporting group description
    		 Active surveillance of participants.

    Reporting group title
    Arm A (atezolizumab plus bevacizumab)
    Reporting group description
    		 Participants received Atezolizumab + Bevacizumab until disease recurrence or unacceptable toxicity.

    Primary: Recurrence-Free Survival (RFS), as Determined by IRF

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    End point title
    		 Recurrence-Free Survival (RFS), as Determined by IRF
    End point description
    RFS is defined as the time from randomization to the first documented occurrence of intrahepatic or extrahepatic HCC as determined by an IRF, or death from any cause (whichever occurs first). Note: 999999 = not estimable.
    End point type
    Primary
    End point timeframe
    Baseline up to approximately 33 months
    End point values
    		 Arm B (active surveillance) Arm A (atezolizumab plus bevacizumab)
    Number of subjects analysed
    334
    334
    Units: Months
        median (confidence interval 95%)
    999999 (21.4 to 999999)
    999999 (22.1 to 999999)
    Statistical analysis title
    		 RFS as Determined by IRF Statistical Analysis
    Statistical analysis description
    Stratification factors include geographic region (Asia Pacific excluding Japan vs. rest of world) and High risk features/curative procedure (Ablation vs. Resection with 1 high risk feature vs. Resection with 2 or more high risk features).
    Comparison groups
    Arm B (active surveillance) v Arm A (atezolizumab plus bevacizumab)
    Number of subjects included in analysis
    668
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.012
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.56
         upper limit
    		 0.93

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS is defined as the time from randomization to death from any cause.
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 91 months
    End point values
    		 Arm B (active surveillance) Arm A (atezolizumab plus bevacizumab)
    Number of subjects analysed
    0 [1]
    0 [2]
    Units: Months
        median (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [1] - To be reported after end of study.
    [2] - To be reported after end of study.
    No statistical analyses for this end point

    Secondary: Time to Recurrence (TTR)

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    End point title
    		 Time to Recurrence (TTR)
    End point description
    TTR defined as the time from randomization to first documented occurrence of intrahepatic or extrahepatic HCC, as determined by the investigator and by an IRF.
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 91 months
    End point values
    		 Arm B (active surveillance) Arm A (atezolizumab plus bevacizumab)
    Number of subjects analysed
    0 [3]
    0 [4]
    Units: Months
        median (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [3] - To be reported after end of study.
    [4] - To be reported after end of study.
    No statistical analyses for this end point

    Secondary: RFS Rate at 24 and 36 Months, as Assessed by the IRF

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    End point title
    		 RFS Rate at 24 and 36 Months, as Assessed by the IRF
    End point description
    End point type
    Secondary
    End point timeframe
    Randomization up to 24 months and up to 36 months
    End point values
    		 Arm B (active surveillance) Arm A (atezolizumab plus bevacizumab)
    Number of subjects analysed
    0 [5]
    0 [6]
    Units: Months
        median (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [5] - To be reported after end of study.
    [6] - To be reported after end of study.
    No statistical analyses for this end point

    Secondary: RFS as Determined by the Investigator

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    End point title
    		 RFS as Determined by the Investigator
    End point description
    RFS is defined as the time from randomization to the first documented occurrence of intrahepatic or extrahepatic HCC as determined by an investigator, or death from any cause (whichever occurs first).
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 91 months
    End point values
    		 Arm B (active surveillance) Arm A (atezolizumab plus bevacizumab)
    Number of subjects analysed
    0 [7]
    0 [8]
    Units: Months
        median (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [7] - To be reported after end of study.
    [8] - To be reported after end of study.
    No statistical analyses for this end point

    Secondary: RFS Rate at 24 and 36 Months, as Assessed by the Investigator

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    End point title
    		 RFS Rate at 24 and 36 Months, as Assessed by the Investigator
    End point description
    End point type
    Secondary
    End point timeframe
    Randomization up to 24 months and up to 36 months
    End point values
    		 Arm B (active surveillance) Arm A (atezolizumab plus bevacizumab)
    Number of subjects analysed
    0 [9]
    0 [10]
    Units: Months
        median (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [9] - To be reported after end of study.
    [10] - To be reported after end of study.
    No statistical analyses for this end point

