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    Clinical Trial Results:
    A 24 month, randomized, controlled, study to evaluate the efficacy and safety of concentration-controlled everolimus plus reduced tacrolimus compared to standard tacrolimus in recipients of living donor liver transplants and long term extension to evaluate the efficacy and safety of concentration-controlled everolimus plus reduced tacrolimus compared to standard tacrolimus in recipients of living donor liver transplants in Japan

    Summary
    EudraCT number
    		 2010-024527-25
    Trial protocol
    		 IT   DE  
    Global end of trial date
    10 Oct 2017

    Results information
    Results version number
    		 v2(current)
    This version publication date
    16 Mar 2019
    First version publication date
    21 Oct 2018
    Other versions
    		 v1
    Version creation reason
    • New data added to full data set
    To add data for the extension trial (CRAD001H2307E1).

    Trial information

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    Trial identification
    Sponsor protocol code
    CRAD001H2307 and CRAD001H2307E1
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01888432
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, novartis.email@novartis.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
    10 Oct 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Oct 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate comparable efficacy as measured by the composite efficacy failure of tBPAR, GL or death (D) with everolimus in combination with reduced tacrolimus compared to standard exposure tacrolimus, at 12 months post-transplantation, in living donor liver transplant recipients.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    25 Sep 2013
    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
    India: 29
    Country: Number of subjects enrolled
    Korea, Republic of: 79
    Country: Number of subjects enrolled
    Saudi Arabia: 2
    Country: Number of subjects enrolled
    Singapore: 6
    Country: Number of subjects enrolled
    Taiwan: 79
    Country: Number of subjects enrolled
    Turkey: 14
    Country: Number of subjects enrolled
    United States: 23
    Country: Number of subjects enrolled
    Canada: 10
    Country: Number of subjects enrolled
    Egypt: 5
    Country: Number of subjects enrolled
    Germany: 5
    Country: Number of subjects enrolled
    Italy: 2
    Country: Number of subjects enrolled
    Russian Federation: 2
    Country: Number of subjects enrolled
    Japan: 28
    Worldwide total number of subjects
    284
    EEA total number of subjects
    7
    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)
    284
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 In all, 284 patients were randomized after transplantation to EVR+Reduced TAC group and TAC Control group. Two patients were not eligible and randomized in IRT by mistake and to whom no study medication was given, and so did not have their data included

    Pre-assignment
    Screening details
    		 A total of 494 patients were screened. Of these, 448 patients received a liver transplant and entered the run-in period. Data reported here are the CRAD001H2307 core study results and its extension (CRAD001H2307E1).

    Period 1
    Period 1 title
    12-month analysis (FAS)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 EVR+Reduced TAC
    Arm description
    		 Everolimus + reduced tacrolimus ± corticosteroids
    Arm type
    		 Experimental

    Investigational medicinal product name
    Everolimus
    Investigational medicinal product code
    RAD001
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use, Intravenous use
    Dosage and administration details
    as 1.0 mg, 0.75 and 0.50 mg tablets

    Arm title
    		 TAC Control
    Arm description
    		 Standard tacrolimus ± corticosteroids
    Arm type
    		 Active comparator

    Investigational medicinal product name
    tacrolimus
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    0.5 mg, 1.0 mg and 5.0 mg capsules

    Number of subjects in period 1
    		EVR+Reduced TAC TAC Control
    Started
    142
    142
    Completed
    131
    133
    Not completed
    11
    9
         Adverse event, serious fatal
    4
    3
         Physician decision
    1
    1
         Consent withdrawn by subject
    6
    3
         Lost to follow-up
    -
    2
    Period 2
    Period 2 title
    24-month analysis (FAS)
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 EVR+Reduced TAC
    Arm description
    		 Everolimus + reduced tacrolimus ± corticosteroids
    Arm type
    		 Experimental

    Investigational medicinal product name
    Everolimus
    Investigational medicinal product code
    RAD001
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use, Intravenous use
    Dosage and administration details
    as 1.0 mg, 0.75 and 0.50 mg tablets

    Arm title
    		 TAC Control
    Arm description
    		 Standard tacrolimus ± corticosteroids
    Arm type
    		 Active comparator

    Investigational medicinal product name
    tacrolimus
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    0.5 mg, 1.0 mg and 5.0 mg capsules

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: The study has an long term extension (CRAD001H2307E1) in Japan and approximately 28 patients were to be included to evaluate the long-term efficacy and safety of concentration controlled everolimus regimen plus reduced tacrolimus compared to standard tacrolimus in recipients of living donor liver transplants in Japan who participated in the CRAD001H2307 study. Data reported in this period are from the extension trial (CRAD001H2307E1).
    Number of subjects in period 2
    		EVR+Reduced TAC TAC Control
    Started
    142
    142
    Completed
    125
    125
    Not completed
    17
    17
         Adverse event, serious fatal
    8
    4
         Physician decision
    2
    4
         Consent withdrawn by subject
    7
    6
         Graft loss
    -
    1
         Lost to follow-up
    -
    2
    Period 3
    Period 3 title
    36-month analysis (extension)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 EVR+Reduced TAC
    Arm description
    		 Everolimus + reduced tacrolimus ± corticosteroids
    Arm type
    		 Experimental

