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    Clinical Trial Results:
    Phase 2, Open-label Single-Arm, Multi-Center Study to Evaluate the Efficacy and Safety of AMG 386 and Sorafenib as First Line Therapy for Subjects with Advanced or Inoperable Hepatocellular Carcinoma.

    Summary
    EudraCT number
    2008-006212-38
    Trial protocol
    FR   DE  
    Global end of trial date
    08 Jun 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    18 Jun 2016
    First version publication date
    18 Jun 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    20080580
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00872014
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Amgen, Inc.
    Sponsor organisation address
    One Amgen Center Drive, Thousand Oaks, CA, United States, 91320
    Public contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com
    Scientific contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.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
    08 Jun 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Jun 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to determine the efficacy of trebananib (AMG 386) in combination with sorafenib as measured by the time to progression event rate at 4-months in subjects with advanced or inoperable hepatocellular carcinoma (HCC).
    Protection of trial subjects
    This study has been conducted in accordance with FDA country-specific national and local laws and with International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) regulations/guidelines. A copy of the protocol, proposed informed consent form, other written subject information, and any proposed advertising materials were submitted to the Independent Ethics Committee (IEC)/Institutional Review Board (IRB) for written approval. A copy of the written approval of the protocol and informed consent form must have been received by Amgen before recruitment of subjects into the study and shipment of trebananib. All subjects provided written informed consent before undergoing any study-related procedures, including screening procedures. In order to ensure subject safety, the study team reviewed safety and pharmacokinetic data, if available, after 10 and 20 subjects in cohort A had been enrolled, had received at least 1 infusion of trebananib and 1 oral dose of sorafenib, and had the opportunity to be followed for ≥ 4 weeks; and after 6, 12, and 20 subjects had been enrolled in cohort B, had received at least 1 infusion of trebananib and 1 oral dose of sorafenib, and had the opportunity to be followed for ≥ 4 weeks.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    26 Aug 2009
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Efficacy, Safety
    Long term follow-up duration
    48 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 26
    Country: Number of subjects enrolled
    Australia: 9
    Country: Number of subjects enrolled
    France: 10
    Country: Number of subjects enrolled
    Germany: 15
    Worldwide total number of subjects
    60
    EEA total number of subjects
    25
    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)
    39
    From 65 to 84 years
    21
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    This study was conducted at 15 centers in Australia, France, Germany, and the United States. The first patient was enrolled on 26 August 2009 and the last patient enrolled on 21 June 2011.

    Pre-assignment
    Screening details
    A total of 90 subjects were screened for enrollment and 60 subjects enrolled: • Cohort A: trebananib 10 mg/kg QW and sorafenib 400 mg • Cohort B: trebananib 15 mg/kg QW and sorafenib 400 mg The 2 cohorts were enrolled sequentially. Enrollment into cohort B commenced after a safety review for cohort A was completed (after 10 subjects enrolled).

    Period 1
    Period 1 title
    Overall sudy (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Trebananib 10 mg/kg + Sorafenib
    Arm description
    Participants received 10 mg/kg trebananib administered by intravenous infusion once a week in combination with sorafenib starting at 400 mg orally twice daily until disease progression, clinical progression, unacceptable toxicity, the subject withdrew consent or died.
    Arm type
    Experimental

    Investigational medicinal product name
    Trebananib
    Investigational medicinal product code
    AMG 386
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Trebananib was administered intravenously once a week.

    Investigational medicinal product name
    Sorafenib
    Investigational medicinal product code
    Other name
    Nexavar®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Sorafenib was self-administered orally starting at 400 mg twice a day (BID).

    Arm title
    Trebananib 15 mg/kg + Sorafenib
    Arm description
    Participants received 15 mg/kg trebananib administered by intravenous infusion once a week in combination with sorafenib starting at 400 mg orally twice daily until disease progression, clinical progression, unacceptable toxicity, the subject withdrew consent or died.
    Arm type
    Experimental

    Investigational medicinal product name
    Trebananib
    Investigational medicinal product code
    AMG 386
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Trebananib was administered intravenously once a week.

    Investigational medicinal product name
    Sorafenib
    Investigational medicinal product code
    Other name
    Nexavar®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Sorafenib was self-administered orally starting at 400 mg twice a day (BID).

    Number of subjects in period 1
    Trebananib 10 mg/kg + Sorafenib Trebananib 15 mg/kg + Sorafenib
    Started
    30
    30
    Completed
    1
    2
    Not completed
    29
    28
         Death
    28
    24
         Consent withdrawn by subject
    1
    3
         Lost to follow-up
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Trebananib 10 mg/kg + Sorafenib
    Reporting group description
    Participants received 10 mg/kg trebananib administered by intravenous infusion once a week in combination with sorafenib starting at 400 mg orally twice daily until disease progression, clinical progression, unacceptable toxicity, the subject withdrew consent or died.