    Secondary: OS Rate at 24 and 36 Months

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    End point title
    		 OS Rate at 24 and 36 Months
    End point description
    OS rate defined as the proportion of patients who have not experienced death from any cause at 24 and 36 months after randomization.
    End point type
    Secondary
    End point timeframe
    Baseline to 24 and 36 months
    End point values
    		 Arm B (active surveillance) Arm A (atezolizumab plus bevacizumab)
    Number of subjects analysed
    0 [11]
    0 [12]
    Units: Months
        median (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [11] - To be reported after end of study.
    [12] - To be reported after end of study.
    No statistical analyses for this end point

    Secondary: RFS in Pd-L1-High Subgroup

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    End point title
    		 RFS in Pd-L1-High Subgroup
    End point description
    RFS after randomization as determined by the investigator and by an IRF, among patients in the PD-L1-high subgroup.
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 91 months
    End point values
    		 Arm B (active surveillance) Arm A (atezolizumab plus bevacizumab)
    Number of subjects analysed
    0 [13]
    0 [14]
    Units: Months
        median (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [13] - To be reported after end of study.
    [14] - To be reported after end of study.
    No statistical analyses for this end point

    Secondary: Time to Extrahepatic Spread (EHS) or Macrovascular Invasion

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    End point title
    		 Time to Extrahepatic Spread (EHS) or Macrovascular Invasion
    End point description
    Time to EHS or macrovascular invasion after randomization, defined as the time from randomization to the first appearance of EHS or macrovascular invasion, as determined by the investigator.
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 91 months
    End point values
    		 Arm B (active surveillance) Arm A (atezolizumab plus bevacizumab)
    Number of subjects analysed
    0 [15]
    0 [16]
    Units: Months
        median (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [15] - To be reported after end of study.
    [16] - To be reported after end of study.
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Adverse Events

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    End point title
    		 Percentage of Participants With Adverse Events
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 91 months
    End point values
    		 Arm B (active surveillance) Arm A (atezolizumab plus bevacizumab)
    Number of subjects analysed
    0 [17]
    0 [18]
    Units: Percentage of particiapnts
        number (not applicable)
    Notes
    [17] - To be reported after end of study.
    [18] - To be reported after end of study.
    No statistical analyses for this end point

    Secondary: Serum Concentration of Atezolizumab

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    End point title
    		 Serum Concentration of Atezolizumab [19]
    End point description
    Serum concentration of atezolizumab. Note: 99999=not estimable.
    End point type
    Secondary
    End point timeframe
    Prior to any drug administration on Day 1 of Cycles 1, 2, 3, 4, 8, 12, and 16, and 30 minutes after end of atezolizumab infusion on Day 1 of Cycle 1 (each cycle is 21 days)
    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: No statistical analysis for this end point.
    End point values
    		 Arm A (atezolizumab plus bevacizumab)
    Number of subjects analysed
    329
    Units: μg/ mL
    arithmetic mean (standard deviation)
        Cycle 1 Day 1 (n=329)
    999999 ( 999999 )
        Cycle 1 Day 1, 30 Min After End of Atezo (n=310)
    440 ( 132 )
        Cycle 2 Day 1 (n=317)
    88.7 ( 30.4 )
        Cycle 3 Day 1 (n=314)
    137 ( 53.0 )
        Cycle 4 Day 1 (n=305)
    159 ( 58.5 )
        Cycle 8 Day 1 (n=264)
    196 ( 86.2 )
        Cycle 12 Day 1 (n=233)
    202 ( 90.1 )
        Cycle 16 Day 1 (n=192)
    204 ( 89.2 )
    No statistical analyses for this end point

