Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register   allows you to search for protocol and results information on:
  • interventional clinical trials that were approved in the European Union (EU)/European Economic Area (EEA) under the Clinical Trials Directive 2001/20/EC
  • clinical trials conducted outside the EU/EEA that are linked to European paediatric-medicine development

    • EU/EEA interventional clinical trials approved under or transitioned to the Clinical Trial Regulation 536/2014 are publicly accessible through the
    Clinical Trials Information System (CTIS).

    The EU Clinical Trials Register currently displays   44334   clinical trials with a EudraCT protocol, of which   7366   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

    Phase 1 trials conducted solely on adults and that are not part of an agreed paediatric investigation plan (PIP) are not publicly available (see Frequently Asked Questions ).  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    A Randomized, Multi-center Phase III Study of Nivolumab Versus Sorafenib as First-Line Treatment in Patients With Advanced Hepatocellular Carcinoma (CheckMate 459: CHECKpoint Pathway and nivoluMAb Clinical Trial Evaluation 459)

    Summary
    EudraCT number
    		 2015-002740-13
    Trial protocol
    		 DE   AT   CZ   GB   SE   FR   ES   PL   IT  
    Global end of trial date
    07 Feb 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 Feb 2025
    First version publication date
    09 Feb 2025
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CA209-459
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02576509
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bristol-Myers Squibb
    Sponsor organisation address
    Chaussée de la Hulpe 185, Brussels, Belgium,
    Public contact
    EU Study Start-Up Unit, Bristol-Myers Squibb International Corporation, clinical.trials@bms.com
    Scientific contact
    EU Study Start-Up Unit, Bristol-Myers Squibb International Corporation, Clinical.Trials@bms.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
    14 Mar 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Feb 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is to determine if nivolumab or sorafenib is more effective in the treatment of Advanced Hepatocellular Carcinoma.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial participants were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 Dec 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy, Safety
    Long term follow-up duration
    		 5 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 21
    Country: Number of subjects enrolled
    Austria: 14
    Country: Number of subjects enrolled
    Belgium: 4
    Country: Number of subjects enrolled
    Canada: 11
    Country: Number of subjects enrolled
    China: 22
    Country: Number of subjects enrolled
    Czechia: 12
    Country: Number of subjects enrolled
    France: 112
    Country: Number of subjects enrolled
    Germany: 59
    Country: Number of subjects enrolled
    Hong Kong: 42
    Country: Number of subjects enrolled
    Israel: 8
    Country: Number of subjects enrolled
    Italy: 30
    Country: Number of subjects enrolled
    Japan: 107
    Country: Number of subjects enrolled
    Poland: 28
    Country: Number of subjects enrolled
    Russian Federation: 12
    Country: Number of subjects enrolled
    Singapore: 20
    Country: Number of subjects enrolled
    Korea, Republic of: 75
    Country: Number of subjects enrolled
    Spain: 13
    Country: Number of subjects enrolled
    Sweden: 7
    Country: Number of subjects enrolled
    Switzerland: 13
    Country: Number of subjects enrolled
    Taiwan: 29
    Country: Number of subjects enrolled
    United Kingdom: 16
    Country: Number of subjects enrolled
    United States: 88
    Worldwide total number of subjects
    743
    EEA total number of subjects
    279
    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)
    361
    From 65 to 84 years
    377
    85 years and over
    5

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Participants were enrolled in 22 countries.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Nivolumab 240 mg
    Arm description
    		 Nivolumab 240 mg IV every 2 weeks until disease progression or unacceptable toxicity
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    240 mg every 2 weeks

    Arm title
    		 Sorafenib 400 mg
    Arm description
    		 Sorafenib 400 mg PO BID until disease progression or unacceptable toxicity
    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
    400 mg PO twice a day

    Number of subjects in period 1
    		Nivolumab 240 mg Sorafenib 400 mg
    Started
    371
    372
    Completed
    367
    363
    Not completed
    4
    9
         Participant withdrew consent
    1
    5
         Participant no longer meets criteria
    3
    2
         Participant request to stop therapy
    -
    2
    Period 2
    Period 2 title
    Treatment Period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Nivolumab 240 mg
    Arm description
    		 Nivolumab 240 mg IV every 2 weeks until disease progression or unacceptable toxicity
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    240 mg every 2 weeks

    Arm title
    		 Sorafenib 400 mg
    Arm description
    		 Sorafenib 400 mg PO BID until disease progression or unacceptable toxicity
    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
    400 mg PO twice a day

