Flag of the European Union EU Clinical Trials Register Help

Clinical trials

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

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


    The EU Clinical Trials Register currently displays   43936   clinical trials with a EudraCT protocol, of which   7310   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

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

    < Back to search results

    Download PDF

    Clinical Trial Results:
    A Phase III randomized, double-blind, placebo-controlled study of sorafenib as adjuvant treatment for hepatocellular carcinoma after surgical resection or local ablation

    Summary
    EudraCT number
    2008-001087-36
    Trial protocol
    SE   GB   ES   AT   BE   FR   IT   PT   DE   GR   BG  
    Global end of trial date
    28 Nov 2014

    Results information
    Results version number
    v4(current)
    This version publication date
    17 Feb 2019
    First version publication date
    24 May 2015
    Other versions
    v1 , v2 , v3
    Version creation reason
    • Correction of full data set
    Control of data.

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    BAY43-9006/12414
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00692770
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Bayer AG
    Sponsor organisation address
    Kaiser-Wilhelm-Allee, Leverkusen, Germany, D-51368
    Public contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
    Scientific contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.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
    27 Feb 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Nov 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Nov 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy and safety of sorafenib versus placebo in the adjuvant treatment of hepatocellular carcinoma (HCC) after potentially curative treatment with surgical resection or local ablation.
    Protection of trial subjects
    The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and the International Conference on Harmonization guideline E6: Good Clinical Practice. A core information and informed consent form was provided. Prior to the beginning of the study, the investigator was required to have the Ethics committee's written approval / favorable opinion of the written informed consent form and any other written information to be provided to subjects. Before entering the study, the informed consent form was read by and explained to all subjects or their legally authorized representative. Each subject had ample opportunity to ask questions and was assured of the right to withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. For the collection of images in post-study follow up, the investigator was required to obtain written informed consent from the subject prior to performing any computed tomography / magnetic resonance imaging scan or chest X-ray imaging procedures according to the protocol image acquisition guidelines.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    15 Aug 2008
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    12 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Portugal: 1
    Country: Number of subjects enrolled
    Romania: 14
    Country: Number of subjects enrolled
    Spain: 25
    Country: Number of subjects enrolled
    Sweden: 7
    Country: Number of subjects enrolled
    United Kingdom: 9
    Country: Number of subjects enrolled
    Austria: 17
    Country: Number of subjects enrolled
    Belgium: 13
    Country: Number of subjects enrolled
    Bulgaria: 1
    Country: Number of subjects enrolled
    France: 59
    Country: Number of subjects enrolled
    Germany: 25
    Country: Number of subjects enrolled
    Greece: 1
    Country: Number of subjects enrolled
    Italy: 146
    Country: Number of subjects enrolled
    Argentina: 3
    Country: Number of subjects enrolled
    Brazil: 7
    Country: Number of subjects enrolled
    Canada: 13
    Country: Number of subjects enrolled
    Chile: 1
    Country: Number of subjects enrolled
    Mexico: 5
    Country: Number of subjects enrolled
    United States: 91
    Country: Number of subjects enrolled
    Australia: 8
    Country: Number of subjects enrolled
    China: 256
    Country: Number of subjects enrolled
    Hong Kong: 31
    Country: Number of subjects enrolled
    Japan: 149
    Country: Number of subjects enrolled
    Korea, Democratic People's Republic of: 126
    Country: Number of subjects enrolled
    New Zealand: 9
    Country: Number of subjects enrolled
    Singapore: 13
    Country: Number of subjects enrolled
    Taiwan: 68
    Country: Number of subjects enrolled
    Switzerland: 5
    Country: Number of subjects enrolled
    Russian Federation: 11
    Worldwide total number of subjects
    1114
    EEA total number of subjects
    318
    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)
    744
    From 65 to 84 years
    369
    85 years and over
    1

    Subject disposition

    Close Top of page
    Recruitment
    Recruitment details
    Subject recruitment period was between 15 August 2008 to 12 November 2010.

    Pre-assignment
    Screening details
    Of 1602 participants who were screened for inclusion in the study, 1114 were enrolled, and 1107 received treatment.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Sorafenib (Nexavar, BAY43-9006)
    Arm description
    Subjects received 2 tablets of Sorafenib [2*200 milligram (mg)] orally twice daily.
    Arm type
    Experimental

    Investigational medicinal product name
    Sorafenib
    Investigational medicinal product code
    BAY43-9006
    Other name
    Nexavar
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received an oral dose of sorafenib 400 mg tablets (each containing 200 mg) twice daily, on a continuous basis until a criterion for withdrawal was reached. Doses could be interrupted or reduced due to clinically significant toxicities that were considered related to protocol therapy.

