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    Clinical Trial Results:
    A Randomized, Double-blind, Multicenter Phase III Study of Brivanib versus Placebo as Adjuvant Therapy to Trans-Arterial Chemo-Embolization (TACE) in Patients with Unresectable Hepatocellular Carcinoma: The BRISK TA Study

    Summary
    EudraCT number
    		 2008-008715-26
    Trial protocol
    		 FR   ES   IT  
    Global end of trial date
    26 Jan 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Mar 2019
    First version publication date
    01 Mar 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CA182-037
    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,
    Public contact
    EU Study Start-Up Unit, Bristol-Myers Squibb International Corporation, 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
    28 Sep 2012
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Sep 2012
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Jan 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The main objective of this study was to compare the overall survival (OS) of hepatocellular carcinoma (HCC) subjects who receive brivanib as adjuvant treatments to TACE therapy, with the OS of HCC subjects who receive matched placebo with TACE therapy.
    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
    20 Jul 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
    Canada: 2
    Country: Number of subjects enrolled
    France: 32
    Country: Number of subjects enrolled
    Hong Kong: 4
    Country: Number of subjects enrolled
    Italy: 2
    Country: Number of subjects enrolled
    Japan: 78
    Country: Number of subjects enrolled
    Korea, Republic of: 68
    Country: Number of subjects enrolled
    China: 244
    Country: Number of subjects enrolled
    Spain: 11
    Country: Number of subjects enrolled
    Taiwan: 28
    Country: Number of subjects enrolled
    Thailand: 12
    Country: Number of subjects enrolled
    United States: 18
    Worldwide total number of subjects
    502
    EEA total number of subjects
    45
    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)
    343
    From 65 to 84 years
    159
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 734 participants were enrolled in the study and 502 were randomized. Of the 232 not randomized, 10 had adverse events, 9 withdrew consent, 1 died, 17 no longer met study criteria, 1 due to administrative reasons by sponsor, 10 due to other reasons and 184 did not qualify for TACE population.

    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, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Placebo, by mouth, once daily after each TACE procedure
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo for BMS-582664-02
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    800 mg (4X 200 mg film coated tablet), by mouth once daily

    Arm title
    		 Brivanib
    Arm description
    		 Brivanib 800 mg by mouth, once daily after each TACE procedure
    Arm type
    		 Experimental

    Investigational medicinal product name
    BMS-582664-02
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    800 mg (4X 200 mg film coated tablet), by mouth once daily

    Number of subjects in period 1
    		Placebo Brivanib
    Started
    253
    249
    Completed
    3
    57
    Not completed
    250
    192
         Subject request to discontinue treatment
    14
    25
         Adverse event, serious fatal
    -
    2
         Disease progression
    91
    45
         Others
    7
    3
         Maximum clinical benefit
    6
    3
         No longer meets study criteria
    2
    1
         Consent withdrawn by subject
    1
    5
         Adverse event, non-fatal
    22
    22
         Study drug toxicity
    6
    65
         Investigator decision
    2
    1
         Transfer to systemic cancer therapy
    2
    -
         Physician judgement
    -
    3
         Poor/non-compliance
    5
    5
         Administrative reason by sponsor
    92
    12

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo, by mouth, once daily after each TACE procedure

    Reporting group title
    Brivanib
    Reporting group description
    		 Brivanib 800 mg by mouth, once daily after each TACE procedure

    Reporting group values
    		 Placebo Brivanib Total
    Number of subjects
    		 253 249 502
    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)
    		 170 173 343
        From 65-84 years
    		 83 76 159
        85 years and over
    		 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 58.3 ( 12.42 ) 57.2 ( 13.02 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 37 43 80
        Male
    		 216 206 422
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 223 218 441
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 1 2 3
        White
    		 28 28 56
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 1 1 2

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo, by mouth, once daily after each TACE procedure

    Reporting group title
    Brivanib
    Reporting group description
    		 Brivanib 800 mg by mouth, once daily after each TACE procedure