    Number of subjects in period 2
    		Nivolumab 240 mg Sorafenib 400 mg
    Started
    367
    363
    Completed
    0
    0
    Not completed
    367
    363
         Adverse event, serious fatal
    1
    1
         Disease progression
    263
    244
         Participant request to stop treatment
    8
    18
         Participant withdrew consent
    3
    7
         Maximum clinical benefit
    1
    -
         Other reason
    12
    8
         Participant no longer meets criteria
    1
    -
         Study drug toxicity
    37
    41
         NOT REPORTED
    1
    -
         Adverse event unrelated to study drug
    39
    41
         Lost to follow-up
    -
    1
         Poor/non-compliance
    1
    1
         Administrative reason by sponsor
    -
    1

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Nivolumab 240 mg
    Reporting group description
    		 Nivolumab 240 mg IV every 2 weeks until disease progression or unacceptable toxicity

    Reporting group title
    Sorafenib 400 mg
    Reporting group description
    		 Sorafenib 400 mg PO BID until disease progression or unacceptable toxicity

    Reporting group values
    		 Nivolumab 240 mg Sorafenib 400 mg Total
    Number of subjects
    		 371 372 743
    Age Categorical
    Units: Participants
        <=18 years
    		 0 0 0
        Between 18 and 65 years
    		 185 176 361
        >=65 years
    		 186 196 382
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 63.9 ( 10.61 ) 64.5 ( 10.91 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 57 55 112
        Male
    		 314 317 631
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 1 1
        Asian
    		 165 167 332
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 3 2 5
        White
    		 199 196 395
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 4 6 10
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 5 10 15
        Not Hispanic or Latino
    		 180 170 350
        Unknown or Not Reported
    		 186 192 378

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Nivolumab 240 mg
    Reporting group description
    		 Nivolumab 240 mg IV every 2 weeks until disease progression or unacceptable toxicity

    Reporting group title
    Sorafenib 400 mg
    Reporting group description
    		 Sorafenib 400 mg PO BID until disease progression or unacceptable toxicity
    Reporting group title
    Nivolumab 240 mg
    Reporting group description
    		 Nivolumab 240 mg IV every 2 weeks until disease progression or unacceptable toxicity

    Reporting group title
    Sorafenib 400 mg
    Reporting group description
    		 Sorafenib 400 mg PO BID until disease progression or unacceptable toxicity

    Primary: Overall Survival (OS)

    		 Close Top of page
    End point title
    		 Overall Survival (OS)
    End point description
    OS is defined as the time from the date of randomization to the date of death due to any cause in all randomized participants. Participants who are alive will be censored at the last known alive dates. Based on Kaplan-Meier Estimates.
    End point type
    Primary
    End point timeframe
    time from the date of randomization to the date of death due to any cause, assessed up to June 2019 (approximately 41 months)
    End point values
    		 Nivolumab 240 mg Sorafenib 400 mg
    Number of subjects analysed
    371
    372
    Units: Months
        median (confidence interval 95%)
    16.39 (13.93 to 18.37)
    14.69 (11.89 to 17.22)
    Statistical analysis title
    		 Statisitical Analysis 1
    Comparison groups
    Nivolumab 240 mg v Sorafenib 400 mg
    Number of subjects included in analysis
    743
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0752 [1]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.71
         upper limit
    		 1.02
    Notes
    [1] - A priori threshold for statistical significance is 0.0419

    Secondary: Objective Response Rate (ORR) per BICR RECIST 1.1

    		 Close Top of page
    End point title
    		 Objective Response Rate (ORR) per BICR RECIST 1.1
    End point description
    ORR is defined as the proportion of participants whose best overall response (BOR) is either a complete response (CR) or partial response (PR). BOR is defined as the best response designation, as determined based on BICR-assessed tumor response according to RECIST 1.1, recorded between the date of randomization and the date of first objectively documented progression or the date of subsequent anti-cancer therapy, whichever occurs first. For participants without documented progression or subsequent anti-cancer therapy, all available response designations will contribute to the BOR determination. For a BOR of CR or PR, the initial response assessment must be confirmed by a consecutive assessment no less than 4 weeks (28 days) later. Estimate of (Nivolumab - Sorafenib) is based on CMH method of weighting, stratified by stratification factors
    End point type
    Secondary
    End point timeframe
    the date of randomization and the date of first objectively documented progression or the date of subsequent anti-cancer therapy, whichever occurs first, assessed up to May 2019 (approximately 40 months)
    End point values
    		 Nivolumab 240 mg Sorafenib 400 mg
    Number of subjects analysed
    371
    372
    Units: Percentage of participants
        number (confidence interval 95%)
    15.4 (11.8 to 19.4)
    7.0 (4.6 to 10.1)
    Statistical analysis title
    		 Statisitical Analysis 2
    Comparison groups
    Nivolumab 240 mg v Sorafenib 400 mg
    Number of subjects included in analysis
    743
    Analysis specification
    Pre-specified
    Analysis type
    		 [2]
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.41
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.48
         upper limit
    		 3.92
    Notes
    [2] - no test was performed due to OS p-value result above the prior threshold
    Statistical analysis title
    		 Statisitical Analysis 1
    Comparison groups
    Nivolumab 240 mg v Sorafenib 400 mg
    Number of subjects included in analysis
    743
    Analysis specification
    Pre-specified
    Analysis type
    		 [3]
    Method
    Parameter type
    		 Difference of ORRs
    Point estimate
    8.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.9
         upper limit
    		 12.7
    Notes
    [3] - no test was performed due to OS p-value result above the prior threshold