    Arm title
    Placebo
    Arm description
    Subjects received 2 tablets of placebo orally twice daily.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received an oral dose of placebo matching to sorafenib 400 mg tablets (each containing 200 mg) twice daily, on a continuous basis until a criterion for withdrawal was reached. Doses could be interrupted or reduced due to clinically significant toxicities that were considered related to protocol therapy.

    Number of subjects in period 1
    Sorafenib (Nexavar, BAY43-9006) Placebo
    Started
    556
    558
    Study drug administered
    553
    554
    Completed
    82
    107
    Not completed
    474
    451
         Disease progression, recurrence or relapse
    165
    274
         Protocol driven decision point
    3
    -
         Non-compliant with study medication
    11
    5
         Adverse event
    133
    41
         Radiological and clinical progression
    8
    8
         Consent withdrawn by subject
    93
    35
         Protocol violation
    2
    7
         Randomized but not treated
    3
    4
         Death
    10
    5
         Completed all planned assessments
    35
    65
         Investigator decision not protocol driven
    2
    1
         Lost to follow-up
    7
    3
         Progression by clinical judgment
    2
    3

    Baseline characteristics

    Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Sorafenib (Nexavar, BAY43-9006)
    Reporting group description
    Subjects received 2 tablets of Sorafenib [2*200 milligram (mg)] orally twice daily.

    Reporting group title
    Placebo
    Reporting group description
    Subjects received 2 tablets of placebo orally twice daily.

    Reporting group values
    Sorafenib (Nexavar, BAY43-9006) Placebo Total
    Number of subjects
    556 558 1114
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    383 361 744
        From 65-84 years
    173 197 370
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    58.1 ± 11.7 58.7 ± 12.2 -
    Gender categorical
    Units: Subjects
        Female
    105 97 202
        Male
    451 461 912

    End points

    Close Top of page
    End points reporting groups
    Reporting group title
    Sorafenib (Nexavar, BAY43-9006)
    Reporting group description
    Subjects received 2 tablets of Sorafenib [2*200 milligram (mg)] orally twice daily.

    Reporting group title
    Placebo
    Reporting group description
    Subjects received 2 tablets of placebo orally twice daily.

    Primary: Recurrence Free Survival (RFS) by Independent Assessment

    Close Top of page
    End point title
    Recurrence Free Survival (RFS) by Independent Assessment
    End point description
    Disease recurrence of HCC (intra or extra hepatic) was defined as the appearance of a new intrahepatic lesions fulfilling the American Association for the Study of Liver Diseases (AASLD) criteria of diagnosis of HCC or a new extra-hepatic lesions according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria version 1.0. In addition to investigator assessment, all images were reviewed by an independent panel of radiologists. The calculation of the RFS was based on the independent evaluation of the scans. RFS was defined as the time from randomization to the first documented disease recurrence by independent radiological assessment or death due to any cause whichever occurred first. For subjects who had not recurred or died at the time of analysis, RFS was censored at their last date of evaluable scan before drop-out for any other reason than recurrence or death.
    End point type
    Primary
    End point timeframe
    From randomization up to 4 years or until disease recurrence whichever came first
    End point values
    Sorafenib (Nexavar, BAY43-9006) Placebo
    Number of subjects analysed
    556
    558
    Units: days
        median (confidence interval 95%)
    1014 (839 to 1339)
    1026 (841 to 1185)
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Placebo v Sorafenib (Nexavar, BAY43-9006)
    Number of subjects included in analysis
    1114
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.258329 [1]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.94
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.78
         upper limit
    1.134
    Notes
    [1] - One sided P-value was stratified by region, risk of recurrence and previous curative treatment.

    Secondary: Time to Recurrence (TTR) by Independent Assessment

    Close Top of page
    End point title
    Time to Recurrence (TTR) by Independent Assessment
    End point description
    TTR was defined as the time from randomization to the first documented disease recurrence by independent radiological assessment. For subjects who had not recurred at the time of analysis, TTR was censored at their last date of evaluable scan before withdrawal for any other reason than recurrence. '99999' in the reported data indicates value could not be estimated due to censored data.
    End point type
    Secondary
    End point timeframe
    From randomization up to 4 years or until disease recurrence whichever came first
    End point values
    Sorafenib (Nexavar, BAY43-9006) Placebo
    Number of subjects analysed
    556
    558
    Units: days
        median (confidence interval 95%)
    1172 (924 to 99999)
    1089 (923 to 1260)
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Sorafenib (Nexavar, BAY43-9006) v Placebo
    Number of subjects included in analysis
    1114
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.121383 [2]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.891
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.735
         upper limit
    1.081
    Notes
    [2] - One-sided P-value was stratified by region, risk of recurrence and previous curative treatment

    Secondary: Overall Survival (OS)