    Investigational medicinal product name
    Everolimus
    Investigational medicinal product code
    RAD001
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Intravenous use, Oral use
    Dosage and administration details
    as 1.0 mg, 0.75 and 0.50 mg tablets

    Investigational medicinal product name
    tacrolimus
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    0.5 mg, 1.0 mg and 5.0 mg capsules

    Arm title
    		 TAC Control
    Arm description
    		 Standard tacrolimus ± corticosteroids
    Arm type
    		 Active comparator

    Investigational medicinal product name
    tacrolimus
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    0.5 mg, 1.0 mg and 5.0 mg capsules

    Number of subjects in period 3 [2]
    		EVR+Reduced TAC TAC Control
    Started
    13
    5
    Completed
    12
    5
    Not completed
    1
    0
         Adverse event, serious fatal
    1
    -
    Notes
    [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: The study has an long term extension (CRAD001H2307E1) in Japan and approximately 28 patients were to be included to evaluate the long-term efficacy and safety of concentration controlled everolimus regimen plus reduced tacrolimus compared to standard tacrolimus in recipients of living donor liver transplants in Japan who participated in the CRAD001H2307 study. Data reported in this period are from the extension trial (CRAD001H2307E1).

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    EVR+Reduced TAC
    Reporting group description
    		 Everolimus + reduced tacrolimus ± corticosteroids

    Reporting group title
    TAC Control
    Reporting group description
    		 Standard tacrolimus ± corticosteroids

    Reporting group values
    		 EVR+Reduced TAC TAC Control Total
    Number of subjects
    		 142 142 284
    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)
    		 142 142 284
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 54.2 ( 8.95 ) 52.7 ( 10.41 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 38 43 81
        Male
    		 104 99 203
    Race/Ethnicity, Customized
    Units: Subjects
        Caucasian
    		 30 30 60
        Asian
    		 111 112 223
        Other
    		 1 0 1

    End points

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    End points reporting groups
    Reporting group title
    EVR+Reduced TAC
    Reporting group description
    		 Everolimus + reduced tacrolimus ± corticosteroids

    Reporting group title
    TAC Control
    Reporting group description
    		 Standard tacrolimus ± corticosteroids
    Reporting group title
    EVR+Reduced TAC
    Reporting group description
    		 Everolimus + reduced tacrolimus ± corticosteroids

    Reporting group title
    TAC Control
    Reporting group description
    		 Standard tacrolimus ± corticosteroids
    Reporting group title
    EVR+Reduced TAC
    Reporting group description
    		 Everolimus + reduced tacrolimus ± corticosteroids

    Reporting group title
    TAC Control
    Reporting group description
    		 Standard tacrolimus ± corticosteroids

    Primary: Number of participants with composite efficacy failure of treated biopsy proven acute rejection, graft loss or death in everolimus with reduced tacrolimus group compared to standard tacrolimus

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    End point title
    		 Number of participants with composite efficacy failure of treated biopsy proven acute rejection, graft loss or death in everolimus with reduced tacrolimus group compared to standard tacrolimus
    End point description
    Rate of composite efficacy failure of treated biopsy proven acute rejection (tBPAR ≥ RAI score 3), graft loss (GL) or death (D) in everolimus with reduced tacrolimus group compared to standard tacrolimus at 12 months
    End point type
    Primary
    End point timeframe
    12 months post transplantation
    End point values
    		 EVR+Reduced TAC TAC Control
    Number of subjects analysed
    142
    142
    Units: Participants
    7
    8
    Statistical analysis title
    		 12-month analysis (FAS)
    Statistical analysis description
    non-inferior efficacy failure of the reduced tacrolimus regimen to control by rejecting the null hypothesis.
    Comparison groups
    EVR+Reduced TAC v TAC Control
    Number of subjects included in analysis
    284
    Analysis specification
    Pre-specified
    Analysis type
    		 [1]
    P-value
    		 < 0.001 [2]
    Method
    		 Z-test
    Parameter type
    		 Kaplan-Meier
    Point estimate
    -0.7
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -5.2
         upper limit
    		 3.7
    Notes
    [1] - HO: πT - πC ≥ 0.12 vs. HA: πT - πC < 0.12, where πT and πC are the true proportions of composite efficacy failure of tBPAR, GL, or D, (tBPAR/GL/D) at 12 months post-transplant for the respective treatment groups. The proportion of 0.12, or 12%, was pre-determined as the non-inferiority (NI) margin for composite efficacy failure.
    [2] - Z-test p-value for non-inferiority test (non-inferiority margin = 12%) is for one-sided test and should be compared to 0.05 significance level.