    Secondary: Progression-Free Survival (PFS)

    		 Close Top of page
    End point title
    		 Progression-Free Survival (PFS)
    End point description
    PFS is defined as the time from the date of randomization to the date of the first objectively documented tumor progression as assessed by BICR according to RECIST 1.1 or death due to any cause in all randomized participants. Participants who die without a reported prior progression and without initiation of subsequent anti-cancer therapy will be considered to have progressed on the date of their death. Participants who did not progress or die will be censored on the date of their last tumor assessment. Participants who did not have baseline tumor assessment will be censored on the date they were randomized. Participants who did not have any on study tumor assessments and did not die will be censored on the date they were randomized. Participants who started any subsequent anti-cancer therapy without a prior reported progression will be censored at the last tumor assessment prior to subsequent anti-cancer therapy.
    End point type
    Secondary
    End point timeframe
    time from the date of randomization to the date of the first objectively documented tumor progression or death, assessed up to May 2019 (approximately 40 months)
    End point values
    		 Nivolumab 240 mg Sorafenib 400 mg
    Number of subjects analysed
    371
    372
    Units: Months
        median (confidence interval 95%)
    3.68 (3.06 to 3.88)
    3.75 (3.71 to 4.47)
    Statistical analysis title
    		 Statisitical Analysis 1
    Comparison groups
    Nivolumab 240 mg v Sorafenib 400 mg
    Number of subjects included in analysis
    743
    Analysis specification
    Pre-specified
    Analysis type
    		 [4]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.79
         upper limit
    		 1.1
    Notes
    [4] - no test was performed due to OS p-value result above the prior threshold

    Secondary: Efficacy based on PD-L1 expression - OS and PFS

    		 Close Top of page
    End point title
    		 Efficacy based on PD-L1 expression - OS and PFS
    End point description
    PD-L1 expression is defined as the percent of tumor cell membrane staining in a minimum of 100 evaluable tumor cells per Dako PD-L1 IHC assay unless otherwise specified. This is referred as quantifiable PD-L1 expression. If the PD-L1 staining could not be quantified, it is further classifies as: Indeterminate: Tumor cell membrane staining hampered for reasons attributed to the biology of the tumor biopsy specimen and not because of improper sample preparation or handling. Not evaluable: Tumor biopsy specimen was not optimally collected or prepared (e.g. PD-L1 expression is neither quantifiable nor indeterminate). PD-L1 status is a dichotomized variable using an X% cut-off for quantifiable PD-L1 expression: • PD-L1 > X %: ≥ X % PD-L1 expression • PD-L1 < X %: < X % PD-L1 expression where X% denotes the PD-L1 expression cut-off of 1%. Additional cut off values may also be explored. Confidence interval based on the Clopper and Pearson method.
    End point type
    Secondary
    End point timeframe
    the date of randomization and the date of first objectively documented progression or the date of subsequent anti-cancer therapy, whichever occurs first, assessed up to May 2019 (approximately 40 months)
    End point values
    		 Nivolumab 240 mg Sorafenib 400 mg
    Number of subjects analysed
    371
    372
    Units: Months
    median (confidence interval 95%)
        >=1%, OS
    16.07 (8.41 to 22.34)
    8.62 (5.72 to 16.30)
        >=1%, PFS
    3.84 (2.10 to 7.62)
    3.58 (1.97 to 5.36)
        <1%, OS
    16.72 (13.93 to 18.56)
    15.24 (12.58 to 18.10)
        <1%, PFS
    3.61 (2.43 to 3.81)
    3.75 (3.71 to 5.32)
        without PD-L1 quantifiable, OS
    16.23 (5.82 to 99999)
    22.05 (1.77 to 99999)
        without PD-L1 quantifiable, PFS
    2.00 (1.87 to 99999)
    6.13 (1.08 to 11.17)
    Statistical analysis title
    		 Statisitical Analysis 1
    Comparison groups
    Nivolumab 240 mg v Sorafenib 400 mg
    Number of subjects included in analysis
    743
    Analysis specification
    Pre-specified
    Analysis type
    		 [5]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.54
         upper limit
    		 1.19
    Notes
    [5] - PD-L1 >= 1%, OS; no test was performed
    Statistical analysis title
    		 Statisitical Analysis 2
    Comparison groups
    Nivolumab 240 mg v Sorafenib 400 mg
    Number of subjects included in analysis
    743
    Analysis specification
    Pre-specified
    Analysis type
    		 [6]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.48
         upper limit
    		 1.03
    Notes
    [6] - PD-L1 >=1%, PFS; no test was performed
    Statistical analysis title
    		 Statisitical Analysis 3
    Comparison groups
    Nivolumab 240 mg v Sorafenib 400 mg
    Number of subjects included in analysis
    743
    Analysis specification
    Pre-specified
    Analysis type
    		 [7]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.69
         upper limit
    		 1.02
    Notes
    [7] - PD-L1 <1%, OS; no test was performed
    Statistical analysis title
    		 Statisitical Analysis 4
    Comparison groups
    Nivolumab 240 mg v Sorafenib 400 mg
    Number of subjects included in analysis
    743
    Analysis specification
    Pre-specified
    Analysis type
    		 [8]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.81
         upper limit
    		 1.17
    Notes
    [8] - PD-L1 <1%, PFS; no test was performed
    Statistical analysis title
    		 Statisitical Analysis 5
    Comparison groups
    Nivolumab 240 mg v Sorafenib 400 mg
    Number of subjects included in analysis
    743
    Analysis specification
    Pre-specified
    Analysis type
    		 [9]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.34
         upper limit
    		 4.74
    Notes
    [9] - without PD-L1 quantifiable, OS; no test was performed
    Statistical analysis title
    		 Statisitical Analysis 5
    Comparison groups
    Nivolumab 240 mg v Sorafenib 400 mg
    Number of subjects included in analysis
    743
    Analysis specification
    Pre-specified
    Analysis type
    		 [10]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.27
         upper limit
    		 3.52
    Notes
    [10] - without PD-L1 quantifiable, PFS; no test was performed