    Close Top of page
    End point title
    Overall Survival (OS)
    End point description
    OS was defined as the time from randomization to date of death due to any cause. OS for subjects alive at the time of analysis was censored at their last date of contact. '99999' in the reported data indicates value could not be estimated due to censored data.
    End point type
    Secondary
    End point timeframe
    From randomization of the first subject until 4 years later.
    End point values
    Sorafenib (Nexavar, BAY43-9006) Placebo
    Number of subjects analysed
    556
    558
    Units: days
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Sorafenib (Nexavar, BAY43-9006) v Placebo
    Number of subjects included in analysis
    1114
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.484742 [3]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.995
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.761
         upper limit
    1.3
    Notes
    [3] - One-sided P-value was stratified by region, risk of recurrence and previous curative treatment

    Other pre-specified: Patient Reported Outcomes: Euroqol-5 Dimensions (EQ-5D) - Index Score

    Close Top of page
    End point title
    Patient Reported Outcomes: Euroqol-5 Dimensions (EQ-5D) - Index Score
    End point description
    The EQ-5D is a generic quality of life preference based on a validated instrument used in cancer and in general population, with 2 parts: Index and Visual Analogue Scale. The EQ-5D Index is a descriptive system of the following health dimensions: mobility, selfcare, usual activities, pain/discomfort, and anxiety/depression. Subjects were asked to choose any one of the 3 response levels for each dimension: no problems, some problems, and severe problems. The 5 health dimensions were summarized into a single score, the EQ-5D Index score which ranged from -0.59 to 1 with higher scores representing better health states (0=death, 1= perfect health, and -0.59=a health state worse than death). A change of at least 0.10 to 0.12 points was considered a minimally important difference using Eastern Cooperative Oncology Group Performance Status as the anchor. The results on the Analysis of covariance of time-adjusted Area under curve for the EQ-5D index score were reported.
    End point type
    Other pre-specified
    End point timeframe
    Cycle (C) Day (D)1, C2D1, C3D1 and subsequent cycles up to C18, end of intervention visit (1 to 2 weeks after last dose)
    End point values
    Sorafenib (Nexavar, BAY43-9006) Placebo
    Number of subjects analysed
    556
    558
    Units: unit on a scale
        least squares mean (confidence interval 95%)
    0.827 (0.804 to 0.85)
    0.866 (0.843 to 0.888)
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    An analysis of covariance (ANCOVA) model was used to estimate the mean difference in the time-adjusted Area Under Curve (AUC) between the two treatment groups, with covariates for baseline scores and stratification factors. To test the treatment effect, a mixed linear model (random coefficient model) was used for the EQ-5D index score. Statistical tests were performed with a 2 sided type I error of 5%.
    Comparison groups
    Sorafenib (Nexavar, BAY43-9006) v Placebo
    Number of subjects included in analysis
    1114
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    ANCOVA
    Parameter type
    Mean difference
    Point estimate
    0.039
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.025
         upper limit
    0.052

    Other pre-specified: Patient Reported Outcomes: Euroqol-5 Dimensions (EQ-5D) - Visual Analogue Scale (VAS) Score

    Close Top of page
    End point title
    Patient Reported Outcomes: Euroqol-5 Dimensions (EQ-5D) - Visual Analogue Scale (VAS) Score
    End point description
    The EQ-5D is a generic quality of life preference based on a validated instrument used in cancer and in general population, with 2 parts: Index and Visual Analogue Scale. The EQ-5D VAS is a measure that represents health status as a single value. It is a 20-centimetre vertical graduated visual analogue scale with scores that ranged from 0 (worst imaginable health state) to 100 (best imaginable health state). The respondent rated his/her current health state by drawing a line from the box marked ‘your own health state today’ to the appropriate point on the EQ-5D VAS. A 3-digit number (including leading zeros) was read off the scale from the point where the respondent’s line crossed the scale, which was the EQ-5D VAS score. A change of at least 7 points on the VAS was considered as minimally important. The results on the ANCOVA analysis of time-adjusted AUC for the EQ-5D VAS score were reported.
    End point type
    Other pre-specified
    End point timeframe
    Cycle (C) Day (D)1, C2D1, C3D1 and subsequent cycles up to C18, end of intervention visit (1 to 2 weeks after last dose)
    End point values
    Sorafenib (Nexavar, BAY43-9006) Placebo
    Number of subjects analysed
    556
    558
    Units: unit on a scale
        least squares mean (confidence interval 95%)
    77.203 (75.184 to 79.223)
    80.181 (78.212 to 82.151)
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    An analysis of covariance (ANCOVA) model was used to estimate the mean difference in the time-adjusted Area Under Curve (AUC) between the two treatment groups, with covariates for baseline scores and stratification factors. To test the treatment effect, a mixed linear model (random coefficient model) was used for the EQ-5D VAS score. Statistical tests were performed with a 2 sided type I error of 5%.
    Comparison groups
    Sorafenib (Nexavar, BAY43-9006) v Placebo
    Number of subjects included in analysis
    1114
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    ANCOVA
    Parameter type
    Mean difference
    Point estimate
    2.978
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.797
         upper limit
    4.159