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

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    End point title
    		 Number of Participants with Anti-Drug Antibodies (ADAs) to Atezolizumab [20]
    End point description
    Number of participants with anti-drug antibodies to atezolizumab.
    End point type
    Secondary
    End point timeframe
    Prior to any drug administration up to approximately 33 month
    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: No statistical analysis for this end point.
    End point values
    		 Arm A (atezolizumab plus bevacizumab)
    Number of subjects analysed
    328
    Units: Participants
        Baseline evaluable participants
    8
        Post-baseline evaluable participants
    75
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first study drug administration to the data cutoff date: 21 October 2022 (up to approximately 33 months).
    Adverse event reporting additional description
    Adverse events reported based on safety population, which included participants who received any amount of any component of study treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    Arm A (Atezolizumab plus Bevacizumab)
    Reporting group description
    		 Participants received Atezolizumab + Bevacizumab until disease recurrence or unacceptable toxicity.

    Reporting group title
    Arm B (Active Surveillance)
    Reporting group description
    		 Active surveillance of participants.

    Reporting group title
    Crossover: Atezolizumab + Bevacizumab
    Reporting group description
    		 Participants randomized to Active Surveillance arm who crossed over to receive treatment with Atezolizumab plus Bevacizumab during the Active Surveillance period or during the follow-up period.

