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    Clinical Trial Results:
    A Randomized, Double-blind, Multi-center Phase III Study of Brivanib plus Best Supportive Care (BSC) Versus Placebo plus BSC in Subjects with Advanced Hepatocellular Carcinoma (HCC) Who Have Failed or Are Intolerant to Sorafenib: the BRISK Study

    Summary
    EudraCT number
    		 2008-005084-34
    Trial protocol
    		 DE   ES   SE   FR   GR   BE   IT  
    Global end of trial date
    15 Nov 2011

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Sep 2018
    First version publication date
    23 Sep 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CA182-034
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bristol-Myers Squibb
    Sponsor organisation address
    Chaussée de la Hulpe 185, Brussels, Belgium, 1170
    Public contact
    Bristol-Myers Squibb International Corporation, EU Study Start-Up Unit, clinical.trials@bms.com
    Scientific contact
    Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, 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
    23 Aug 2012
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Nov 2011
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Nov 2011
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the overall survival (OS) of subjects with advanced HCC, who have progressed on/after or are intolerant to sorafenib, and receive brivanib alaninate plus BSC to those receiving placebo plus BSC.
    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 subjects were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    19 Feb 2009
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 3
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    Brazil: 17
    Country: Number of subjects enrolled
    Canada: 19
    Country: Number of subjects enrolled
    China: 16
    Country: Number of subjects enrolled
    France: 141
    Country: Number of subjects enrolled
    Germany: 25
    Country: Number of subjects enrolled
    Greece: 3
    Country: Number of subjects enrolled
    Hong Kong: 2
    Country: Number of subjects enrolled
    India: 6
    Country: Number of subjects enrolled
    Italy: 33
    Country: Number of subjects enrolled
    Japan: 60
    Country: Number of subjects enrolled
    Korea, Republic of: 101
    Country: Number of subjects enrolled
    Mexico: 9
    Country: Number of subjects enrolled
    Puerto Rico: 1
    Country: Number of subjects enrolled
    Russian Federation: 12
    Country: Number of subjects enrolled
    Spain: 5
    Country: Number of subjects enrolled
    Taiwan: 39
    Country: Number of subjects enrolled
    United States: 72
    Worldwide total number of subjects
    565
    EEA total number of subjects
    208
    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)
    311
    From 65 to 84 years
    251
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 565 participants enrolled; 395 participants randomized; 170 were not randomized: 144 no longer met study criteria; 17 with drew consent; 1 adverse event; 1 poor/non-compliance; 1 died; 6 other

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Brivanib
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Brivanib Alaninate BMS-582664
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Brivanib alaninate (800 mg once daily [QD]), as 200-mg film-coated tablets administered orally

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo Brivanib Alaninate BMS-582664
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo for Brivanib alaninate (800 mg once daily [QD]), as 200-mg film-coated tablets administered orally

    Number of subjects in period 1 [1]
    		Brivanib Placebo
    Started
    263
    132
    Completed
    26
    11
    Not completed
    237
    121
         No Longer Meets Study Criteria
    2
    1
         Subject Withdrew Consent
    2
    1
         Adverse Event Unrelated to Study Drug
    21
    10
         Poor/Non-compliance
    -
    2
         Study Drug Toxicity
    61
    9
         Request to Discontinue Study Treatment
    19
    5
         Disease Progression
    132
    93
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial as out of 565 subjects who were enrolled only 395 were randomised. 170 were not randomized.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Brivanib
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group values
    		 Brivanib Placebo Total
    Number of subjects
    		 263 132 395
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 139 76 215
        From 65-84 years
    		 122 55 177
        85 years and over
    		 2 1 3
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 62.5 ( 12.14 ) 61.1 ( 12.86 ) -
    Gender categorical
    Units: Subjects
        Female
    		 47 19 66
        Male
    		 216 113 329

    End points

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    End points reporting groups
    Reporting group title
    Brivanib
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Primary: To compare overall survival of subjects with advanced HCC who have progressed on/after or are intolerant to Sorafenib and receive Brivanib plus best supportive care (BSC) to those receiving placebo plus BSC