    Other pre-specified: Patient Reported Outcomes: Functional Assessment of Cancer Therapy (FACT)-Hepatobiliary Subscale (HEP) Score

    Close Top of page
    End point title
    Patient Reported Outcomes: Functional Assessment of Cancer Therapy (FACT)-Hepatobiliary Subscale (HEP) Score
    End point description
    The FACT-HEP is a 45 item, self-administered, multi-dimensional, psychometrically sound questionnaire used extensively in oncology clinical trials. FACT-HEP consisted of five subscales: Physical Well-Being (PWB), Social Well-Being (SWB), Emotional Well-Being (EWB), Functional Well-Being (FWB), and Hepatobiliary Cancer Subscale (HCS). The PWB, FWB, SWB and EWB were summed to form the FACT-General (FACT-G) total score. The FACT-G and HCS scores were summed to form the FACT-HEP total score. FACT-HEP scores ranged from 0 to 180 and the higher scores represented a better quality of life. Subjects responded to each item on a 5-point Likert-type scale ranging from 0 (not at all) to 4 (very much). The minimally important difference (MID) for the FACT-Hep total score was in the range of 8 to 9. The results on the ANCOVA analysis of time-adjusted AUC for the FACT-HEP score were reported.
    End point type
    Other pre-specified
    End point timeframe
    Cycle (C) Day (D)1, C2D1, C3D1 and subsequent cycles up to C18, end of intervention visit (1 to 2 weeks after last dose)
    End point values
    Sorafenib (Nexavar, BAY43-9006) Placebo
    Number of subjects analysed
    556
    558
    Units: unit on a scale`
        least squares mean (confidence interval 95%)
    138.7 (135.9 to 141.5)
    143.79 (141.1 to 146.5)
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    An ANCOVA model was used to estimate the mean difference in the time-adjusted AUC between the two treatment groups, with covariates for baseline scores and stratification factors. To test the treatment effect, a mixed linear model (random coefficient model) was used for the FACT-HEP score. Statistical tests were performed with a 2 sided type I error of 5%.
    Comparison groups
    Sorafenib (Nexavar, BAY43-9006) v Placebo
    Number of subjects included in analysis
    1114
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    ANCOVA
    Parameter type
    Mean difference
    Point estimate
    5.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    3.5
         upper limit
    6.7

    Other pre-specified: Patient Reported Outcomes: Functional Assessment of Cancer Therapy (FACT)-General (G) Total Score

    Close Top of page
    End point title
    Patient Reported Outcomes: Functional Assessment of Cancer Therapy (FACT)-General (G) Total Score
    End point description
    The PWB, FWB, SWB and EWB were summed to form the FACT-G total score. Subjects responded to each item on a 5-point Likert-type scale ranging from 0 (not at all) to 4 (very much). FACT-G scores ranged from 0 to 108 and the higher scores represented a better quality of life. The MID for the FACT-G total score was in the range of 6 to 7. The results on the ANCOVA analysis of time-adjusted AUC for the FACT-G score were reported.
    End point type
    Other pre-specified
    End point timeframe
    Cycle (C) Day (D)1, C2D1, C3D1 and subsequent cycles up to C18, end of intervention visit (1 to 2 weeks after last dose)
    End point values
    Sorafenib (Nexavar, BAY43-9006) Placebo
    Number of subjects analysed
    556
    558
    Units: unit on a scale
        least squares mean (confidence interval 95%)
    80.46 (78.6 to 82.3)
    82.95 (81.1 to 84.8)
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    An ANCOVA model was used to estimate the mean difference in the time-adjusted AUC between the two treatment groups, with covariates for baseline scores and stratification factors. To test the treatment effect, a mixed linear model (random coefficient model) was used for the FACT-G score. Statistical tests were performed with a 2 sided type I error of 5%.
    Comparison groups
    Sorafenib (Nexavar, BAY43-9006) v Placebo
    Number of subjects included in analysis
    1114
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    ANCOVA
    Parameter type
    Mean difference
    Point estimate
    2.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.4
         upper limit
    3.6

    Adverse events

    Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    After the subject has signed the informed consent, up to 30 days post treatment discontinuation
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Subjects received 2 tablets of placebo orally twice daily.

    Reporting group title
    Sorafenib (Nexavar, BAY43-9006)
    Reporting group description
    Subjects received 2 tablets of Sorafenib [2*200 milligram (mg)] orally twice daily.