    Reporting group title
    Trebananib 15 mg/kg + Sorafenib
    Reporting group description
    Participants received 15 mg/kg trebananib administered by intravenous infusion once a week in combination with sorafenib starting at 400 mg orally twice daily until disease progression, clinical progression, unacceptable toxicity, the subject withdrew consent or died.

    Reporting group values
    Trebananib 10 mg/kg + Sorafenib Trebananib 15 mg/kg + Sorafenib Total
    Number of subjects
    30 30 60
    Age categorical
    Units: Subjects
        < 65 years
    17 22 39
        ≥ 65 years
    13 8 21
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    64.1 ± 9.2 61.2 ± 9.8 -
    Gender categorical
    Units: Subjects
        Female
    7 3 10
        Male
    23 27 50
    Race
    Units: Subjects
        White or Caucasian
    23 19 42
        Black or African American
    0 4 4
        Hispanic or Latino
    2 2 4
        Asian
    3 5 8
        Japanese
    1 0 1
        Native Hawaiian or Other Pacific Islander
    1 0 1

    End points

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    End points reporting groups
    Reporting group title
    Trebananib 10 mg/kg + Sorafenib
    Reporting group description
    Participants received 10 mg/kg trebananib administered by intravenous infusion once a week in combination with sorafenib starting at 400 mg orally twice daily until disease progression, clinical progression, unacceptable toxicity, the subject withdrew consent or died.

    Reporting group title
    Trebananib 15 mg/kg + Sorafenib
    Reporting group description
    Participants received 15 mg/kg trebananib administered by intravenous infusion once a week in combination with sorafenib starting at 400 mg orally twice daily until disease progression, clinical progression, unacceptable toxicity, the subject withdrew consent or died.

    Primary: Progression-free Survival Rate at 4 Months

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    End point title
    Progression-free Survival Rate at 4 Months [1]
    End point description
    Progression-free survival rate at 4 months is defined as the Kaplan-Meier estimate of participants alive and without radiographic disease progression at 4 months. Disease progression was based on the investigator’s assessment of radiological assessments using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 with modifications. Participants alive and without progression at the time of the analysis data cut-off date were censored at the time of the last evaluable radiographic assessment. Progressive disease (PD): At least a 20% increase in the size of target lesions, taking as reference the smallest size recorded since the treatment began, the appearance of one or more new lesions and/or unequivocal progression of any non-target lesions.
    End point type
    Primary
    End point timeframe
    Progression-free survival rate at 4 months was analyzed after all participants completed follow-up; the median follow-up time was 69.1 weeks for cohort A and 44.6 weeks for cohort B.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical hypothesis was tested.
    End point values
    Trebananib 10 mg/kg + Sorafenib Trebananib 15 mg/kg + Sorafenib
    Number of subjects analysed
    30
    30
    Units: percentage of participants
        number (confidence interval 80%)
    58.6 (43.4 to 69.2)
    57.1 (43.4 to 69.2)
    No statistical analyses for this end point

    Secondary: Number of Participants with Adverse Events

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    End point title
    Number of Participants with Adverse Events
    End point description
    The National Cancer Institute, Common Terminology Criteria for Adverse Events (CTCAE), version 3.0, was used to assess the severity of adverse events according to the following: Grade 1 = Mild, Grade 2 = Moderate, Grade 3 = Severe, Grade 4 = Life-threatening and Grade 5 = Death. The investigator assessed the relationship of each AE to trebabanib or sorafenib. A serious adverse event (SAE) is defined as an adverse event that - is fatal - is life threatening (places the subject at immediate risk of death) - requires in-patient hospitalization or prolongation of existing hospitalization - results in persistent or significant disability/incapacity - is a congenital anomaly/birth defect - other significant medical hazard
    End point type
    Secondary
    End point timeframe
    From first dose until 30 days after last dose
    End point values
    Trebananib 10 mg/kg + Sorafenib Trebananib 15 mg/kg + Sorafenib
    Number of subjects analysed
    30
    30
    Units: participants
        Any adverse event
    30
    30
        Grade ≥ 3
    26
    23
        Grade ≥ 4
    7
    11
        Fatal adverse events
    4
    4
        Serious adverse events
    19
    15
        Leading to discontinuation of trebananib
    6
    9
        Leading to sorafenib dose altered or withheld
    19
    17
        Treatment-related adverse events (TRAEs)
    30
    30
        TRAE grade ≥ 3
    20
    22
        TRAE grade ≥ 4
    3
    4
        Treatment-related fatal adverse events
    1
    2
        Treatment-related serious adverse events
    12
    10
        Trebananib-related adverse events
    27
    24
        Trebananib-related grade ≥ 3
    12
    15
        Trebananib-related grade ≥ 4
    2
    3
        Trebananib-related fatal adverse events
    1
    1
        Trebananib-related serious adverse events
    11
    9
        Sorafenib-related adverse events
    30
    29
        Sorafenib-related grade ≥ 3
    19
    21
        Sorafenib-related grade ≥ 4
    2
    4
        Sorafenib-related fatal adverse events
    1
    2
        Sorafenib-related serious adverse events
    11
    9
    No statistical analyses for this end point