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    End point title
    		 To compare overall survival of subjects with advanced HCC who have progressed on/after or are intolerant to Sorafenib and receive Brivanib plus best supportive care (BSC) to those receiving placebo plus BSC
    End point description
    Overall survival was defined per subject as the time from randomization to the time of death from any cause. The primary efficacy objective was to compare the OS of subjects with locally advanced or metastatic HCC (who have progressed on/after or are intolerant to sorafenib) who received brivanib alaninate plus BSC to those receiving placebo plus BSC.
    End point type
    Primary
    End point timeframe
    computerized tomography (CT)/ magnetic resonance imaging (MRI) every six weeks until progression or death
    End point values
    		 Brivanib Placebo
    Number of subjects analysed
    263
    132
    Units: months
        median (confidence interval 95%)
    9.4 (8.0 to 11.0)
    8.2 (6.2 to 10.3)
    Statistical analysis title
    		 Hazard Ratio (95.8%) Stratified Log-Rank
    Statistical analysis description
    Stratified by ECOG PS(0 versus 1&2), whether subjects had progressed or were intolerant to sorafenib, extrahepatic spread and/or vascular invasion at randomization Confidence interval (CI) for the hazard
    Comparison groups
    Brivanib v Placebo
    Number of subjects included in analysis
    395
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3307 [1]
    Method
    		 STRATIFIED LOG-RANK P-VALUE
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.89
    Confidence interval
         level
    		 95.8%
         sides
    2-sided
         lower limit
    		 0.69
         upper limit
    		 1.15
    Notes
    [1] - No statistical claim can be made because of hierarchical testing

    Secondary: To compare time to progression (TTP) (Investigator assessed using modified Response Evaluation Criteria In Solid Tumors (RECIST) for HCC criteria)

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    End point title
    		 To compare time to progression (TTP) (Investigator assessed using modified Response Evaluation Criteria In Solid Tumors (RECIST) for HCC criteria)
    End point description
    Time to progression was defined as the time (in months) from randomization to the time of radiographic disease progression. Time to Progression as Assessed by the IRRC Using HCC mRECIST Criteria (Censoring for Additional Follow-up Anticancer Therapy)
    End point type
    Secondary
    End point timeframe
    35 months
    End point values
    		 Brivanib Placebo
    Number of subjects analysed
    263
    132
    Units: months
        median (confidence interval 95%)
    4.2 (3.0 to 4.5)
    2.7 (1.5 to 2.8)
    Statistical analysis title
    		 STRATIFIED LOG-RANK P-VALUE
    Statistical analysis description
    Stratified by ECOG PS(0 versus 1&2), whether subjects had progressed or were intolerant to sorafenib, extrahepatic spread and/or vascular invasion at randomization
    Comparison groups
    Brivanib v Placebo
    Number of subjects included in analysis
    395
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0001
    Method
    		 Stratified Log-Rank P-Value
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.42
         upper limit
    		 0.76

    Secondary: To compare the Independent Radiological Review Committee (IRRC) assessed disease control rate (DCR) using modified RECIST for HCC criteria

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    End point title
    		 To compare the Independent Radiological Review Committee (IRRC) assessed disease control rate (DCR) using modified RECIST for HCC criteria
    End point description
    Disease control rate was defined as the number of CR, PR or stable disease (SD) divided by the total number of response-evaluable subjects as assessed by IRRC using mRECIST criteria for HCC.
    End point type
    Secondary
    End point timeframe
    35 months
    End point values
    		 Brivanib Placebo
    Number of subjects analysed
    263
    132
    Units: number of subject
        arithmetic mean (confidence interval 95%)
    71.2 (64.86 to 77.05)
    49.1 (39.33 to 58.87)
    Statistical analysis title
    		 COCHRAN-MANTEL-HAENSZEL
    Statistical analysis description
    Stratified by ECOG PS(0 versus 1&2), whether subjects had progressed or were intolerant to sorafenib, extrahepatic spread and/or vascular invasion at randomization
    Comparison groups
    Brivanib v Placebo
    Number of subjects included in analysis
    395
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.69
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.65
         upper limit
    		 4.38

    Secondary: To compare the Independent Radiological Review Committee (IRCC) assessed Objective Response Rate (ORR) using modified RECIST for HCC criteria