    Secondary: Renal function by estimated glomerular filtration rate (eGFR) from randomization

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    End point title
    		 Renal function by estimated glomerular filtration rate (eGFR) from randomization
    End point description
    Renal function (change in estimated glomerular filtration rate (eGFR)) from randomization to Month 12 post transplantation with everolimus (EVR) in combination with reduced tacrolimus (rTAC) compared to standard exposure tacrolimus (TAC) in living donor liver transplant recipients.
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    		 EVR+Reduced TAC TAC Control
    Number of subjects analysed
    142
    142
    Units: mL/min/1.73 m^2
        least squares mean (standard error)
    -7.94 ( 1.839 )
    -12.09 ( 1.824 )
    Statistical analysis title
    		 12-month
    Comparison groups
    EVR+Reduced TAC v TAC Control
    Number of subjects included in analysis
    284
    Analysis specification
    Pre-specified
    Analysis type
    		 [3]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    4.15
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -0.09
         upper limit
    		 8.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.574
    Notes
    [3] - the null hypothesis below was tested at the one-sided α = 0.05 level: H0: μT - μC ≤ -6 mL/min/1.73 m2 vs. HA: μT - μC > -6 mL/min/1.73 m^2, where μT and μC are the true means of change in eGFR (MDRD-4) from randomization to Month 12 post-transplant for the reduced tacrolimus group and control group, respectively.

    Secondary: Compare renal function over time assessed by the change by eGFR, post-randomization

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    End point title
    		 Compare renal function over time assessed by the change by eGFR, post-randomization
    End point description
    Compare evolution of post-randomization renal function over time assessed by the change in estimated GFR (MDRD-4), including changes from randomization to Months 12 and 24. Rate of change of renal function.
    End point type
    Secondary
    End point timeframe
    Month 24
    End point values
    		 EVR+Reduced TAC TAC Control
    Number of subjects analysed
    142
    142
    Units: Paricipants
        least squares mean (standard error)
    -11.01 ( 1.928 )
    -14.26 ( 1.914 )
    Statistical analysis title
    		 12-month
    Comparison groups
    EVR+Reduced TAC v TAC Control
    Number of subjects included in analysis
    284
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    3.25
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -1.21
         upper limit
    		 7.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.699

    Secondary: Compare incidence of a composite of tBPAR, graft loss, and death

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    End point title
    		 Compare incidence of a composite of tBPAR, graft loss, and death
    End point description
    Compare between the treatment group EVR with rTAC vs standard TAC: incidence of a composite of tBPAR, graft loss, death
    End point type
    Secondary
    End point timeframe
    Month 24 post transplantation
    End point values
    		 EVR+Reduced TAC TAC Control
    Number of subjects analysed
    142
    142
    Units: Participant
        tBPAR/graft loss/death|
    12
    11
        On-treatment tBPAR/graft loss/death|
    7
    9
    No statistical analyses for this end point

    Secondary: Compare incidence of tBPAR

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    End point title
    		 Compare incidence of tBPAR
    End point description
    Compare between the treatment group EVR with rTAC vs standard TAC: Incidence of tBPAR
    End point type
    Secondary
    End point timeframe
    Month 12 and Month 24 post transplantation
    End point values
    		 EVR+Reduced TAC TAC Control
    Number of subjects analysed
    142
    142
    Units: Participants
        tBPAR - month 12|
    3
    5
        tBPAR - month 24|
    4
    6
        On-treatment tBPAR - month 24|
    3
    6
    Statistical analysis title
    		 Month 12
    Comparison groups
    EVR+Reduced TAC v TAC Control
    Number of subjects included in analysis
    284
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Kaplan-Meier
    Point estimate
    -1.4
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -4.7
         upper limit
    		 2
    Statistical analysis title
    		 Month 24 (tBPAR)
    Comparison groups
    EVR+Reduced TAC v TAC Control
    Number of subjects included in analysis
    284
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Kaplan-Meier
    Point estimate
    -1.2
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -5.1
         upper limit
    		 2.6
    Statistical analysis title
    		 Month 24 (on-treatment tBPAR)
    Comparison groups
    EVR+Reduced TAC v TAC Control
    Number of subjects included in analysis
    284
    Analysis specification
    Pre-specified
    Analysis type
    		 [4]
    Method
    Parameter type
    		 Kaplan-Meier
    Point estimate
    -2.1
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -5.7
         upper limit
    		 1.4
    Notes
    [4] - On-treatment tBPAR - month 24

    Secondary: Compare incidence of BPAR

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    End point title
    		 Compare incidence of BPAR
    End point description
    Compare between the treatment group EVR with rTAC vs standard TAC: incidence of a composite of biopsy proven acute rejection (BPAR)
    End point type
    Secondary
    End point timeframe
    Month 12 and Month 24 post transplantation
    End point values
    		 EVR+Reduced TAC TAC Control
    Number of subjects analysed
    142
    142
    Units: Participants
        Month 12|
    7
    6
        Month 24|
    8
    7
    Statistical analysis title
    		 Month 12
    Comparison groups
    EVR+Reduced TAC v TAC Control
    Number of subjects included in analysis
    284
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Kaplan-Meier
    Point estimate
    0.9
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -3.4
         upper limit
    		 5.1
    Statistical analysis title
    		 Month 24
    Comparison groups
    EVR+Reduced TAC v TAC Control
    Number of subjects included in analysis
    284
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Kaplan-Meier
    Point estimate
    1
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -3.6
         upper limit
    		 5.6