    Secondary: Efficacy based on PD-L1 expression - ORR

    		 Close Top of page
    End point title
    		 Efficacy based on PD-L1 expression - ORR
    End point description
    PD-L1 expression is defined as the percent of tumor cell membrane staining in a minimum of 100 evaluable tumor cells per Dako PD-L1 IHC assay unless otherwise specified. This is referred as quantifiable PD-L1 expression. If the PD-L1 staining could not be quantified, it is further classifies as: Indeterminate: Tumor cell membrane staining hampered for reasons attributed to the biology of the tumor biopsy specimen and not because of improper sample preparation or handling. Not evaluable: Tumor biopsy specimen was not optimally collected or prepared (e.g. PD-L1 expression is neither quantifiable nor indeterminate). PD-L1 status is a dichotomized variable using an X% cut-off for quantifiable PD-L1 expression: • PD-L1 > X %: ≥ X % PD-L1 expression • PD-L1 < X %: < X % PD-L1 expression where X% denotes the PD-L1 expression cut-off of 1%. Additional cut off values may also be explored. Confidence interval based on the Clopper and Pearson method.
    End point type
    Secondary
    End point timeframe
    the date of randomization and the date of first objectively documented progression or the date of subsequent anti-cancer therapy, whichever occurs first, assessed up to May 2019 (approximately 40 months)
    End point values
    		 Nivolumab 240 mg Sorafenib 400 mg
    Number of subjects analysed
    371
    372
    Units: Percentage of participants
    number (confidence interval 95%)
        >=1%, ORR
    28.2 (18.1 to 40.1)
    9.4 (3.5 to 19.3)
        <1%, ORR
    12.2 (8.7 to 16.5)
    6.7 (4.1 to 10.1)
        without PD-L1 quantifiable, ORR
    20.0 (0.5 to 71.6)
    0.0 (0.0 to 36.9)
    Statistical analysis title
    		 Statisitical Analysis 2
    Comparison groups
    Nivolumab 240 mg v Sorafenib 400 mg
    Number of subjects included in analysis
    743
    Analysis specification
    Pre-specified
    Analysis type
    		 [11]
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.1
         upper limit
    		 3.45
    Notes
    [11] - PD-L1 <1%, ORR; no test was performed
    Statistical analysis title
    		 Statisitical Analysis 1
    Comparison groups
    Nivolumab 240 mg v Sorafenib 400 mg
    Number of subjects included in analysis
    743
    Analysis specification
    Pre-specified
    Analysis type
    		 [12]
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.41
         upper limit
    		 10.17
    Notes
    [12] - PD-L1 >=1%, ORR; no test was performed