    Serious adverse events
    Placebo Sorafenib (Nexavar, BAY43-9006)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    230 / 548 (41.97%)
    228 / 559 (40.79%)
         number of deaths (all causes)
    131
    114
         number of deaths resulting from adverse events
    9
    15
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    1 / 548 (0.18%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign hepatic neoplasm
         subjects affected / exposed
    1 / 548 (0.18%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    1 / 548 (0.18%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    1 / 548 (0.18%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic myeloid leukaemia
         subjects affected / exposed
    1 / 548 (0.18%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    1 / 548 (0.18%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric cancer
         subjects affected / exposed
    1 / 548 (0.18%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemangioma of liver
         subjects affected / exposed
    1 / 548 (0.18%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic neoplasm
         subjects affected / exposed
    1 / 548 (0.18%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngeal squamous cell carcinoma
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to lung
         subjects affected / exposed
    2 / 548 (0.36%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastatic pain
         subjects affected / exposed
    1 / 548 (0.18%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-Hodgkin's lymphoma
         subjects affected / exposed
    1 / 548 (0.18%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Oesophageal adenocarcinoma
         subjects affected / exposed
    1 / 548 (0.18%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal adenocarcinoma
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Schwannoma
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin papilloma
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of the hypopharynx
         subjects affected / exposed
    1 / 548 (0.18%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenocarcinoma pancreas
         subjects affected / exposed
    1 / 548 (0.18%)
    0 / 559 (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 / 548 (0.36%)
    4 / 559 (0.72%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Desmoid tumour
         subjects affected / exposed
    1 / 548 (0.18%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 548 (0.18%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary neoplasm
         subjects affected / exposed
    1 / 548 (0.18%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasopharyngeal cancer
         subjects affected / exposed
    1 / 548 (0.18%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lip and/or oral cavity cancer
         subjects affected / exposed
    1 / 548 (0.18%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasm recurrence
         subjects affected / exposed
    2 / 548 (0.36%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Huerthle cell carcinoma
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral papilloma
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         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
    130 / 548 (23.72%)
    82 / 559 (14.67%)
         occurrences causally related to treatment / all
    0 / 154
    0 / 98
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Vascular disorders
    Arteriovenous fistula
         subjects affected / exposed
    1 / 548 (0.18%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 548 (0.00%)
    2 / 559 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral vascular disorder
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inferior vena caval occlusion
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral embolism
         subjects affected / exposed
    1 / 548 (0.18%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Artery dissection
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Incisional hernia repair
         subjects affected / exposed
    1 / 548 (0.18%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasm prophylaxis
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Removal of foreign body from gastrointestinal tract
         subjects affected / exposed
    1 / 548 (0.18%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 548 (0.18%)
    2 / 559 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 548 (0.18%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Drowning
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Fatigue
         subjects affected / exposed
    0 / 548 (0.00%)
    3 / 559 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    0 / 548 (0.00%)
    3 / 559 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Pyrexia
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden cardiac death
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Coronary artery restenosis
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inflammation
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Unevaluable event
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 548 (0.00%)
    2 / 559 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 548 (0.18%)
    1 / 559 (0.18%)
         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 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngeal oedema
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 548 (0.18%)
    3 / 559 (0.54%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    2 / 548 (0.36%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 548 (0.18%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         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
    4 / 548 (0.73%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 5
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary granuloma
         subjects affected / exposed
    0 / 548 (0.00%)
    2 / 559 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    1 / 548 (0.18%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary mass
         subjects affected / exposed
    0 / 548 (0.00%)
    2 / 559 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis noninfective
         subjects affected / exposed
    1 / 548 (0.18%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Alcohol abuse
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alcoholism
         subjects affected / exposed
    1 / 548 (0.18%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    1 / 548 (0.18%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 548 (0.00%)
    2 / 559 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 548 (0.18%)
    2 / 559 (0.36%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lipase increased
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    0 / 548 (0.00%)
    2 / 559 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    1 / 548 (0.18%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arterial injury
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 548 (0.18%)
    0 / 559 (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
    1 / 548 (0.18%)
    2 / 559 (0.36%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament sprain
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    3 / 548 (0.55%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 548 (0.18%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sternal fracture
         subjects affected / exposed
    1 / 548 (0.18%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    1 / 548 (0.18%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ulna fracture
         subjects affected / exposed