    Secondary: Compare incidence of graft loss

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    End point title
    		 Compare incidence of graft loss
    End point description
    Compare between the treatment group EVR with rTAC vs standard TAC: incidence of graft loss
    End point type
    Secondary
    End point timeframe
    Month 12 and Month 24 post transplantation
    End point values
    		 EVR+Reduced TAC TAC Control
    Number of subjects analysed
    142
    142
    Units: Participants
        Month 12|
    0
    0
        month 24|
    0
    1
        month 24 (on-treatment graft loss)|
    0
    0
    Statistical analysis title
    		 graft loss at month 24
    Comparison groups
    EVR+Reduced TAC v TAC Control
    Number of subjects included in analysis
    284
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Kaplan-Meier
    Point estimate
    -0.8
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -2.1
         upper limit
    		 0.5

    Secondary: Compare incidence of a composite of death or graft loss

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    End point title
    		 Compare incidence of a composite of death or graft loss
    End point description
    Compare between the treatment group EVR with rTAC vs standard TAC: Incidence of a composite of death or graft loss
    End point type
    Secondary
    End point timeframe
    Month 12 and Month 24 post transplantation
    End point values
    		 EVR+Reduced TAC TAC Control
    Number of subjects analysed
    142
    142
    Units: Participants
        Month 12|
    4
    3
        Month 24|
    8
    5
    Statistical analysis title
    		 Month 24
    Comparison groups
    EVR+Reduced TAC v TAC Control
    Number of subjects included in analysis
    284
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Kaplan-Meier
    Point estimate
    2.3
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -2.1
         upper limit
    		 6.6
    Statistical analysis title
    		 Month 12
    Comparison groups
    EVR+Reduced TAC v TAC Control
    Number of subjects included in analysis
    284
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Kaplan-Meier
    Point estimate
    0.7
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -2.5
         upper limit
    		 3.8

    Secondary: Compare incidence of death

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    End point title
    		 Compare incidence of death
    End point description
    Compare between the treatment group EVR with rTAC vs standard TAC: incidence of death
    End point type
    Secondary
    End point timeframe
    Month 12 and Month 24 post transplantation
    End point values
    		 EVR+Reduced TAC TAC Control
    Number of subjects analysed
    142
    142
    Units: Participants
        Month 12|
    4
    3
        Month 24|
    8
    4
        Month 24 (on-treatment death)|
    4
    3
    Statistical analysis title
    		 Month 12
    Comparison groups
    EVR+Reduced TAC v TAC Control
    Number of subjects included in analysis
    284
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Kaplan-Meier
    Point estimate
    0.7
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -2.5
         upper limit
    		 3.8
    Statistical analysis title
    		 Month 24
    Comparison groups
    EVR+Reduced TAC v TAC Control
    Number of subjects included in analysis
    284
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Kaplan-Meier
    Point estimate
    3
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -1.1
         upper limit
    		 7.2
    Statistical analysis title
    		 Month 24 (On-treatment death)
    Comparison groups
    EVR+Reduced TAC v TAC Control
    Number of subjects included in analysis
    284
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Kaplan-Meier
    Point estimate
    0.7
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -2.5
         upper limit
    		 3.9

    Secondary: Compare incidence of AR

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    End point title
    		 Compare incidence of AR
    End point description
    Compare between the treatment group EVR with rTAC vs standard TAC: incidence of acute rejection (AR)
    End point type
    Secondary
    End point timeframe
    Month 12 and Month 24 post transplantation
    End point values
    		 EVR+Reduced TAC TAC Control
    Number of subjects analysed
    142
    142
    Units: Participants
        Month 12|
    9
    8
        Month 24|
    12
    9
    Statistical analysis title
    		 Incidence rate of AR - month 12
    Comparison groups
    EVR+Reduced TAC v TAC Control
    Number of subjects included in analysis
    284
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.7
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -3.9
         upper limit
    		 5.3
    Statistical analysis title
    		 Incidence rate of AR - month 24
    Comparison groups
    EVR+Reduced TAC v TAC Control
    Number of subjects included in analysis
    284
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    2.1
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -3
         upper limit
    		 7.2

    Secondary: Compare incidence of tAR

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    End point title
    		 Compare incidence of tAR
    End point description
    Compare between the treatment group EVR with rTAC vs standard TAC: incidence of treated acute rejection (tAR).
    End point type
    Secondary
    End point timeframe
    Month 12 and Month 24 post transplantation
    End point values
    		 EVR+Reduced TAC TAC Control
    Number of subjects analysed
    142
    142
    Units: Participants
        Month 12|
    5
    6
        Month 24|
    7
    7
    Statistical analysis title
    		 Incidence rate of tAR - month 12
    Comparison groups
    EVR+Reduced TAC v TAC Control
    Number of subjects included in analysis
    284
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    -0.7
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -4.5
         upper limit
    		 3.1
    Statistical analysis title
    		 Incidence rate of tAR - month 24
    Comparison groups
    EVR+Reduced TAC v TAC Control
    Number of subjects included in analysis
    284
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -4.2
         upper limit
    		 4.2

    Secondary: Compare time to recurrence of HCC in subjects with a diagnosis of HCC at the time of liver transplantation