    Adverse events

    		 Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    Serious and non-serious adverse events were collected from first dose till 100 days after last dose of study therapy (up to approximately 95 months).
    Adverse event reporting additional description
    All cause mortality, serious and non serious adverse events were collected for all participants who received at least one dose of the study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.1
    Reporting groups
    Reporting group title
    Sorafenib 400 mg
    Reporting group description
    		 Sorafenib 400 mg PO BID until disease progression or unacceptable toxicity

    Reporting group title
    Nivolumab 240 mg
    Reporting group description
    		 Nivolumab 240 mg IV every 2 weeks until disease progression or unacceptable toxicity

    Serious adverse events
    		 Sorafenib 400 mg Nivolumab 240 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    216 / 363 (59.50%)
    216 / 367 (58.86%)
         number of deaths (all causes)
    329
    319
         number of deaths resulting from adverse events
    105
    99
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Hepatocellular carcinoma
         subjects affected / exposed
    2 / 363 (0.55%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cancer pain
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver carcinoma ruptured
         subjects affected / exposed
    2 / 363 (0.55%)
    4 / 367 (1.09%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Malignant neoplasm progression
         subjects affected / exposed
    70 / 363 (19.28%)
    69 / 367 (18.80%)
         occurrences causally related to treatment / all
    0 / 71
    2 / 70
         deaths causally related to treatment / all
    0 / 64
    0 / 55
    Neoplasm malignant
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to liver
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to spinal cord
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to bone
         subjects affected / exposed
    0 / 363 (0.00%)
    2 / 367 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Rectal adenocarcinoma
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    4 / 363 (1.10%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    1 / 363 (0.28%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour thrombosis
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour associated fever
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Bleeding varicose vein
         subjects affected / exposed
    1 / 363 (0.28%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Aneurysm ruptured
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Surgical and medical procedures
    Assisted suicide
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    3 / 363 (0.83%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Catheter site related reaction
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    2 / 363 (0.55%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Chest discomfort
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypothermia
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    General physical health deterioration
         subjects affected / exposed
    14 / 363 (3.86%)
    8 / 367 (2.18%)
         occurrences causally related to treatment / all
    0 / 14
    0 / 8
         deaths causally related to treatment / all
    0 / 11
    0 / 5
    Fatigue
         subjects affected / exposed
    4 / 363 (1.10%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    1 / 4
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pain
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Performance status decreased
         subjects affected / exposed
    1 / 363 (0.28%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 363 (0.00%)
    3 / 367 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Pyrexia
         subjects affected / exposed
    7 / 363 (1.93%)
    8 / 367 (2.18%)
         occurrences causally related to treatment / all
    3 / 8
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza like illness
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    1 / 363 (0.28%)
    2 / 367 (0.54%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nasal ulcer
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung consolidation
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 363 (0.00%)
    2 / 367 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atelectasis
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Agonal respiration
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 363 (0.55%)
    2 / 367 (0.54%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Respiratory failure
         subjects affected / exposed
    1 / 363 (0.28%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary mass
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    3 / 363 (0.83%)
    2 / 367 (0.54%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 363 (0.00%)
    4 / 367 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    6 / 7
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Pleurisy
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Suicide attempt
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 363 (0.28%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical condition abnormal
         subjects affected / exposed
    0 / 363 (0.00%)
    3 / 367 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza A virus test positive
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test increased
         subjects affected / exposed
    0 / 363 (0.00%)
    2 / 367 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Occult blood positive
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Exposure to communicable disease
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fracture
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hepatic rupture
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periprosthetic fracture
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    0 / 363 (0.00%)
    3 / 367 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meniscus injury
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    2 / 363 (0.55%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 363 (0.28%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 363 (0.28%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Subdural haemorrhage
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Upper limb fracture
         subjects affected / exposed
    1 / 363 (0.28%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic valve incompetence
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Atrial fibrillation
         subjects affected / exposed
    0 / 363 (0.00%)
    5 / 367 (1.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 363 (0.00%)
    2 / 367 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Myocardial infarction
         subjects affected / exposed
    1 / 363 (0.28%)
    3 / 367 (0.82%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Coronary artery disease
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Ataxia
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Altered state of consciousness
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 363 (0.00%)
    3 / 367 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cerebral infarction
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    3 / 363 (0.83%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Headache
         subjects affected / exposed
    2 / 363 (0.55%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    4 / 363 (1.10%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 363 (0.28%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Cognitive disorder
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic encephalopathy
         subjects affected / exposed
    6 / 363 (1.65%)
    6 / 367 (1.63%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 6
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    Hypoglycaemic coma
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Middle cerebral artery stroke
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Neuritis
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant spinal cord compression
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Transient ischaemic attack
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    6 / 363 (1.65%)
    8 / 367 (2.18%)
         occurrences causally related to treatment / all
    2 / 6
    2 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eyelid function disorder
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glaucoma
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal artery occlusion
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal vascular disorder
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Abdominal pain
         subjects affected / exposed
    11 / 363 (3.03%)
    7 / 367 (1.91%)
         occurrences causally related to treatment / all
    1 / 11
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Abdominal pain lower