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    End point title
    		 To compare the Independent Radiological Review Committee (IRCC) assessed Objective Response Rate (ORR) using modified RECIST for HCC criteria
    End point description
    Objective response rate was defined as the number of responders (complete response [CR] and partial response [PR]) divided by the total number of response-evaluable subjects as assessed by IRRC using mRECIST criteria for HCC.
    End point type
    Secondary
    End point timeframe
    35 months
    End point values
    		 Brivanib Placebo
    Number of subjects analysed
    263
    132
    Units: Number of Subjects (percentage)
        arithmetic mean (confidence interval 95%)
    11.5 (7.65 to 16.40)
    1.9 (0.23 to 6.53)
    Statistical analysis title
    		 COCHRAN-MANTEL-HAENSZEL
    Statistical analysis description
    Stratified by ECOG PS(0 versus 1&2), whether subjects had progressed or were intolerant to sorafenib, extra-hepatic spread and/or vascular invasion at randomization
    Comparison groups
    Brivanib v Placebo
    Number of subjects included in analysis
    395
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0032 [2]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    5.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.4
         upper limit
    		 23.62
    Notes
    [2] - No statistical claim can be made because of hierarchical testing

    Secondary: To assess time to response (TTR)

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    End point title
    		 To assess time to response (TTR)
    End point description
    Secondary endpoint were based on independent radiology review committee (IRRC)-assessed progression and tumor response using modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria for HCC.
    End point type
    Secondary
    End point timeframe
    6 weeks
    End point values
    		 Brivanib Placebo
    Number of subjects analysed
    26
    2
    Units: months
        median (confidence interval 95%)
    1.4 (1.4 to 2.7)
    2.2 (1.7 to 2.7)
    No statistical analyses for this end point

    Secondary: To assess duration of response (DOR)

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    End point title
    		 To assess duration of response (DOR)
    End point description
    Secondary endpoint were based on independent radiology review committee (IRRC)-assessed progression and tumor response using modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria for HCC.
    End point type
    Secondary
    End point timeframe
    6 weeks
    End point values
    		 Brivanib Placebo
    Number of subjects analysed
    26
    2
    Units: months
        median (confidence interval 95%)
    5.6 (4.2 to 9.5)
    6.6 (5.6 to 7.7)
    No statistical analyses for this end point

    Secondary: To assess duration of disease control (DDC)

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    End point title
    		 To assess duration of disease control (DDC)
    End point description
    Secondary endpoint were based on independent radiology review committee (IRRC)-assessed progression and tumor response using modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria for HCC.
    End point type
    Secondary
    End point timeframe
    6 weeks
    End point values
    		 Brivanib Placebo
    Number of subjects analysed
    161
    53
    Units: months
        median (confidence interval 95%)
    2.7 (1.5 to 4.2)
    3.4 (2.9 to 4.2)
    No statistical analyses for this end point

    Secondary: To assess safety profile of brivanib. Safety will be assessed by the number of adverse events (AEs), serious adverse events (SAEs), periodic data monitoring committee (DMC) review

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    End point title
    		 To assess safety profile of brivanib. Safety will be assessed by the number of adverse events (AEs), serious adverse events (SAEs), periodic data monitoring committee (DMC) review
    End point description
    Includes AE with onset on or after the first dosing date and on or prior to the last dosing date +14 days. Includes SAE with onset on or after the first dosing date and on or prior to the last dosing date +30 days. Related AE or SAE defined as AE or SAE with Related or Missing relationship to study medication MedDRA Version: 14.1
    End point type
    Secondary
    End point timeframe
    35 months
    End point values
    		 Brivanib Placebo
    Number of subjects analysed
    261
    131
    Units: number of subjects
    number (not applicable)
        Adverse Events
    259
    123
        Serious Adverse Events
    165
    74
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    On-treatment Adverse events (AEs) and serious AEs (SAE) were reported with onset on or after the first dosing date and on or prior to the last dosing date +14 days and +30 days respectively.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14.1
    Reporting groups
    Reporting group title
    Brivanib
    Reporting group description
    		 Brivanib 800 mg oral tablet dosed once daily until disease progression or toxicity.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo 0 mg oral tablet dosed once daily until disease progression or toxicity.