    1 / 548 (0.18%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular injury
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    1 / 548 (0.18%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    1 / 548 (0.18%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Face injury
         subjects affected / exposed
    1 / 548 (0.18%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain contusion
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound evisceration
         subjects affected / exposed
    1 / 548 (0.18%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural bile leak
         subjects affected / exposed
    1 / 548 (0.18%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    1 / 548 (0.18%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Limb crushing injury
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    1 / 548 (0.18%)
    0 / 559 (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 / 548 (0.18%)
    2 / 559 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Angina pectoris
         subjects affected / exposed
    2 / 548 (0.36%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic valve stenosis
         subjects affected / exposed
    1 / 548 (0.18%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriosclerosis coronary artery
         subjects affected / exposed
    0 / 548 (0.00%)
    2 / 559 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Bradycardia
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 548 (0.18%)
    2 / 559 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 548 (0.00%)
    2 / 559 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 548 (0.18%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    1 / 548 (0.18%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Carotid artery thrombosis
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebellar haemorrhage
         subjects affected / exposed
    1 / 548 (0.18%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 548 (0.18%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    1 / 1
    Cerebral infarction
         subjects affected / exposed
    0 / 548 (0.00%)
    2 / 559 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    1 / 548 (0.18%)
    2 / 559 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 548 (0.00%)
    3 / 559 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Guillain-Barre syndrome
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 548 (0.00%)
    2 / 559 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic encephalopathy
         subjects affected / exposed
    2 / 548 (0.36%)
    3 / 559 (0.54%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive encephalopathy
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         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
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord infarction
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 548 (0.18%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 548 (0.18%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone marrow failure
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Deafness
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tinnitus
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertigo
         subjects affected / exposed
    2 / 548 (0.36%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 548 (0.18%)
    4 / 559 (0.72%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal vein occlusion
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 548 (0.00%)
    3 / 559 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 548 (0.18%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 548 (0.18%)
    3 / 559 (0.54%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Crohn's disease
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diaphragmatic hernia, obstructive
         subjects affected / exposed
    1 / 548 (0.18%)
    0 / 559 (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 / 548 (0.36%)
    2 / 559 (0.36%)
         occurrences causally related to treatment / all
    1 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenitis
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 548 (0.18%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral hernia
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer haemorrhage
         subjects affected / exposed
    1 / 548 (0.18%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 548 (0.00%)
    4 / 559 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Impaired gastric emptying
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    3 / 548 (0.55%)
    2 / 559 (0.36%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    1 / 548 (0.18%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal varices haemorrhage
         subjects affected / exposed
    0 / 548 (0.00%)
    4 / 559 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 548 (0.18%)
    2 / 559 (0.36%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    2 / 548 (0.36%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 548 (0.18%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 548 (0.36%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric volvulus
         subjects affected / exposed
    1 / 548 (0.18%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    1 / 548 (0.18%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Varices oesophageal
         subjects affected / exposed
    2 / 548 (0.36%)
    2 / 559 (0.36%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric varices haemorrhage
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal hernia
         subjects affected / exposed
    2 / 548 (0.36%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Localised intraabdominal fluid collection
         subjects affected / exposed
    1 / 548 (0.18%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    1 / 548 (0.18%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary fistula
         subjects affected / exposed
    1 / 548 (0.18%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    2 / 548 (0.36%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis acute
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 548 (0.18%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 548 (0.00%)
    2 / 559 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hepatic function abnormal
         subjects affected / exposed
    1 / 548 (0.18%)
    4 / 559 (0.72%)
         occurrences causally related to treatment / all
    2 / 2
    9 / 9
         deaths causally related to treatment / all
    0 / 0
    3 / 3
    Hepatorenal syndrome
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Jaundice cholestatic
         subjects affected / exposed
    1 / 548 (0.18%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Portal vein thrombosis
         subjects affected / exposed
    0 / 548 (0.00%)
    2 / 559 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bile duct stenosis
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic mass
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biloma
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver injury
         subjects affected / exposed
    0 / 548 (0.00%)
    2 / 559 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermal cyst
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatitis allergic
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    1 / 548 (0.18%)
    10 / 559 (1.79%)
         occurrences causally related to treatment / all
    1 / 1
    11 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pruritus
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    0 / 548 (0.00%)
    2 / 559 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Telangiectasia