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    End point title
    		 Compare time to recurrence of HCC in subjects with a diagnosis of HCC at the time of liver transplantation
    End point description
    Patients transplanted for HCC or with HCC diagnosed at time of transplantation were monitored for HCC recurrence according to local practice. For example routine laboratory monitoring/tests, tumor markers, hepatic ultrasound, computed tomography scans (CAT, CT) or MRI (especially Fe-MRI) on a regular basis per local practice.
    End point type
    Secondary
    End point timeframe
    Month 12 and Month 24
    End point values
    		 EVR+Reduced TAC TAC Control
    Number of subjects analysed
    142
    141
    Units: Participants
        HCC recurrence (n/M) - month 12|
    0
    5
        HCC recurrence (n/M) - month 24|
    1
    6
    No statistical analyses for this end point

    Secondary: Number of subjects experiencing adverse events/infections by SOC

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    End point title
    		 Number of subjects experiencing adverse events/infections by SOC
    End point description
    End point type
    Secondary
    End point timeframe
    Month 24
    End point values
    		 EVR+Reduced TAC TAC Control
    Number of subjects analysed
    142
    141
    Units: Participants
        Any AE/infection|
    140
    136
        Blood and lymphatic system disorders|
    44
    32
        Cardiac disorders|
    15
    12
        Congenital, familial and genetic disorders|
    1
    2
        Ear and labyrinth disorders|
    2
    5
        Endocrine disorders|
    1
    2
        Eye disorders|
    17
    15
        Gastrointestinal disorders|
    98
    74
        General disorders&admin site conditions|
    48
    42
        Hepatobiliary disorders|
    44
    40
        Immune system disorders|
    8
    11
        Infections and infestations|
    84
    70
        Injury, poisoning&proced. complications|
    36
    28
        Investigations|
    61
    68
        Metabolism and nutrition disorders|
    87
    60
        Musculoskeletal and connective tissue disorders|
    30
    43
        Neo benign, malig&unspecified (cysts&polyps)|
    10
    17
        Nervous system disorders|
    38
    44
        Product issues#|
    1
    1
        Psychiatric disorders|
    33
    26
        Renal and urinary disorders|
    46
    36
        Reproductive system&breast dis.|
    9
    12
        Respiratory, thoracic&mediastinal dis.|
    34
    39
        Skin&subcutaneous tissue disorders|
    39
    44
        Vascular disorders|
    38
    30
    No statistical analyses for this end point

    Secondary: Compare incidence of notable safety events (SAEs, infections and serious infections leading to premature discontinuation)

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    End point title
    		 Compare incidence of notable safety events (SAEs, infections and serious infections leading to premature discontinuation)
    End point description
    Notable events include death, Serious AE/infection,, and AE/infection leading to discontinuation of study medication.
    End point type
    Secondary
    End point timeframe
    Month 24
    End point values
    		 EVR+Reduced TAC TAC Control
    Number of subjects analysed
    142
    141
    Units: Participants
        Any notable events|
    86
    82
        Death|
    8
    4
        Serious AE/Infection|
    83
    78
        AE/Infection lead. to premature disc of study med|
    21
    18
    No statistical analyses for this end point

    Other pre-specified: Composite efficacy failure of treated biopsy in everolimus with reduced tacrolimus group compared to standard tacrolimus in patients from Japan only

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    End point title
    		 Composite efficacy failure of treated biopsy in everolimus with reduced tacrolimus group compared to standard tacrolimus in patients from Japan only
    End point description
    Rate of composite efficacy failure of treated biopsy in everolimus with reduced tacrolimus group compared to standard tacrolimus from randomization in core study up to 36 months in the extension study. Composite endpoint = treated BPAR, graft loss or death. AR = Acute rejection; tAR = treated AR; BPR = biopsy proven rejection; BPAR = biopsy proven acute rejection; tBPAR = treated BPAR
    End point type
    Other pre-specified
    End point timeframe
    From randomization in core study up to 36 months post transplantion
    End point values
    		 EVR+Reduced TAC TAC Control
    Number of subjects analysed
    16
    12
    Units: Participants
        Composite endpoint
    2
    1
        On-treatment composite endpoint
    1
    0
        Graft loss/death
    1
    1
        tBPAR
    2
    0
        Graft loss
    0
    1
        Death
    1
    0
        AR
    3
    2
        tAR
    2
    0
        BPR
    6
    3
        BPAR
    3
    2
    Statistical analysis title
    		 Composite endpoint up to 36 months
    Comparison groups
    EVR+Reduced TAC v TAC Control
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in Kaplan-Meier estimate
    Point estimate
    5.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -19.9
         upper limit
    		 30.6
    Statistical analysis title
    		 On-treatment composite endpoint up to 36 months
    Comparison groups
    EVR+Reduced TAC v TAC Control
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in Kaplan-Meier estimate
    Point estimate
    6.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6
         upper limit
    		 19.3
    Statistical analysis title
    		 Graft loss/death at up to 36 months
    Comparison groups
    EVR+Reduced TAC v TAC Control
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in Kaplan-Meier estimate
    Point estimate
    2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -24.6
         upper limit
    		 28.7
    Statistical analysis title
    		 tBPAR up to 36 months
    Comparison groups
    TAC Control v EVR+Reduced TAC
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in Kaplan-Meier estimate
    Point estimate
    14.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.2
         upper limit
    		 33.1
    Statistical analysis title
    		 Death up to 36 months
    Comparison groups
    EVR+Reduced TAC v TAC Control
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in Kaplan-Meier estimate
    Point estimate
    11.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.4
         upper limit
    		 31.6
    Statistical analysis title
    		 AR up to 36 months
    Comparison groups
    EVR+Reduced TAC v TAC Control
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in Kaplan-Meier estimate
    Point estimate
    3.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -28.9
         upper limit
    		 35.2
    Statistical analysis title
    		 tAR up to 36 months
    Comparison groups
    TAC Control v EVR+Reduced TAC
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in Kaplan-Meier estimate
    Point estimate
    14.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.2
         upper limit
    		 33.1
    Statistical analysis title
    		 BPR up to 36 months
    Comparison groups
    EVR+Reduced TAC v TAC Control
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in Kaplan-Meier estimate
    Point estimate
    14.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -22.3
         upper limit
    		 52.1
    Statistical analysis title
    		 BPAR up to 36 months
    Comparison groups
    EVR+Reduced TAC v TAC Control
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in Kaplan-Meier estimate
    Point estimate
    3.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -28.9
         upper limit
    		 35.2