    Primary: Overall Survival (OS) - Univariate analysis; Brivanib vs placebo

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    End point title
    		 Overall Survival (OS) - Univariate analysis; Brivanib vs placebo
    End point description
    Overall Survival, OS: defined as the time from randomization to death from any cause. Subjects who did not die were censored at the last known alive date. Here, '99999' signifies data not available for this endpoint.
    End point type
    Primary
    End point timeframe
    Assessed from from the date of randomization to the date of death from any cause.
    End point values
    		 Placebo Brivanib
    Number of subjects analysed
    253
    249
    Units: Months
    median (confidence interval 95%)
        OS
    26.1 (19.0 to 30.9)
    26.4 (19.1 to 9999)
    Statistical analysis title
    		 Kaplan-Meier Analysis of OS - Randomized Subjects
    Comparison groups
    Placebo v Brivanib
    Number of subjects included in analysis
    502
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.5289
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.66
         upper limit
    		 1.23

    Secondary: Time-to-disease progression (TTDP)

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    End point title
    		 Time-to-disease progression (TTDP)
    End point description
    TTDP is defined for all randomized patients as the time from the date of the first TACE to the date the disease progresses to an advanced stage during the course of TACE therapy as determined by the occurrence of any one of the following events: • Development of extrahepatic metastasis. • Development of vascular invasion. • Death • Deterioration of liver function to Child-Pugh Class C. • Deterioration of ECOG performance status by 2 points if liver disease related OR, if not liver disease related, deterioration of ECOG performance status by 2 points AND lasting > 2 weeks in duration. Subjects without any progression events and who did not die were censored at the last date of assessment date. Analysis was performed on all subjects who were randomized to any treatment.
    End point type
    Secondary
    End point timeframe
    From the first TACE and then every 8 weeks
    End point values
    		 Placebo Brivanib
    Number of subjects analysed
    253
    249
    Units: Months
    median (confidence interval 95%)
        TTDP
    10.9 (8.4 to 14.4)
    12.0 (9.5 to 15.3)
    Statistical analysis title
    		 Kaplan-Meier Analysis of TTDP
    Comparison groups
    Placebo v Brivanib
    Number of subjects included in analysis
    502
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.6209
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.72
         upper limit
    		 1.22

    Secondary: Time to Extrahepatic Spread or Vascular Invasion

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    End point title
    		 Time to Extrahepatic Spread or Vascular Invasion
    End point description
    Time to extrahepatic spread or vascular invasion is defined as the time from the date of the first TACE to the date extrahepatic spread or vascular invasion was documented, whichever comes first. Subjects without any progression events and who did not die were censored at the last date of assessment date. Analysis was performed on all subjects who were randomized to any treatment.
    End point type
    Secondary
    End point timeframe
    From the date of the first TACE to the date extrahepatic spread or vascular invasion was documented
    End point values
    		 Placebo Brivanib
    Number of subjects analysed
    253
    249
    Units: Months
    median (confidence interval 95%)
        TTES or VI
    24.9 (13.8 to 9999)
    9999 (17.6 to 9999)
    Statistical analysis title
    		 K-M Analysis of Time to Extrahepatic Spread
    Comparison groups
    Placebo v Brivanib
    Number of subjects included in analysis
    502
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0096
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.45
         upper limit
    		 0.9

    Secondary: Rate of TACE Sessions

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    End point title
    		 Rate of TACE Sessions
    End point description
    The total number of TACE procedures is defined for all randomized subjects as the number of TACE procedures the patient received between randomization and the time of event or censoring of TTDP. All TACE procedures were counted as separate events whatever the reason for repeating the procedure. The TACE procedure performed prior to randomization was not counted.
    End point type
    Secondary
    End point timeframe
    From randomization and the time of event or censoring of the main secondary endpoint Time-To-Disease Progression
    End point values
    		 Placebo Brivanib
    Number of subjects analysed
    253
    249
    Units: Number
    arithmetic mean (standard deviation)
        TACE Procedures prior to DP / censoring
    1.47 ( 1.717 )
    1.10 ( 1.840 )
        TACE Procedures, all
    1.96 ( 1.861 )
    1.37 ( 2.008 )
    Statistical analysis title
    		 Rate of TACE sessions
    Comparison groups
    Placebo v Brivanib
    Number of subjects included in analysis
    502
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0002
    Method
    		 Andersen-Gill Model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.61
         upper limit
    		 0.86

    Secondary: Number of subjects with Adverse events (AEs), Drug related AEs. Serious adverse events (SAEs), Treatment related SAEs, AEs leading to discontinuation, AEs of special interest (AEOSI) and death