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Calculus urinary
         subjects affected / exposed
    0 / 548 (0.00%)
    2 / 559 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    2 / 548 (0.36%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrotic syndrome
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    1 / 548 (0.18%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Renal failure acute
         subjects affected / exposed
    0 / 548 (0.00%)
    2 / 559 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureteric obstruction
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 548 (0.18%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic nephropathy
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 548 (0.18%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone formation increased
         subjects affected / exposed
    1 / 548 (0.18%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Exostosis
         subjects affected / exposed
    1 / 548 (0.18%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gouty arthritis
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 548 (0.18%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    1 / 548 (0.18%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    0 / 16
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    2 / 548 (0.36%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spondylolisthesis
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 548 (0.18%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 548 (0.18%)
    3 / 559 (0.54%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    1 / 548 (0.18%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis B
         subjects affected / exposed
    1 / 548 (0.18%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hepatitis C
         subjects affected / exposed
    1 / 548 (0.18%)
    0 / 559 (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
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia
         subjects affected / exposed
    1 / 548 (0.18%)
    2 / 559 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 548 (0.18%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 548 (0.36%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Superinfection
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tuberculosis
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 548 (0.18%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 548 (0.00%)
    2 / 559 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 548 (0.18%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal abscess
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary sepsis
         subjects affected / exposed
    1 / 548 (0.18%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute hepatitis B
         subjects affected / exposed
    1 / 548 (0.18%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Abdominal abscess
         subjects affected / exposed
    3 / 548 (0.55%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis bacterial
         subjects affected / exposed
    1 / 548 (0.18%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected dermal cyst
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    2 / 548 (0.36%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    2 / 548 (0.36%)
    0 / 559 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 548 (0.00%)
    1 / 559 (0.18%)
         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
    Placebo Sorafenib (Nexavar, BAY43-9006)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    360 / 548 (65.69%)
    522 / 559 (93.38%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    38 / 548 (6.93%)
    54 / 559 (9.66%)
         occurrences all number
    177
    251
    Aspartate aminotransferase increased
         subjects affected / exposed
    35 / 548 (6.39%)
    51 / 559 (9.12%)
         occurrences all number
    188
    226
    Platelet count decreased
         subjects affected / exposed
    26 / 548 (4.74%)
    48 / 559 (8.59%)
         occurrences all number
    202
    300
    Weight decreased
         subjects affected / exposed
    13 / 548 (2.37%)
    60 / 559 (10.73%)
         occurrences all number
    41
    254
    Weight increased
         subjects affected / exposed
    42 / 548 (7.66%)
    14 / 559 (2.50%)
         occurrences all number
    310
    68
    Vascular disorders
    Hypertension
         subjects affected / exposed
    65 / 548 (11.86%)
    142 / 559 (25.40%)
         occurrences all number
    331
    869
    Nervous system disorders
    Headache
         subjects affected / exposed
    33 / 548 (6.02%)
    40 / 559 (7.16%)
         occurrences all number
    108
    111
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    14 / 548 (2.55%)
    29 / 559 (5.19%)
         occurrences all number
    97
    217
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    66 / 548 (12.04%)
    83 / 559 (14.85%)
         occurrences all number
    300
    315
    Pyrexia
         subjects affected / exposed
    24 / 548 (4.38%)
    33 / 559 (5.90%)
         occurrences all number
    32
    39
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    46 / 548 (8.39%)
    55 / 559 (9.84%)
         occurrences all number
    115
    156
    Abdominal pain upper
         subjects affected / exposed
    14 / 548 (2.55%)
    28 / 559 (5.01%)
         occurrences all number
    36
    75
    Ascites
         subjects affected / exposed
    19 / 548 (3.47%)
    39 / 559 (6.98%)
         occurrences all number
    67
    145
    Constipation
         subjects affected / exposed
    36 / 548 (6.57%)
    41 / 559 (7.33%)
         occurrences all number
    122
    105
    Diarrhoea
         subjects affected / exposed
    64 / 548 (11.68%)
    242 / 559 (43.29%)
         occurrences all number
    186
    1201
    Dyspepsia
         subjects affected / exposed
    30 / 548 (5.47%)
    20 / 559 (3.58%)
         occurrences all number
    125
    112
    Nausea
         subjects affected / exposed
    24 / 548 (4.38%)
    50 / 559 (8.94%)
         occurrences all number
    45
    119
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    44 / 548 (8.03%)
    30 / 559 (5.37%)
         occurrences all number
    116
    76
    Dysphonia
         subjects affected / exposed
    3 / 548 (0.55%)
    41 / 559 (7.33%)
         occurrences all number
    7
    133
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    18 / 548 (3.28%)
    187 / 559 (33.45%)
         occurrences all number
    65
    750
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    27 / 548 (4.93%)
    390 / 559 (69.77%)
         occurrences all number
    139
    2196
    Pruritus
         subjects affected / exposed
    58 / 548 (10.58%)
    47 / 559 (8.41%)
         occurrences all number
    263
    133
    Rash
         subjects affected / exposed
    45 / 548 (8.21%)
    95 / 559 (16.99%)
         occurrences all number
    126
    296
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    31 / 548 (5.66%)
    24 / 559 (4.29%)
         occurrences all number
    178
    111
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    30 / 548 (5.47%)
    34 / 559 (6.08%)
         occurrences all number
    139
    162
    Back pain
         subjects affected / exposed
    37 / 548 (6.75%)
    43 / 559 (7.69%)
         occurrences all number
    192
    152
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    38 / 548 (6.93%)
    30 / 559 (5.37%)
         occurrences all number
    69
    66
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    18 / 548 (3.28%)
    40 / 559 (7.16%)
         occurrences all number
    52
    104