    Other pre-specified: Renal function by estimated Glomerular Filtration Rate (all extension patients)

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    End point title
    		 Renal function by estimated Glomerular Filtration Rate (all extension patients)
    End point description
    Renal function (change in estimated glomerular filtration rate (eGFR)) from randomization to Month 36 post transplantation with everolimus (EVR) in combination with reduced tacrolimus (rTAC) compared to standard exposure tacrolimus (TAC) in living donor liver transplant recipients in Japan.
    End point type
    Other pre-specified
    End point timeframe
    randomization, at 36 months post transplantation
    End point values
    		 EVR+Reduced TAC TAC Control
    Number of subjects analysed
    13
    5
    Units: mL/min/1.73m2
        least squares mean (standard error)
    -26.88 ( 10.114 )
    -16.87 ( 19.412 )
    Statistical analysis title
    		 eGFR (all extension patients)
    Comparison groups
    EVR+Reduced TAC v TAC Control
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Median difference (final values)
    Point estimate
    -10.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -59.91
         upper limit
    		 39.89
    Variability estimate
    Standard error of the mean
    Dispersion value
    22.059

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events (AEs) are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All AEs reported in this record are from date of First Patient First Treatment until Last Patient Last Visit) up to approximately 4 years.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    EVR+Reduced TAC
    Reporting group description
    		 EVR+Reduced TAC

    Reporting group title
    TAC Control
    Reporting group description
    		 TAC Control