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    End point title
    		 Number of subjects with Adverse events (AEs), Drug related AEs. Serious adverse events (SAEs), Treatment related SAEs, AEs leading to discontinuation, AEs of special interest (AEOSI) and death
    End point description
    AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment and may or may not be related to treatment. SAE=an untoward medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Drug-related=having certain, probable, possible, or missing relationship to study drug. Analysis was performed in all treated subjects.
    End point type
    Secondary
    End point timeframe
    All non-serious adverse events (NSAEs) and SAEs, were reported from first dose to 14 days and 30 days post final dose respectively
    End point values
    		 Placebo Brivanib
    Number of subjects analysed
    253
    249
    Units: Subjects
        SAEs
    94
    118
        Related SAEs
    9
    56
        AEs leading to discontinuation
    46
    98
        >= Grade 3 AEs
    128
    221
        AEOSI - Arterial Thromboembolic
    3
    0
        AEOSI - Hepatic
    130
    137
        AEOSI - Hypertension
    30
    116
        AEOSI - Hyponatremia
    27
    71
        AEOSI - Hypothyroidism
    18
    66
        AEOSI - Proteinuria
    28
    76
        AEOSI - RPL Syndrome
    0
    1
        Death
    12
    18
    No statistical analyses for this end point

    Secondary: Number of Participants With Grade 3-4 Abnormalities on Laboratory Test Results

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    End point title
    		 Number of Participants With Grade 3-4 Abnormalities on Laboratory Test Results
    End point description
    End point type
    Secondary
    End point timeframe
    ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; ULN=upper limit of normal. Here, 'n' represents number of subjects evaluable for each category.
    End point values
    		 Placebo Brivanib
    Number of subjects analysed
    253
    246
    Units: Subjects
        Absolute neutrophil count (n=252,244)
    19
    26
        Hemoglobin (n=252,244)
    12
    6
        Leukocytes (n=252,244)
    12
    22
        Neutrophils (n=238,230)
    17
    26
        Platelet count (n=252,244)
    19
    40
        ALT (n=252,244)
    39
    46
        ALP (n=250,243)
    9
    4
        AST (n=252,244)
    58
    60
        Bilirubin Total (n=252,244)
    17
    25
    No statistical analyses for this end point

    Secondary: Number of subjects with percent reduction from baseline and on-study Left Ventricular Ejection Fraction (LVEF) <10%, 10%-<=20% and 20%-<40%

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    End point title
    		 Number of subjects with percent reduction from baseline and on-study Left Ventricular Ejection Fraction (LVEF) <10%, 10%-<=20% and 20%-<40%
    End point description
    A single 12-lead electrocardiogram was performed. The analysis was performed for on-study subjects with available reduction. Here, 'number of subjects analysed' represents number of subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    At baseline, 12 weeks after start of treatment, and thereafter whenever clinically indicated
    End point values
    		 Placebo Brivanib
    Number of subjects analysed
    192
    169
    Units: Subjects
        <10%
    161
    134
        10%-<20%
    31
    33
        20%-<40%
    0
    2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All non-serious adverse events (NSAEs) and serious adverse events (SAEs) were reported from first dose to 14 days and 30 days post final dose respectively.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received Brivanib alaninate matching placebo as oral tablets once daily until the criteria for discontinuation of subjects from treatment was met.

    Reporting group title
    Brivanib
    Reporting group description
    		 Subjects received 800 milligram (mg) Brivanib alaninate as oral tablets (each tablet of 200 mg * 4) once daily until the criteria for discontinuation of subjects from treatment was met.