    Serious adverse events
    		 Brivanib Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    165 / 261 (63.22%)
    74 / 131 (56.49%)
         number of deaths (all causes)
    182
    100
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Brain cancer metastatic
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cancer pain
         subjects affected / exposed
    1 / 261 (0.38%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic neoplasm malignant
         subjects affected / exposed
    2 / 261 (0.77%)
    3 / 131 (2.29%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial tumour haemorrhage
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver carcinoma ruptured
         subjects affected / exposed
    1 / 261 (0.38%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metastases to central nervous system
         subjects affected / exposed
    1 / 261 (0.38%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple myeloma
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasm malignant
         subjects affected / exposed
    45 / 261 (17.24%)
    27 / 131 (20.61%)
         occurrences causally related to treatment / all
    0 / 46
    0 / 28
         deaths causally related to treatment / all
    0 / 16
    0 / 14
    Neoplasm progression
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tongue neoplasm malignant stage unspecified
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aneurysm ruptured
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    2 / 261 (0.77%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    2 / 261 (0.77%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    General disorders and administration site conditions
    Adverse drug reaction
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    2 / 261 (0.77%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    7 / 261 (2.68%)
    2 / 131 (1.53%)
         occurrences causally related to treatment / all
    7 / 8
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    7 / 261 (2.68%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    5 / 8
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Malaise
         subjects affected / exposed
    2 / 261 (0.77%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema
         subjects affected / exposed
    1 / 261 (0.38%)
    2 / 131 (1.53%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    3 / 261 (1.15%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    6 / 261 (2.30%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Immune system disorders
    Liver and pancreas transplant rejection
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Epididymal cyst
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchitis chronic
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    3 / 261 (1.15%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infiltration
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    3 / 261 (1.15%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    3 / 261 (1.15%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 131 (0.76%)
         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
    0 / 261 (0.00%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delusion
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disorientation
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug abuse
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    3 / 261 (1.15%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    C-Reactive protein increased
         subjects affected / exposed
    2 / 261 (0.77%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical condition abnormal
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Weight decreased
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 261 (0.00%)
    2 / 131 (1.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    2 / 261 (0.77%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 261 (0.38%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure congestive
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-Respiratory arrest
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Ventricular fibrillation
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nervous system disorders
    Brain oedema
         subjects affected / exposed
    2 / 261 (0.77%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cognitive disorder
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coma
         subjects affected / exposed
    2 / 261 (0.77%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Coma hepatic
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Dizziness
         subjects affected / exposed
    2 / 261 (0.77%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Encephalopathy
         subjects affected / exposed
    3 / 261 (1.15%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic encephalopathy
         subjects affected / exposed
    12 / 261 (4.60%)
    2 / 131 (1.53%)
         occurrences causally related to treatment / all
    7 / 12
    1 / 2
         deaths causally related to treatment / all
    2 / 4
    0 / 1
    Metabolic encephalopathy
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Neuralgia
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraplegia
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Posterior reversible encephalopathy syndrome
         subjects affected / exposed
    2 / 261 (0.77%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 131 (0.76%)
         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
    1 / 261 (0.38%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 261 (0.38%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxic encephalopathy
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 261 (0.77%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Neutropenia
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal artery occlusion
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal artery thrombosis
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (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
    2 / 261 (0.77%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    9 / 261 (3.45%)
    9 / 131 (6.87%)
         occurrences causally related to treatment / all
    5 / 12