    Serious adverse events
    		 EVR+Reduced TAC TAC Control
    Total subjects affected by serious adverse events
         subjects affected / exposed
    83 / 142 (58.45%)
    78 / 141 (55.32%)
         number of deaths (all causes)
    8
    4
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of colon
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone giant cell tumour
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic angiosarcoma
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic neoplasm
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatocellular carcinoma
         subjects affected / exposed
    1 / 142 (0.70%)
    4 / 141 (2.84%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Lipofibroma
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    2 / 142 (1.41%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to bone
         subjects affected / exposed
    0 / 142 (0.00%)
    2 / 141 (1.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metastases to central nervous system
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to lung
         subjects affected / exposed
    0 / 142 (0.00%)
    5 / 141 (3.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metastases to spine
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (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 of the hypopharynx
         subjects affected / exposed
    1 / 142 (0.70%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Squamous cell carcinoma of the oral cavity
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Vascular disorders
    Arterial haemorrhage
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hot flush
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphangiopathy
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vena cava thrombosis
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous stenosis
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Crepitations
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperpyrexia
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incarcerated hernia
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    11 / 142 (7.75%)
    8 / 141 (5.67%)
         occurrences causally related to treatment / all
    2 / 15
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Liver transplant rejection
         subjects affected / exposed
    3 / 142 (2.11%)
    3 / 141 (2.13%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transplant rejection
         subjects affected / exposed
    2 / 142 (1.41%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (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 / 142 (0.70%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 142 (0.70%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngeal ulceration
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (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
    1 / 142 (0.70%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary infarction
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pulmonary mass
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Wheezing
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Alcoholism
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Insomnia
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicidal behaviour
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (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
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 142 (0.00%)
    2 / 141 (1.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    4 / 142 (2.82%)
    2 / 141 (1.42%)
         occurrences causally related to treatment / all
    0 / 7
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immunosuppressant drug level increased
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test increased
         subjects affected / exposed
    1 / 142 (0.70%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    1 / 142 (0.70%)
    2 / 141 (1.42%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Anastomotic stenosis
         subjects affected / exposed
    2 / 142 (1.41%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary anastomosis complication
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Burns second degree
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chemical peritonitis
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Graft loss
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incarcerated incisional hernia
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incision site pain
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incisional hernia
         subjects affected / exposed
    5 / 142 (3.52%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple injuries
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural bile leak
         subjects affected / exposed
    1 / 142 (0.70%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural inflammation
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural complication
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    1 / 142 (0.70%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    2 / 142 (1.41%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac discomfort
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Altered state of consciousness
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Dizziness
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 142 (0.00%)
    2 / 141 (1.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoaesthesia
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Restless legs syndrome
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 142 (0.70%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Tremor
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wernicke's encephalopathy
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         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
    2 / 142 (1.41%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombotic microangiopathy
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 142 (0.70%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lens dislocation
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal hernia
         subjects affected / exposed
    3 / 142 (2.11%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal incarcerated hernia
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    7 / 142 (4.93%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal incontinence
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 142 (0.00%)
    2 / 141 (1.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Crohn's disease
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 142 (1.41%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal perforation
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    1 / 142 (0.70%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer haemorrhage
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal inflammation
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 142 (0.70%)
    1 / 141 (0.71%)
         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
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incarcerated umbilical hernia
         subjects affected / exposed
    1 / 142 (0.70%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 142 (0.00%)
    2 / 141 (1.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intra-abdominal fluid collection
         subjects affected / exposed
    1 / 142 (0.70%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukoplakia oral
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mesenteric haemorrhage
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 142 (0.70%)
    1 / 141 (0.71%)
         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 / 142 (0.70%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parotid gland enlargement
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peptic ulcer perforation
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pouchitis
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal haemorrhage
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Small intestine ulcer
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Strangulated umbilical hernia
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 142 (1.41%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Autoimmune hepatitis
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bile duct obstruction
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bile duct stenosis
         subjects affected / exposed
    10 / 142 (7.04%)
    6 / 141 (4.26%)
         occurrences causally related to treatment / all
    0 / 19
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bile duct stone
         subjects affected / exposed
    2 / 142 (1.41%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary cirrhosis primary
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary dilatation
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary fistula
         subjects affected / exposed
    2 / 142 (1.41%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biloma
         subjects affected / exposed
    1 / 142 (0.70%)
    2 / 141 (1.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    8 / 142 (5.63%)
    9 / 141 (6.38%)
         occurrences causally related to treatment / all
    2 / 12
    0 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis acute
         subjects affected / exposed
    2 / 142 (1.41%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis obstructive
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dilatation intrahepatic duct acquired
         subjects affected / exposed
    1 / 142 (0.70%)
    2 / 141 (1.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic artery thrombosis
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic steatosis
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis cholestatic
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    0 / 142 (0.00%)
    2 / 141 (1.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Portal vein stenosis
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Portal vein thrombosis
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         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