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    5 / 363 (1.38%)
    2 / 367 (0.54%)
         occurrences causally related to treatment / all
    1 / 6
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    7 / 363 (1.93%)
    9 / 367 (2.45%)
         occurrences causally related to treatment / all
    0 / 9
    1 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Colitis
         subjects affected / exposed
    0 / 363 (0.00%)
    5 / 367 (1.36%)
         occurrences causally related to treatment / all
    0 / 0
    6 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diaphragmatic hernia
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 363 (0.28%)
    5 / 367 (1.36%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal fistula
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric varices
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenitis haemorrhagic
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulum intestinal
         subjects affected / exposed
    0 / 363 (0.00%)
    2 / 367 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    2 / 363 (0.55%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal perforation
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastrointestinal haemorrhage
         subjects affected / exposed
    6 / 363 (1.65%)
    7 / 367 (1.91%)
         occurrences causally related to treatment / all
    2 / 8
    0 / 9
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Gastrointestinal disorder
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal varices haemorrhage
         subjects affected / exposed
    8 / 363 (2.20%)
    4 / 367 (1.09%)
         occurrences causally related to treatment / all
    1 / 8
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Oesophageal haemorrhage
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 363 (0.55%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 363 (0.28%)
    3 / 367 (0.82%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intra-abdominal haemorrhage
         subjects affected / exposed
    1 / 363 (0.28%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 363 (0.83%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Varices oesophageal
         subjects affected / exposed
    2 / 363 (0.55%)
    3 / 367 (0.82%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    6 / 363 (1.65%)
    3 / 367 (0.82%)
         occurrences causally related to treatment / all
    2 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Stomatitis
         subjects affected / exposed
    0 / 363 (0.00%)
    2 / 367 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Acute hepatic failure
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cholangitis
         subjects affected / exposed
    4 / 363 (1.10%)
    4 / 367 (1.09%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biloma
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary obstruction
         subjects affected / exposed
    1 / 363 (0.28%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary dilatation
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bile duct stenosis
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Autoimmune hepatitis
         subjects affected / exposed
    0 / 363 (0.00%)
    2 / 367 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    2 / 363 (0.55%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    2 / 363 (0.55%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hepatic failure
         subjects affected / exposed
    7 / 363 (1.93%)
    10 / 367 (2.72%)
         occurrences causally related to treatment / all
    2 / 7
    2 / 11
         deaths causally related to treatment / all
    1 / 6
    2 / 6
    Hepatic cirrhosis
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemobilia
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholestasis
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic haemorrhage
         subjects affected / exposed
    1 / 363 (0.28%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertransaminasaemia
         subjects affected / exposed
    0 / 363 (0.00%)
    2 / 367 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Immune-mediated hepatic disorder
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune-mediated hepatitis
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic lesion
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatocellular injury
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hepatorenal syndrome
         subjects affected / exposed
    3 / 363 (0.83%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    2 / 363 (0.55%)
    4 / 367 (1.09%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    0 / 363 (0.00%)
    3 / 367 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Jaundice cholestatic
         subjects affected / exposed
    1 / 363 (0.28%)
    2 / 367 (0.54%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Liver injury
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Portal vein thrombosis
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Skin and subcutaneous tissue disorders
    Blister
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukoplakia
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkeratosis
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erythema multiforme
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    2 / 363 (0.55%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatitis bullous
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Purpura
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pruritus
         subjects affected / exposed
    1 / 363 (0.28%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug reaction with eosinophilia and systemic symptoms
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin reaction
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stevens-Johnson syndrome
         subjects affected / exposed
    0 / 363 (0.00%)
    2 / 367 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxic epidermal necrolysis
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    0 / 363 (0.00%)
    2 / 367 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash erythematous
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    2 / 363 (0.55%)
    2 / 367 (0.54%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    5 / 363 (1.38%)
    2 / 367 (0.54%)
         occurrences causally related to treatment / all
    3 / 5
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic nephropathy
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 363 (0.28%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 363 (0.28%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    0 / 363 (0.00%)
    2 / 367 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypophysitis
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthropathy
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 363 (0.28%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    2 / 363 (0.55%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint swelling
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc compression
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc degeneration
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fistula
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 363 (0.00%)
    3 / 367 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Anal abscess
         subjects affected / exposed
    2 / 363 (0.55%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess limb
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal infection
         subjects affected / exposed
    2 / 363 (0.55%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain abscess
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Biliary tract infection
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary sepsis
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial infection
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 363 (0.28%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia bacteraemia
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 363 (0.00%)
    3 / 367 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epididymitis
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cellulitis
         subjects affected / exposed
    2 / 363 (0.55%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Genitourinary tract infection
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infective exacerbation of chronic obstructive airways disease
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 363 (0.28%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected lymphocele
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma infection
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella sepsis
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed
    2 / 363 (0.55%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 363 (0.00%)
    2 / 367 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis bacterial