    1 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    2 / 261 (0.77%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    7 / 261 (2.68%)
    5 / 131 (3.82%)
         occurrences causally related to treatment / all
    7 / 8
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    5 / 261 (1.92%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer haemorrhage
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric varices haemorrhage
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 261 (0.77%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Haematemesis
         subjects affected / exposed
    2 / 261 (0.77%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal haemorrhage
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Melaena
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (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
    3 / 261 (1.15%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal haemorrhage
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal varices haemorrhage
         subjects affected / exposed
    4 / 261 (1.53%)
    2 / 131 (1.53%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Periodontitis
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    3 / 261 (1.15%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Varices oesophageal
         subjects affected / exposed
    1 / 261 (0.38%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    4 / 261 (1.53%)
    2 / 131 (1.53%)
         occurrences causally related to treatment / all
    4 / 4
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Acute hepatic failure
         subjects affected / exposed
    1 / 261 (0.38%)
    2 / 131 (1.53%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Bile duct obstruction
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    8 / 261 (3.07%)
    2 / 131 (1.53%)
         occurrences causally related to treatment / all
    2 / 8
    0 / 2
         deaths causally related to treatment / all
    1 / 6
    0 / 2
    Hepatic function abnormal
         subjects affected / exposed
    5 / 261 (1.92%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hepatic pain
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatorenal syndrome
         subjects affected / exposed
    1 / 261 (0.38%)
    2 / 131 (1.53%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Hyperbilirubinaemia
         subjects affected / exposed
    4 / 261 (1.53%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    1 / 261 (0.38%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Portal vein thrombosis
         subjects affected / exposed
    1 / 261 (0.38%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute prerenal failure
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder dysplasia
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrotic syndrome
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstructive uropathy
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oliguria
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 261 (0.38%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Renal failure acute
         subjects affected / exposed
    4 / 261 (1.53%)
    2 / 131 (1.53%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureteric obstruction
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal mass
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypothyroidism
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 261 (0.77%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint range of motion decreased
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 131 (0.76%)
         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
    4 / 261 (1.53%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (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 / 261 (0.00%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    2 / 261 (0.77%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    H1n1 influenza
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    3 / 261 (1.15%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral fungal infection
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis bacterial
         subjects affected / exposed
    1 / 261 (0.38%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia
         subjects affected / exposed
    3 / 261 (1.15%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Septic shock
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tuberculosis
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 261 (0.77%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Acidosis
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Decreased appetite
         subjects affected / exposed
    10 / 261 (3.83%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    10 / 12
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    6 / 261 (2.30%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    5 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fluid retention
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperammonaemia
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 261 (0.38%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    2 / 261 (0.77%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    4 / 261 (1.53%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Brivanib Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    250 / 261 (95.79%)
    111 / 131 (84.73%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    123 / 261 (47.13%)
    18 / 131 (13.74%)
         occurrences all number
    159
    21
    Hypotension
         subjects affected / exposed
    14 / 261 (5.36%)
    1 / 131 (0.76%)
         occurrences all number
    15
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    57 / 261 (21.84%)
    24 / 131 (18.32%)
         occurrences all number
    72
    26
    Fatigue
         subjects affected / exposed
    122 / 261 (46.74%)
    31 / 131 (23.66%)
         occurrences all number
    169
    35
    Mucosal inflammation
         subjects affected / exposed
    27 / 261 (10.34%)
    4 / 131 (3.05%)
         occurrences all number
    30
    4
    Pain
         subjects affected / exposed
    16 / 261 (6.13%)
    4 / 131 (3.05%)
         occurrences all number
    16
    4
    Oedema peripheral
         subjects affected / exposed
    39 / 261 (14.94%)