    Serious adverse events
    		 Arm A (Atezolizumab plus Bevacizumab) Arm B (Active Surveillance) Crossover: Atezolizumab + Bevacizumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    80 / 332 (24.10%)
    34 / 330 (10.30%)
    10 / 81 (12.35%)
         number of deaths (all causes)
    28
    19
    11
         number of deaths resulting from adverse events
    2
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tonsillar neoplasm benign
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 330 (0.30%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Papillary thyroid cancer
         subjects affected / exposed
    0 / 332 (0.00%)
    0 / 330 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestine benign neoplasm
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 330 (0.30%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Glioma
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 330 (0.30%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric cancer
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 330 (0.30%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric adenoma
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 330 (0.30%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic myeloid leukaemia
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric cancer stage 0
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 330 (0.30%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tumour necrosis
         subjects affected / exposed
    0 / 332 (0.00%)
    0 / 330 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Aortic dissection
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery thrombosis
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 330 (0.30%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    3 / 332 (0.90%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Impaired healing
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Localised oedema
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    3 / 81 (3.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hernia
         subjects affected / exposed
    0 / 332 (0.00%)
    0 / 330 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 330 (0.30%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Prostatitis
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 330 (0.30%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    3 / 332 (0.90%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    2 / 332 (0.60%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hydrothorax
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 330 (0.30%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicidal ideation
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 330 (0.30%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Insomnia
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 330 (0.30%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 330 (0.30%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 332 (0.00%)
    0 / 330 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    3 / 332 (0.90%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 330 (0.30%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood glucose increased
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Bone contusion
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    2 / 332 (0.60%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 330 (0.30%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 330 (0.30%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arteriosclerosis coronary artery
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 330 (0.30%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 332 (0.00%)
    0 / 330 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Epilepsy
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic encephalopathy
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myasthenia gravis
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Immune-mediated encephalitis
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombotic microangiopathy
         subjects affected / exposed
    0 / 332 (0.00%)
    0 / 330 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 332 (0.00%)
    0 / 330 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Deafness neurosensory
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 332 (0.00%)
    2 / 330 (0.61%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uveitis
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retinal tear
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 330 (0.30%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal wall mass
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal hernia
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 330 (0.30%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 332 (0.60%)
    1 / 330 (0.30%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anal haemorrhage
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    3 / 332 (0.90%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    2 / 332 (0.60%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer haemorrhage
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anal fistula
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal perforation
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Proctitis
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal varices haemorrhage
         subjects affected / exposed
    5 / 332 (1.51%)
    2 / 330 (0.61%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    5 / 6
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    1 / 332 (0.30%)
    1 / 330 (0.30%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intra-abdominal haematoma
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 330 (0.30%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Incarcerated inguinal hernia
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 332 (0.00%)
    0 / 330 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Varices oesophageal
         subjects affected / exposed
    2 / 332 (0.60%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Acute hepatic failure
         subjects affected / exposed
    2 / 332 (0.60%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bile duct stone
         subjects affected / exposed
    0 / 332 (0.00%)
    3 / 330 (0.91%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bile duct stenosis
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 330 (0.30%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Portal vein thrombosis
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 330 (0.30%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune-mediated hepatitis
         subjects affected / exposed
    2 / 332 (0.60%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 330 (0.30%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholangitis acute
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 330 (0.30%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Pyoderma gangrenosum
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tubulointerstitial nephritis
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Proteinuria
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Calculus bladder
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 330 (0.30%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephrotic syndrome
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypopituitarism
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Foot deformity
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 332 (0.30%)
    1 / 330 (0.30%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Acute sinusitis
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    4 / 332 (1.20%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 330 (0.30%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Implant site infection
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed
    1 / 332 (0.30%)