    Serious adverse events
    		 Placebo Brivanib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    94 / 253 (37.15%)
    118 / 246 (47.97%)
         number of deaths (all causes)
    12
    18
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenoma benign
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric cancer
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic cancer metastatic
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic neoplasm malignant
         subjects affected / exposed
    8 / 253 (3.16%)
    6 / 246 (2.44%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic neoplasm malignant recurrent
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 246 (0.41%)
         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
    2 / 253 (0.79%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    38 / 253 (15.02%)
    15 / 246 (6.10%)
         occurrences causally related to treatment / all
    0 / 40
    0 / 17
         deaths causally related to treatment / all
    0 / 12
    0 / 3
    Neoplasm
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostatic adenoma
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 246 (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 / 253 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Tumour thrombosis
         subjects affected / exposed
    1 / 253 (0.40%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 253 (0.00%)
    4 / 246 (1.63%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 253 (0.40%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    2 / 253 (0.79%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 253 (0.40%)
    3 / 246 (1.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 3
    Fatigue
         subjects affected / exposed
    3 / 253 (1.19%)
    3 / 246 (1.22%)
         occurrences causally related to treatment / all
    1 / 3
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 253 (0.00%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hernia
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Oedema peripheral
         subjects affected / exposed
    2 / 253 (0.79%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    5 / 253 (1.98%)
    6 / 246 (2.44%)
         occurrences causally related to treatment / all
    1 / 5
    3 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 246 (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
    2 / 253 (0.79%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hiccups
         subjects affected / exposed
    2 / 253 (0.79%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 246 (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 / 253 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 253 (0.00%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 253 (0.00%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood urea increased
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 246 (0.41%)
         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
    Ankle fracture
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Limb traumatic amputation
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 246 (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
    5 / 253 (1.98%)
    3 / 246 (1.22%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Hydrocele
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 246 (0.41%)
         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
    0 / 253 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 246 (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
    Carpal tunnel syndrome
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dementia
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 253 (0.00%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Grand mal convulsion
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 253 (0.00%)
    3 / 246 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Headache
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 246 (0.41%)
         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
    2 / 253 (0.79%)
    5 / 246 (2.03%)
         occurrences causally related to treatment / all
    0 / 3
    2 / 9
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Posterior reversible encephalopathy syndrome
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord infarction
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hypersplenism
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 253 (0.00%)
    3 / 246 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    0 / 253 (0.00%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    4 / 253 (1.58%)
    6 / 246 (2.44%)
         occurrences causally related to treatment / all
    0 / 6
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 253 (0.40%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal fistula
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    6 / 253 (2.37%)
    8 / 246 (3.25%)
         occurrences causally related to treatment / all
    0 / 6
    3 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 253 (0.40%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Food poisoning
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric polyps
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 246 (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
    0 / 253 (0.00%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 253 (0.40%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus paralytic
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Irritable bowel syndrome
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mouth haemorrhage
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 253 (0.79%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal varices haemorrhage
         subjects affected / exposed
    1 / 253 (0.40%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 253 (0.40%)
    5 / 246 (2.03%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Varices oesophageal
         subjects affected / exposed
    2 / 253 (0.79%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Volvulus
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 253 (0.79%)
    3 / 246 (1.22%)
         occurrences causally related to treatment / all
    0 / 2
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct obstruction
         subjects affected / exposed
    1 / 253 (0.40%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bile duct stone
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biloma
         subjects affected / exposed
    2 / 253 (0.79%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    2 / 253 (0.79%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    2 / 253 (0.79%)