    22 / 131 (16.79%)
         occurrences all number
    54
    30
    Pyrexia
         subjects affected / exposed
    32 / 261 (12.26%)
    12 / 131 (9.16%)
         occurrences all number
    40
    14
    Respiratory, thoracic and mediastinal disorders
    Dysphonia
         subjects affected / exposed
    56 / 261 (21.46%)
    2 / 131 (1.53%)
         occurrences all number
    70
    3
    Cough
         subjects affected / exposed
    38 / 261 (14.56%)
    16 / 131 (12.21%)
         occurrences all number
    41
    16
    Dyspnoea
         subjects affected / exposed
    36 / 261 (13.79%)
    14 / 131 (10.69%)
         occurrences all number
    43
    15
    Epistaxis
         subjects affected / exposed
    14 / 261 (5.36%)
    3 / 131 (2.29%)
         occurrences all number
    18
    3
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    27 / 261 (10.34%)
    11 / 131 (8.40%)
         occurrences all number
    33
    11
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    40 / 261 (15.33%)
    8 / 131 (6.11%)
         occurrences all number
    49
    10
    Aspartate aminotransferase increased
         subjects affected / exposed
    52 / 261 (19.92%)
    18 / 131 (13.74%)
         occurrences all number
    58
    19
    Weight decreased
         subjects affected / exposed
    60 / 261 (22.99%)
    9 / 131 (6.87%)
         occurrences all number
    66
    9
    Weight increased
         subjects affected / exposed
    7 / 261 (2.68%)
    7 / 131 (5.34%)
         occurrences all number
    10
    7
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    38 / 261 (14.56%)
    8 / 131 (6.11%)
         occurrences all number
    44
    9
    Dysgeusia
         subjects affected / exposed
    19 / 261 (7.28%)
    0 / 131 (0.00%)
         occurrences all number
    19
    0
    Headache
         subjects affected / exposed
    55 / 261 (21.07%)
    11 / 131 (8.40%)
         occurrences all number
    66
    11
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    14 / 261 (5.36%)
    6 / 131 (4.58%)
         occurrences all number
    15
    6
    Thrombocytopenia
         subjects affected / exposed
    27 / 261 (10.34%)
    3 / 131 (2.29%)
         occurrences all number
    32
    3
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    25 / 261 (9.58%)
    13 / 131 (9.92%)
         occurrences all number
    27
    15
    Abdominal pain
         subjects affected / exposed
    69 / 261 (26.44%)
    22 / 131 (16.79%)
         occurrences all number
    86
    23
    Abdominal pain upper
         subjects affected / exposed
    44 / 261 (16.86%)
    14 / 131 (10.69%)
         occurrences all number
    49
    18
    Constipation
         subjects affected / exposed
    50 / 261 (19.16%)
    19 / 131 (14.50%)
         occurrences all number
    70
    21
    Ascites
         subjects affected / exposed
    32 / 261 (12.26%)
    15 / 131 (11.45%)
         occurrences all number
    34
    16
    Dry mouth
         subjects affected / exposed
    17 / 261 (6.51%)
    4 / 131 (3.05%)
         occurrences all number
    19
    4
    Diarrhoea
         subjects affected / exposed
    120 / 261 (45.98%)
    19 / 131 (14.50%)
         occurrences all number
    226
    27
    Dyspepsia
         subjects affected / exposed
    34 / 261 (13.03%)
    4 / 131 (3.05%)
         occurrences all number
    36
    4
    Nausea
         subjects affected / exposed
    95 / 261 (36.40%)
    27 / 131 (20.61%)
         occurrences all number
    133
    31
    Stomatitis
         subjects affected / exposed
    23 / 261 (8.81%)
    1 / 131 (0.76%)
         occurrences all number
    24
    1
    Vomiting
         subjects affected / exposed
    81 / 261 (31.03%)
    11 / 131 (8.40%)
         occurrences all number
    115
    17
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    33 / 261 (12.64%)
    13 / 131 (9.92%)
         occurrences all number
    39
    16
    Skin and subcutaneous tissue disorders
    Palmar-Plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    38 / 261 (14.56%)
    9 / 131 (6.87%)
         occurrences all number
    45
    9
    Pruritus
         subjects affected / exposed
    26 / 261 (9.96%)
    13 / 131 (9.92%)
         occurrences all number
    31
    17
    Rash
         subjects affected / exposed
    24 / 261 (9.20%)
    9 / 131 (6.87%)
         occurrences all number
    31
    9
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    27 / 261 (10.34%)
    3 / 131 (2.29%)
         occurrences all number
    33
    3
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    41 / 261 (15.71%)
    3 / 131 (2.29%)
         occurrences all number
    42
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    14 / 261 (5.36%)
    7 / 131 (5.34%)
         occurrences all number
    14
    8
    Back pain
         subjects affected / exposed
    29 / 261 (11.11%)
    11 / 131 (8.40%)
         occurrences all number
    32
    12
    Musculoskeletal pain
         subjects affected / exposed
    15 / 261 (5.75%)
    5 / 131 (3.82%)
         occurrences all number
    15
    5
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    155 / 261 (59.39%)
    31 / 131 (23.66%)
         occurrences all number
    209
    35
    Hyperkalaemia
         subjects affected / exposed
    23 / 261 (8.81%)
    3 / 131 (2.29%)
         occurrences all number
    29
    3
    Hypoalbuminaemia
         subjects affected / exposed
    29 / 261 (11.11%)
    6 / 131 (4.58%)
         occurrences all number
    36
    6
    Hyponatraemia
         subjects affected / exposed
    52 / 261 (19.92%)
    10 / 131 (7.63%)
         occurrences all number
    78
    13

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Sep 2009
    Includes a change in the efficacy criteria to Modified RECIST for HCC, addition of an independent radiology vendor, updates to CYP3 data and other administrative issues.
    29 Jun 2010
    Increase patient number by up to 75 patients for timeline mitigation due to slower than expected event rate
    10 Feb 2011
    Includes changes for the optional long term open label extension (LTOLE) portion of the study.

    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.

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