    Skin ulcer
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 142 (1.41%)
    2 / 141 (1.42%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chromaturia
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    2 / 142 (1.41%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proteinuria
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    2 / 142 (1.41%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         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 / 142 (1.41%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 142 (0.00%)
    2 / 141 (1.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spondylolisthesis
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal abscess
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriovenous graft site infection
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary tract infection
         subjects affected / exposed
    1 / 142 (0.70%)
    2 / 141 (1.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    3 / 142 (2.11%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    3 / 142 (2.11%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus viraemia
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea infectious
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterococcal bacteraemia
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epididymitis
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fungal sepsis
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    4 / 142 (2.82%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis norovirus
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Groin abscess
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis C
         subjects affected / exposed
    5 / 142 (3.52%)
    3 / 141 (2.13%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hepatitis E
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 142 (0.70%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed
    2 / 142 (1.41%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Orchitis
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (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
    10 / 142 (7.04%)
    5 / 141 (3.55%)
         occurrences causally related to treatment / all
    2 / 11
    1 / 6
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Pneumonia legionella
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural cellulitis
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural sepsis
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostatic abscess
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 142 (0.70%)
    2 / 141 (1.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic infection
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         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 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 142 (2.11%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection bacterial
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 142 (0.70%)
    3 / 141 (2.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    2 / 142 (1.41%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fluid overload
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gout
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 142 (0.70%)
    3 / 141 (2.13%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertriglyceridaemia
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (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
    2 / 142 (1.41%)
    2 / 141 (1.42%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obesity
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 EVR+Reduced TAC TAC Control
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    125 / 142 (88.03%)
    120 / 141 (85.11%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    29 / 142 (20.42%)
    23 / 141 (16.31%)
         occurrences all number
    31
    25
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    16 / 142 (11.27%)
    8 / 141 (5.67%)
         occurrences all number
    17
    11
    Pyrexia
         subjects affected / exposed
    18 / 142 (12.68%)
    20 / 141 (14.18%)
         occurrences all number
    40
    29
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    12 / 142 (8.45%)
    15 / 141 (10.64%)
         occurrences all number
    14
    16
    Psychiatric disorders
    Depression
         subjects affected / exposed
    2 / 142 (1.41%)
    8 / 141 (5.67%)
         occurrences all number
    2
    8
    Insomnia
         subjects affected / exposed
    26 / 142 (18.31%)
    13 / 141 (9.22%)
         occurrences all number
    31
    17
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    5 / 142 (3.52%)
    8 / 141 (5.67%)
         occurrences all number
    5
    8
    Blood creatinine increased
         subjects affected / exposed
    10 / 142 (7.04%)
    13 / 141 (9.22%)
         occurrences all number
    11
    21
    Hepatic enzyme abnormal
         subjects affected / exposed
    8 / 142 (5.63%)
    19 / 141 (13.48%)
         occurrences all number
    13
    36
    Hepatic enzyme increased
         subjects affected / exposed
    16 / 142 (11.27%)
    19 / 141 (13.48%)
         occurrences all number
    21
    29
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    3 / 142 (2.11%)
    9 / 141 (6.38%)
         occurrences all number
    3
    9
    Headache
         subjects affected / exposed
    19 / 142 (13.38%)
    14 / 141 (9.93%)
         occurrences all number
    21
    18
    Tremor
         subjects affected / exposed
    4 / 142 (2.82%)
    11 / 141 (7.80%)
         occurrences all number
    4
    11
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    18 / 142 (12.68%)
    15 / 141 (10.64%)
         occurrences all number
    20
    20
    Leukopenia
         subjects affected / exposed
    16 / 142 (11.27%)
    7 / 141 (4.96%)
         occurrences all number
    34
    8
    Thrombocytopenia
         subjects affected / exposed
    14 / 142 (9.86%)
    3 / 141 (2.13%)
         occurrences all number
    14
    4
    Eye disorders
    Cataract
         subjects affected / exposed
    8 / 142 (5.63%)
    4 / 141 (2.84%)
         occurrences all number
    8
    4
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    19 / 142 (13.38%)
    12 / 141 (8.51%)
         occurrences all number
    19
    15
    Constipation
         subjects affected / exposed
    13 / 142 (9.15%)
    16 / 141 (11.35%)
         occurrences all number
    18
    16
    Diarrhoea
         subjects affected / exposed
    32 / 142 (22.54%)
    19 / 141 (13.48%)
         occurrences all number
    41
    28
    Nausea
         subjects affected / exposed
    7 / 142 (4.93%)
    9 / 141 (6.38%)
         occurrences all number
    7
    9
    Mouth ulceration
         subjects affected / exposed
    17 / 142 (11.97%)
    6 / 141 (4.26%)
         occurrences all number
    18
    7
    Stomatitis
         subjects affected / exposed
    19 / 142 (13.38%)
    5 / 141 (3.55%)
         occurrences all number
    25
    6
    Vomiting
         subjects affected / exposed
    7 / 142 (4.93%)
    10 / 141 (7.09%)
         occurrences all number
    12
    11
    Hepatobiliary disorders
    Hepatic steatosis
         subjects affected / exposed
    10 / 142 (7.04%)
    7 / 141 (4.96%)
         occurrences all number
    10
    7
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    22 / 142 (15.49%)
    18 / 141 (12.77%)
         occurrences all number
    26
    22
    Rash
         subjects affected / exposed
    7 / 142 (4.93%)
    10 / 141 (7.09%)
         occurrences all number
    11
    10
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    3 / 142 (2.11%)
    13 / 141 (9.22%)
         occurrences all number
    3
    15
    Renal impairment
         subjects affected / exposed
    11 / 142 (7.75%)
    5 / 141 (3.55%)
         occurrences all number
    12
    7
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 142 (3.52%)
    9 / 141 (6.38%)
         occurrences all number
    5
    9
    Back pain
         subjects affected / exposed
    8 / 142 (5.63%)
    10 / 141 (7.09%)
         occurrences all number
    8
    10
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    20 / 142 (14.08%)
    16 / 141 (11.35%)
         occurrences all number
    38
    22
    Upper respiratory tract infection
         subjects affected / exposed
    18 / 142 (12.68%)
    11 / 141 (7.80%)
         occurrences all number
    25
    17
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    9 / 142 (6.34%)
    13 / 141 (9.22%)
         occurrences all number
    10
    14
    Dyslipidaemia
         subjects affected / exposed
    13 / 142 (9.15%)
    4 / 141 (2.84%)
         occurrences all number
    14
    5
    Hypercholesterolaemia
         subjects affected / exposed
    22 / 142 (15.49%)
    2 / 141 (1.42%)
         occurrences all number
    31
    2
    Hyperkalaemia
         subjects affected / exposed
    20 / 142 (14.08%)
    13 / 141 (9.22%)
         occurrences all number
    25
    21
    Hyperlipidaemia
         subjects affected / exposed
    22 / 142 (15.49%)
    8 / 141 (5.67%)
         occurrences all number
    23
    8
    Hyperuricaemia
         subjects affected / exposed
    7 / 142 (4.93%)
    8 / 141 (5.67%)
         occurrences all number
    9
    11
    Hypokalaemia
         subjects affected / exposed
    10 / 142 (7.04%)
    3 / 141 (2.13%)
         occurrences all number
    11
    4
    Hypomagnesaemia
         subjects affected / exposed
    10 / 142 (7.04%)
    11 / 141 (7.80%)
         occurrences all number
    13
    14

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Jan 2015
    The amendment introduced the following changes: 1. The sample size reduction and power recalculation 2. A standardized definition for the assessment of NODM 3. The central reading of the tumor biopsy from the explanted liver of patients with HCC

    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.
    Data recorded here are the CRAD001H2307 core study results and its extension trial (CRAD001H2307E1) in Japan.
    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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