    More information

    Close Top of page

    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 May 2008
    Amendment 1 dated 26 MAY 2008 (IND modification serial number 2656) - Removed tumor block sampling - Minor clarifications of inclusion and exclusion criteria - Added PK sampling - Clarified that randomization codes for investigators or pharmacists would be managed by the IVRS system - Clarified end of post study follow-up - Clarified study medication storage conditions
    12 Jun 2008
    Amendment 2 (local amendment for Japan), dated 12 JUN 2008 - Japan specific changes with regard to AE monitoring, SAEs, unexpected AEs, ethics committees, identity of investigational products and premature termination of the study/closure of a center.
    01 May 2009
    Amendment 3 dated 1 MAY 2009 (IND modification serial number 2776) - Increased cap for Asia Pacific patients from 450 to 550 patients allowing a balanced enrollment compared with Western patients while taking into account the higher prevalence of HCC patients in the Asia Pacific region compared with the rest of the world. - Clarified timing definitions for inclusion/exclusion criteria - Clarified exclusion criteria definition regarding potential transplant patients - Clarified study medication storage conditions for blister pack used in the Asia Pacific region - Amended criteria for serious adverse events (SAE) reporting in case of hospitalization in line with updated procedures
    02 Oct 2009
    Amendment 4 dated 2 OCT 2009 (IND modification serial number2805) - Expanded time window for time from surgery/ablation to eligibility CT or MRI scan: The additional time beyond the targeted 4 weeks from curative treatment to eligibility scan was expanded to ensure maximum recovery time from curative treatment, while maintaining a short enough timeframe from curative treatment to commencing adjuvant treatment to derive maximum adjuvant treatment benefit. The minimum time of 3 weeks (21 days) was maintained to ensure a valid assessment of the remission status. - Clarified ablation definitions to allow a combination of percutaneous ethanol injection (PEI) and percutaneous or intraoperative radiofrequency ablation (RFA)
    11 Feb 2010
    Amendment 5 dated 11 FEB 2010 (IND modification serial number 2870) - Removed Asia Pacific cap: This was done in order to allow completely competitive enrolment across all geographical regions. This was decided based on a blinded inspection of patients’ safety profiles, treatment duration, and frequency of discontinuation that did not reveal any unexpected issues or concerns and confirmed that no relevant differences regarding these parameters could be observed across geographical regions. It was therefore considered appropriate to allow complete competitive enrolment into the study and to remove the predefined recruitment cap on the Asia-Pacific region. In addition, it was thought that this would allow a representative ethnical distribution across the regions. It was further considered that despite removing the cap on Asian patients, that the large overall sample size of 1100 subjects would still allow a sufficiently large number of Western patients, which was expected to be greater than 400 subjects.
    26 Jan 2011
    Amendment 6 dated 26 JAN 2011 (for all countries other than the USA) (IND modification serial number 2999) - Allowed the continuation of collection of CT/MRI scans beyond premature termination of treatment, into the Post Study Follow Up - Statistical section was modified to state that recurrence events observed from scans collected during post study follow up would be used in the primary analysis. This was done because it was thought that the additional scan evaluations collected post study would reduce the censoring rate and therefore reduce the possibility of biasing the results of the primary endpoint.
    31 May 2011
    Amendment 8 dated 31 MAY 2011 (for USA only) (IND modification serial number3033) - Following feedback from FDA regarding protocol amendment 6, this amendment stated that recurrence events observed from scans collected during post study follow up would not be used in the primary analysis. This data would be used for supportive sensitivity analyses only.
    31 May 2011
    Amendment 9 dated 31 MAY 2011 (for all countries other than the USA) - Following feedback from FDA regarding protocol amendment 6, this amendment stated that recurrence events observed from scans collected during post study follow up would not be used in the primary analysis. This data would be used for supportive sensitivity analyses only.
    20 Jun 2012
    Amendment 10, dated 20 JUN 2012 (applicable to all countries) (IND modification serial number 3120) - Power of the primary end point reduced from 90% to 80%, thereby reducing the number of centrally confirmed recurrences required from 611 to 457. It was decided that this change would shorten the duration of the study and thereby reduce the amount of missing data due to patient drop-outs. - Clarification was included, stating that 4 years was equal to 204 weeks and that patients who reached 4 years on treatment would continue to be followed for recurrence during follow up. CT/MRI scans were to be performed every 6 months per study image acquisition guidelines. Any recurrences observed in this group of patients could then be included in the primary analysis. - For patients who discontinued treatment prematurely and continued scan collection during follow up (according to amendment 6), the frequency of scan collection was to decrease from 3 monthly to 6 monthly once the patient reached their date of randomization + 204 weeks. Recurrences observed during follow up for patients who withdrew prematurely from treatment (per protocol amendment 6) were still not to be included in the primary analysis (per amendments 8 and 9).
    06 Aug 2012
    Amendment 11, dated 6 AUG 2012 (applicable to all countries) (IND modification serial number 3120) - Administrative only - corrects inconsistency within protocol amendment 10

    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.
    Decimal places were automatically truncated if last decimal equals zero.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

    European Medicines Agency © 1995-2024 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    EMA HMA