    1 / 330 (0.30%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meningitis bacterial
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Otitis media
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Periodontitis
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    2 / 332 (0.60%)
    1 / 330 (0.30%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Post procedural sepsis
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Type 2 diabetes mellitus
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 330 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Arm A (Atezolizumab plus Bevacizumab) Arm B (Active Surveillance) Crossover: Atezolizumab + Bevacizumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    296 / 332 (89.16%)
    111 / 330 (33.64%)
    63 / 81 (77.78%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    126 / 332 (37.95%)
    10 / 330 (3.03%)
    25 / 81 (30.86%)
         occurrences all number
    157
    11
    28
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    28 / 332 (8.43%)
    4 / 330 (1.21%)
    5 / 81 (6.17%)
         occurrences all number
    31
    4
    5
    Pyrexia
         subjects affected / exposed
    33 / 332 (9.94%)
    7 / 330 (2.12%)
    6 / 81 (7.41%)
         occurrences all number
    41
    7
    7
    Oedema peripheral
         subjects affected / exposed
    18 / 332 (5.42%)
    2 / 330 (0.61%)
    1 / 81 (1.23%)
         occurrences all number
    20
    2
    3
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    22 / 332 (6.63%)
    7 / 330 (2.12%)
    1 / 81 (1.23%)
         occurrences all number
    22
    7
    1
    Epistaxis
         subjects affected / exposed
    20 / 332 (6.02%)
    1 / 330 (0.30%)
    6 / 81 (7.41%)
         occurrences all number
    23
    1
    6
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    33 / 332 (9.94%)
    23 / 330 (6.97%)
    7 / 81 (8.64%)
         occurrences all number
    59
    30
    8
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    17 / 332 (5.12%)
    5 / 330 (1.52%)
    3 / 81 (3.70%)
         occurrences all number
    26
    5
    4
    Lymphocyte count decreased
         subjects affected / exposed
    22 / 332 (6.63%)
    6 / 330 (1.82%)
    2 / 81 (2.47%)
         occurrences all number
    37
    7
    3
    Aspartate aminotransferase increased
         subjects affected / exposed
    51 / 332 (15.36%)
    18 / 330 (5.45%)
    13 / 81 (16.05%)
         occurrences all number
    67
    18
    16
    Alanine aminotransferase increased
         subjects affected / exposed
    46 / 332 (13.86%)
    18 / 330 (5.45%)
    12 / 81 (14.81%)
         occurrences all number
    58
    19
    16
    Neutrophil count decreased
         subjects affected / exposed
    29 / 332 (8.73%)
    8 / 330 (2.42%)
    5 / 81 (6.17%)
         occurrences all number
    60
    12
    5
    Platelet count decreased
         subjects affected / exposed
    66 / 332 (19.88%)
    22 / 330 (6.67%)
    17 / 81 (20.99%)
         occurrences all number
    101
    27
    19
    Weight increased
         subjects affected / exposed
    17 / 332 (5.12%)
    11 / 330 (3.33%)
    0 / 81 (0.00%)
         occurrences all number
    26
    12
    0
    White blood cell count decreased
         subjects affected / exposed
    28 / 332 (8.43%)
    10 / 330 (3.03%)
    3 / 81 (3.70%)
         occurrences all number
    76
    13
    4
    Nervous system disorders
    Headache
         subjects affected / exposed
    19 / 332 (5.72%)
    6 / 330 (1.82%)
    2 / 81 (2.47%)
         occurrences all number
    23
    6
    3
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    12 / 332 (3.61%)
    4 / 330 (1.21%)
    5 / 81 (6.17%)
         occurrences all number
    12
    4
    8
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    29 / 332 (8.73%)
    10 / 330 (3.03%)
    4 / 81 (4.94%)
         occurrences all number
    38
    11
    4
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    40 / 332 (12.05%)
    3 / 330 (0.91%)
    6 / 81 (7.41%)
         occurrences all number
    45
    3
    7
    Rash
         subjects affected / exposed
    40 / 332 (12.05%)
    1 / 330 (0.30%)
    9 / 81 (11.11%)
         occurrences all number
    44
    1
    9
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    21 / 332 (6.33%)
    2 / 330 (0.61%)
    3 / 81 (3.70%)
         occurrences all number
    34
    2
    3
    Proteinuria
         subjects affected / exposed
    153 / 332 (46.08%)
    12 / 330 (3.64%)
    25 / 81 (30.86%)
         occurrences all number
    227
    14
    29
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    47 / 332 (14.16%)
    1 / 330 (0.30%)
    9 / 81 (11.11%)
         occurrences all number
    49
    1
    9
    Hyperthyroidism
         subjects affected / exposed
    21 / 332 (6.33%)
    0 / 330 (0.00%)
    4 / 81 (4.94%)
         occurrences all number
    21
    0
    5
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    40 / 332 (12.05%)
    8 / 330 (2.42%)
    8 / 81 (9.88%)
         occurrences all number
    43
    9
    9
    Myalgia
         subjects affected / exposed
    32 / 332 (9.64%)
    1 / 330 (0.30%)
    1 / 81 (1.23%)
         occurrences all number
    39
    1
    1
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    25 / 332 (7.53%)
    9 / 330 (2.73%)
    1 / 81 (1.23%)
         occurrences all number
    27
    11
    1
    Metabolism and nutrition disorders
    Hypoalbuminaemia
         subjects affected / exposed
    21 / 332 (6.33%)
    2 / 330 (0.61%)
    0 / 81 (0.00%)
         occurrences all number
    32
    2
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Dec 2019
    Protocol was amended to include combining three of the previous stratification factors and restructured to combine high-risk features, curative procedures, and adjuvant TACE into one stratification factor with 5 strata. IRF and investigator-assessed RFS rate at 24 and 36 months after randomization was added as a secondary endpoint. An exclusion criterion was added to clarify that participants who have more than one treatment with TACE were excluded from the study. The list of atezolizumab risks was updated to include myositis. SIA was replaced by HLH and MAS in the list of potential risks for atezolizumab and the management guidelines for SIA were replaced with management guidelines for HLH and MAS.
    03 Dec 2020
    Protocol was amended to include treatment language to allow participants to receive up to 17 cycles of treatment even if this extended beyond 12 months. Exclusion criteria was amended with co-infection with HBV and hepatitis D virus was not allowed. Language in exclusion criteria was updated regarding use of anticoagulants to address the risk of upper gastrointestinal bleeding in patients with HCC. Lists of identified risks for atezolizumab was revised to include severe cutaneous adverse reactions. All identified risks related to bevacizumab was added.
    30 Nov 2021
    Protocol was amended to include language to indicate that bevacizumab should be held in the event that atezolizumab was held for an Adverse Event during both the treatment period and the crossover period. Details of the OS analyses including the estimated number of events expected at the interim and final analyses and the efficacy boundaries that will be used have been added for completeness.
    25 Oct 2022
    Protocol has been amended to include pericardial disorders in the list of identified risks for atezolizumab.
    23 Mar 2023
    Protocol has been amended to include revision to the list of identified risks for atezolizumab to include myelitis and facial paresis. Hemophagocytic lymphohistiocytosis has been updated from a potential risk to an identified risk associated with atezolizumab and language has been revised accordingly.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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