    4 / 246 (1.63%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 4
         deaths causally related to treatment / all
    1 / 2
    0 / 1
    Hepatic function abnormal
         subjects affected / exposed
    1 / 253 (0.40%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic haemorrhage
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic necrosis
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic pain
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    2 / 253 (0.79%)
    4 / 246 (1.63%)
         occurrences causally related to treatment / all
    0 / 2
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    1 / 253 (0.40%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Palmar-Plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxic skin eruption
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrotic syndrome
         subjects affected / exposed
    0 / 253 (0.00%)
    3 / 246 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Proteinuria
         subjects affected / exposed
    0 / 253 (0.00%)
    3 / 246 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal injury
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 246 (0.41%)
         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
    Back pain
         subjects affected / exposed
    2 / 253 (0.79%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal column stenosis
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 246 (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
    Abdominal infection
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis perforated
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary tract infection
         subjects affected / exposed
    0 / 253 (0.00%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Empyema
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 246 (0.41%)
         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 / 253 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic infection
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 246 (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
    0 / 253 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected skin ulcer
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infectious peritonitis
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Liver abscess
         subjects affected / exposed
    2 / 253 (0.79%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral candidiasis
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis media chronic
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis bacterial
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 246 (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
    1 / 253 (0.40%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 253 (0.40%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Tuberculosis
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tuberculous pleurisy
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 253 (0.40%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 253 (0.79%)
    5 / 246 (2.03%)
         occurrences causally related to treatment / all
    2 / 2
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fluid retention
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 246 (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
    0 / 253 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 253 (0.40%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypochloraemia
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 253 (0.40%)
    3 / 246 (1.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 253 (0.40%)
    3 / 246 (1.22%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoproteinaemia
         subjects affected / exposed
    1 / 253 (0.40%)
    3 / 246 (1.22%)
         occurrences causally related to treatment / all
    0 / 1
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sodium retention
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Brivanib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    236 / 253 (93.28%)
    241 / 246 (97.97%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    29 / 253 (11.46%)
    115 / 246 (46.75%)
         occurrences all number
    43
    169
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    5 / 253 (1.98%)
    18 / 246 (7.32%)
         occurrences all number
    5
    32
    Fatigue
         subjects affected / exposed
    58 / 253 (22.92%)
    100 / 246 (40.65%)
         occurrences all number
    80
    138
    Oedema peripheral
         subjects affected / exposed
    17 / 253 (6.72%)
    40 / 246 (16.26%)
         occurrences all number
    17
    51
    Pain
         subjects affected / exposed
    15 / 253 (5.93%)
    14 / 246 (5.69%)
         occurrences all number
    22
    17
    Pyrexia
         subjects affected / exposed
    114 / 253 (45.06%)
    89 / 246 (36.18%)
         occurrences all number
    207
    173
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    19 / 253 (7.51%)
    31 / 246 (12.60%)
         occurrences all number
    24
    43
    Dyspnoea
         subjects affected / exposed
    8 / 253 (3.16%)
    17 / 246 (6.91%)
         occurrences all number
    9
    21
    Dysphonia
         subjects affected / exposed
    5 / 253 (1.98%)
    45 / 246 (18.29%)
         occurrences all number
    7
    59
    Epistaxis
         subjects affected / exposed
    4 / 253 (1.58%)
    20 / 246 (8.13%)
         occurrences all number
    6
    23
    Oropharyngeal pain
         subjects affected / exposed
    4 / 253 (1.58%)
    21 / 246 (8.54%)
         occurrences all number
    5
    24
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    25 / 253 (9.88%)
    30 / 246 (12.20%)
         occurrences all number
    33
    36
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    84 / 253 (33.20%)
    87 / 246 (35.37%)
         occurrences all number
    148
    162
    Aspartate aminotransferase increased
         subjects affected / exposed
    95 / 253 (37.55%)
    84 / 246 (34.15%)
         occurrences all number
    157
    141
    Blood albumin decreased
         subjects affected / exposed
    15 / 253 (5.93%)
    21 / 246 (8.54%)
         occurrences all number
    21
    29
    Blood alkaline phosphatase increased
         subjects affected / exposed
    28 / 253 (11.07%)
    23 / 246 (9.35%)
         occurrences all number
    39
    39
    Blood bilirubin increased
         subjects affected / exposed
    11 / 253 (4.35%)
    15 / 246 (6.10%)
         occurrences all number
    16