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    2 / 363 (0.55%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Perirectal abscess
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis acute
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia mycoplasmal
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia klebsiella
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 363 (1.10%)
    6 / 367 (1.63%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhinovirus infection
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 363 (0.55%)
    7 / 367 (1.91%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 7
         deaths causally related to treatment / all
    0 / 1
    0 / 6
    Tooth abscess
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spontaneous bacterial peritonitis
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    2 / 363 (0.55%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheitis
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 363 (0.28%)
    2 / 367 (0.54%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 363 (0.55%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral pharyngitis
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Virologic failure
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cell death
         subjects affected / exposed
    1 / 363 (0.28%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    4 / 363 (1.10%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    2 / 363 (0.55%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Failure to thrive
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fulminant type 1 diabetes mellitus
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 363 (0.00%)
    4 / 367 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic metabolic decompensation
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperlipasaemia
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 363 (0.00%)
    2 / 367 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hypokalaemia
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 367 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ketoacidosis
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lactic acidosis
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Sorafenib 400 mg Nivolumab 240 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    351 / 363 (96.69%)
    339 / 367 (92.37%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    85 / 363 (23.42%)
    33 / 367 (8.99%)
         occurrences all number
    97
    37
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    43 / 363 (11.85%)
    40 / 367 (10.90%)
         occurrences all number
    63
    52
    Fatigue
         subjects affected / exposed
    117 / 363 (32.23%)
    103 / 367 (28.07%)
         occurrences all number
    134
    131
    Pyrexia
         subjects affected / exposed
    58 / 363 (15.98%)
    71 / 367 (19.35%)
         occurrences all number
    71
    90
    Oedema peripheral
         subjects affected / exposed
    41 / 363 (11.29%)
    43 / 367 (11.72%)
         occurrences all number
    45
    49
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    47 / 363 (12.95%)
    45 / 367 (12.26%)
         occurrences all number
    53
    63
    Dyspnoea
         subjects affected / exposed
    23 / 363 (6.34%)
    27 / 367 (7.36%)
         occurrences all number
    24
    32
    Dysphonia
         subjects affected / exposed
    49 / 363 (13.50%)
    11 / 367 (3.00%)
         occurrences all number
    55
    11
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    31 / 363 (8.54%)
    32 / 367 (8.72%)
         occurrences all number
    31
    35
    Investigations
    Blood alkaline phosphatase increased
         subjects affected / exposed
    17 / 363 (4.68%)
    19 / 367 (5.18%)
         occurrences all number
    21
    20
    Aspartate aminotransferase increased
         subjects affected / exposed
    60 / 363 (16.53%)
    84 / 367 (22.89%)
         occurrences all number
    74
    108
    Amylase increased
         subjects affected / exposed
    14 / 363 (3.86%)
    26 / 367 (7.08%)
         occurrences all number
    23
    65
    Alanine aminotransferase increased
         subjects affected / exposed
    38 / 363 (10.47%)
    51 / 367 (13.90%)
         occurrences all number
    51
    57
    Blood bilirubin increased
         subjects affected / exposed
    48 / 363 (13.22%)
    41 / 367 (11.17%)
         occurrences all number
    62
    53
    Lipase increased
         subjects affected / exposed
    27 / 363 (7.44%)
    38 / 367 (10.35%)
         occurrences all number
    36
    80
    Weight decreased
         subjects affected / exposed
    68 / 363 (18.73%)
    34 / 367 (9.26%)
         occurrences all number
    78
    38
    Platelet count decreased
         subjects affected / exposed
    28 / 363 (7.71%)
    17 / 367 (4.63%)
         occurrences all number
    42
    19
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    14 / 363 (3.86%)
    23 / 367 (6.27%)
         occurrences all number
    14
    25
    Headache
         subjects affected / exposed
    33 / 363 (9.09%)
    24 / 367 (6.54%)
         occurrences all number
    39
    30
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    30 / 363 (8.26%)
    35 / 367 (9.54%)
         occurrences all number
    37
    36
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    22 / 363 (6.06%)
    15 / 367 (4.09%)
         occurrences all number
    26
    15
    Abdominal pain
         subjects affected / exposed
    82 / 363 (22.59%)
    69 / 367 (18.80%)
         occurrences all number
    97
    86
    Abdominal pain upper
         subjects affected / exposed
    50 / 363 (13.77%)
    42 / 367 (11.44%)
         occurrences all number
    57
    46
    Ascites
         subjects affected / exposed
    44 / 363 (12.12%)
    46 / 367 (12.53%)
         occurrences all number
    55
    51
    Constipation
         subjects affected / exposed
    52 / 363 (14.33%)
    50 / 367 (13.62%)
         occurrences all number
    68
    58
    Diarrhoea
         subjects affected / exposed
    191 / 363 (52.62%)
    100 / 367 (27.25%)
         occurrences all number
    363
    140
    Stomatitis
         subjects affected / exposed
    25 / 363 (6.89%)
    16 / 367 (4.36%)
         occurrences all number
    29
    21
    Nausea
         subjects affected / exposed
    70 / 363 (19.28%)
    62 / 367 (16.89%)
         occurrences all number
    90
    78
    Vomiting
         subjects affected / exposed
    40 / 363 (11.02%)
    36 / 367 (9.81%)
         occurrences all number
    51
    41
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    21 / 363 (5.79%)
    16 / 367 (4.36%)
         occurrences all number
    23
    17
    Alopecia
         subjects affected / exposed
    71 / 363 (19.56%)
    6 / 367 (1.63%)
         occurrences all number
    72
    7
    Rash
         subjects affected / exposed
    59 / 363 (16.25%)
    75 / 367 (20.44%)
         occurrences all number
    70
    98
    Erythema
         subjects affected / exposed
    31 / 363 (8.54%)
    5 / 367 (1.36%)
         occurrences all number
    37
    5
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    181 / 363 (49.86%)
    29 / 367 (7.90%)
         occurrences all number
    236
    30
    Pruritus
         subjects affected / exposed
    51 / 363 (14.05%)
    88 / 367 (23.98%)
         occurrences all number
    54
    115
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    12 / 363 (3.31%)
    29 / 367 (7.90%)
         occurrences all number
    12
    42
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    36 / 363 (9.92%)
    54 / 367 (14.71%)
         occurrences all number
    38
    64
    Back pain
         subjects affected / exposed
    33 / 363 (9.09%)
    38 / 367 (10.35%)
         occurrences all number
    34
    95
    Muscle spasms
         subjects affected / exposed
    29 / 363 (7.99%)
    16 / 367 (4.36%)
         occurrences all number
    37
    18
    Myalgia
         subjects affected / exposed
    12 / 363 (3.31%)
    19 / 367 (5.18%)
         occurrences all number
    12
    22
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    23 / 363 (6.34%)
    33 / 367 (8.99%)
         occurrences all number
    25
    48
    Upper respiratory tract infection
         subjects affected / exposed
    15 / 363 (4.13%)
    29 / 367 (7.90%)
         occurrences all number
    20
    42
    Metabolism and nutrition disorders
    Hypoalbuminaemia
         subjects affected / exposed
    31 / 363 (8.54%)
    19 / 367 (5.18%)
         occurrences all number
    38
    20
    Hyperglycaemia
         subjects affected / exposed
    8 / 363 (2.20%)
    21 / 367 (5.72%)
         occurrences all number
    8
    23
    Decreased appetite
         subjects affected / exposed
    135 / 363 (37.19%)
    77 / 367 (20.98%)
         occurrences all number
    167
    88
    Hypokalaemia
         subjects affected / exposed
    21 / 363 (5.79%)
    13 / 367 (3.54%)
         occurrences all number
    42
    16

    More information

    		 Close Top of page

    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Oct 2015
    Addition of collection of peripheral blood mononuclear cells (PBMCs) and myeloid derived suppressor cells (MDSCs) collected from subjects at baseline from selected sites, reduction of frequency of HCV RNA testing for HCV infected subjects, clarification of locoregional therapy inclusion criteria
    24 Aug 2016
    Updated Study Director/Medical Monitor information; Co-primary endpoint and objective changed from time to progression (TTP) to objective response rate (ORR); Added requirement for confirmatory scan to be performed for CR/PR assessment of best overall response (BOR); Management algorithms updated per revised nivolumab IB
    15 Aug 2017
    The purpose of this amendment is to change Overall Response Rate (ORR) from a co-primary objective to a secondary objective of the study. Overall Survival (OS) will be the sole Primary Endpoint of the study.
    15 Jan 2019
    The primary reason for this amendment is to update several protocol sections to reflect the most recent guidance for treating study participants with nivolumab. In addition, an exploratory objective evaluating the correlation of tumor inflammation with efficacy based on recent preliminary data has been added. Several minor inconsistencies in study objectives and endpoints and minor administrative changes are also addressed.

    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
    For support, Contact us.
    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.

    European Medicines Agency © 1995-Fri May 02 19:06:21 CEST 2025 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    EMA HMA