    22
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    5 / 253 (1.98%)
    30 / 246 (12.20%)
         occurrences all number
    5
    31
    Gamma-Glutamyltransferase increased
         subjects affected / exposed
    34 / 253 (13.44%)
    32 / 246 (13.01%)
         occurrences all number
    49
    50
    Haemoglobin decreased
         subjects affected / exposed
    19 / 253 (7.51%)
    23 / 246 (9.35%)
         occurrences all number
    21
    37
    International normalised ratio increased
         subjects affected / exposed
    16 / 253 (6.32%)
    22 / 246 (8.94%)
         occurrences all number
    24
    29
    Neutrophil count decreased
         subjects affected / exposed
    29 / 253 (11.46%)
    31 / 246 (12.60%)
         occurrences all number
    64
    58
    Platelet count decreased
         subjects affected / exposed
    42 / 253 (16.60%)
    58 / 246 (23.58%)
         occurrences all number
    103
    112
    Prothrombin time prolonged
         subjects affected / exposed
    10 / 253 (3.95%)
    16 / 246 (6.50%)
         occurrences all number
    12
    17
    Weight decreased
         subjects affected / exposed
    11 / 253 (4.35%)
    20 / 246 (8.13%)
         occurrences all number
    11
    23
    White blood cell count decreased
         subjects affected / exposed
    48 / 253 (18.97%)
    53 / 246 (21.54%)
         occurrences all number
    103
    123
    White blood cell count increased
         subjects affected / exposed
    13 / 253 (5.14%)
    13 / 246 (5.28%)
         occurrences all number
    17
    15
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    8 / 253 (3.16%)
    34 / 246 (13.82%)
         occurrences all number
    8
    45
    Headache
         subjects affected / exposed
    15 / 253 (5.93%)
    39 / 246 (15.85%)
         occurrences all number
    16
    55
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    7 / 253 (2.77%)
    15 / 246 (6.10%)
         occurrences all number
    10
    22
    Thrombocytopenia
         subjects affected / exposed
    11 / 253 (4.35%)
    25 / 246 (10.16%)
         occurrences all number
    19
    36
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    3 / 253 (1.19%)
    14 / 246 (5.69%)
         occurrences all number
    5
    20
    Abdominal distension
         subjects affected / exposed
    25 / 253 (9.88%)
    35 / 246 (14.23%)
         occurrences all number
    29
    52
    Abdominal pain
         subjects affected / exposed
    101 / 253 (39.92%)
    88 / 246 (35.77%)
         occurrences all number
    188
    182
    Abdominal pain upper
         subjects affected / exposed
    35 / 253 (13.83%)
    43 / 246 (17.48%)
         occurrences all number
    64
    78
    Constipation
         subjects affected / exposed
    41 / 253 (16.21%)
    37 / 246 (15.04%)
         occurrences all number
    49
    57
    Ascites
         subjects affected / exposed
    16 / 253 (6.32%)
    39 / 246 (15.85%)
         occurrences all number
    17
    51
    Dyspepsia
         subjects affected / exposed
    7 / 253 (2.77%)
    17 / 246 (6.91%)
         occurrences all number
    7
    23
    Diarrhoea
         subjects affected / exposed
    25 / 253 (9.88%)
    88 / 246 (35.77%)
         occurrences all number
    28
    171
    Nausea
         subjects affected / exposed
    67 / 253 (26.48%)
    70 / 246 (28.46%)
         occurrences all number
    116
    115
    Stomatitis
         subjects affected / exposed
    3 / 253 (1.19%)
    23 / 246 (9.35%)
         occurrences all number
    4
    34
    Vomiting
         subjects affected / exposed
    56 / 253 (22.13%)
    63 / 246 (25.61%)
         occurrences all number
    92
    106
    Hepatobiliary disorders
    Hepatic pain
         subjects affected / exposed
    10 / 253 (3.95%)
    14 / 246 (5.69%)
         occurrences all number
    15
    23
    Hyperbilirubinaemia
         subjects affected / exposed
    57 / 253 (22.53%)
    57 / 246 (23.17%)
         occurrences all number
    102
    121
    Skin and subcutaneous tissue disorders
    Palmar-Plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    5 / 253 (1.98%)
    77 / 246 (31.30%)
         occurrences all number
    5
    138
    Pruritus
         subjects affected / exposed
    14 / 253 (5.53%)
    14 / 246 (5.69%)
         occurrences all number
    15
    21
    Rash
         subjects affected / exposed
    13 / 253 (5.14%)
    24 / 246 (9.76%)
         occurrences all number
    16
    34
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    24 / 253 (9.49%)
    69 / 246 (28.05%)
         occurrences all number
    29
    109
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    18 / 253 (7.11%)
    66 / 246 (26.83%)
         occurrences all number
    19
    74
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    20 / 253 (7.91%)
    16 / 246 (6.50%)
         occurrences all number
    21
    22
    Musculoskeletal pain
         subjects affected / exposed
    10 / 253 (3.95%)
    14 / 246 (5.69%)
         occurrences all number
    13
    20
    Pain in extremity
         subjects affected / exposed
    3 / 253 (1.19%)
    16 / 246 (6.50%)
         occurrences all number
    3
    23
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    6 / 253 (2.37%)
    15 / 246 (6.10%)
         occurrences all number
    7
    24
    Upper respiratory tract infection
         subjects affected / exposed
    8 / 253 (3.16%)
    13 / 246 (5.28%)
         occurrences all number
    9
    18
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    55 / 253 (21.74%)
    105 / 246 (42.68%)
         occurrences all number
    76
    149
    Hyperglycaemia
         subjects affected / exposed
    17 / 253 (6.72%)
    11 / 246 (4.47%)
         occurrences all number
    22
    14
    Hyperkalaemia
         subjects affected / exposed
    7 / 253 (2.77%)
    16 / 246 (6.50%)
         occurrences all number
    7
    21
    Hypoalbuminaemia
         subjects affected / exposed
    33 / 253 (13.04%)
    54 / 246 (21.95%)
         occurrences all number
    46
    92
    Hypokalaemia
         subjects affected / exposed
    20 / 253 (7.91%)
    22 / 246 (8.94%)
         occurrences all number
    24
    28
    Hyponatraemia
         subjects affected / exposed
    26 / 253 (10.28%)
    65 / 246 (26.42%)
         occurrences all number
    37
    89

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

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

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

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