    Secondary: Objective Response Rate

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    End point title
    Objective Response Rate
    End point description
    Tumor response was based on radiological assessments using RECIST version 1.0 with modifications. An objective response is either a complete response or partial response confirmed by consecutive repeat assessments no less than 28 days after the criteria for response were first met. Complete response (CR): Disappearance of all target and non-target lesions and no new lesions. Partial response (PR): Disappearance of all target lesions with persistence of one or more non-target lesions and no new lesions, or, at least a 30% decrease in the size of target lesions, and no new lesions or unequivocal progression of non-target lesions.
    End point type
    Secondary
    End point timeframe
    Tumor response was assessed every 8 weeks from day 1 of week 1 for 2 years, and then at least every 4 months thereafter; the median follow-up time was 69.1 weeks for cohort A and 44.6 weeks for cohort B.
    End point values
    Trebananib 10 mg/kg + Sorafenib Trebananib 15 mg/kg + Sorafenib
    Number of subjects analysed
    30
    30
    Units: percentage of participants
        number (confidence interval 80%)
    3.3 (0.4 to 12.4)
    10 (3.7 to 20.9)
    No statistical analyses for this end point

    Secondary: Time to Progression

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    End point title
    Time to Progression
    End point description
    Time to progression (TTP) was defined as the time from the first dose of investigational product to disease progression. Subjects who did not meet the criteria for disease progression by the final analysis data cutoff date and subjects who died without evidence of radiographic disease progression were censored at their last evaluable disease assessment date. Time to progression was analyzed using the Kaplan-Meier method.
    End point type
    Secondary
    End point timeframe
    Tumor response was assessed every 8 weeks from day 1 of week 1 for 2 years, and then at least every 4 months thereafter; the median follow-up time was 69.1 weeks for cohort A and 44.6 weeks for cohort B.
    End point values
    Trebananib 10 mg/kg + Sorafenib Trebananib 15 mg/kg + Sorafenib
    Number of subjects analysed
    30
    30
    Units: months
        median (confidence interval 80%)
    9 (3.6 to 12.6)
    6.9 (3.6 to 9.1)
    No statistical analyses for this end point

    Secondary: Progression-free Survival

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    End point title
    Progression-free Survival
    End point description
    Progression-free survival (PFS) time is the time from the first dose to the first observed radiographic progression or death, whichever occurs first. Subjects alive and without progression at the time of the analysis data cutoff date were censored at the time of the last evaluable radiographic assessment. (PFS) time is the time from the first dose to the first observed radiographic progression or death, whichever occurs first. Subjects alive and without progression at the time of the analysis data cutoff date were censored at the time of the last evaluable radiographic assessment. Progression-free survival was analyzed using the Kaplan-Meier method.
    End point type
    Secondary
    End point timeframe
    Tumor response was assessed every 8 weeks from day 1 of week 1 for 2 years, and then at least every 4 months thereafter; the median follow-up time was 69.1 weeks for cohort A and 44.6 weeks for cohort B.
    End point values
    Trebananib 10 mg/kg + Sorafenib Trebananib 15 mg/kg + Sorafenib
    Number of subjects analysed
    30
    30
    Units: months
        median (confidence interval 80%)
    9 (3.5 to 11.1)
    6.2 (3.7 to 9)
    No statistical analyses for this end point

    Secondary: Disease Control Rate

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    End point title
    Disease Control Rate
    End point description
    Disease control rate is defined as a best response of at least stable disease on study with a duration of ≥ 16 weeks from study day 1 or a confirmed objective response, per RECIST v1.0 with modifications. Stable Disease (SD): Neither sufficient shrinkage of target lesions to qualify for PR nor sufficient increase of target lesions to qualify for PD, taking as reference the smallest lesion size, with no new lesions or unequivocal progression of non-target lesions.
    End point type
    Secondary
    End point timeframe
    Tumor response was assessed every 8 weeks from day 1 of week 1 for 2 years, and then at least every 4 months thereafter; the median follow-up time was 69.1 weeks for cohort A and 44.6 weeks for cohort B.
    End point values
    Trebananib 10 mg/kg + Sorafenib Trebananib 15 mg/kg + Sorafenib
    Number of subjects analysed
    30
    30
    Units: percentage of participnts
        number (confidence interval 80%)
    50 (37 to 63)
    46.7 (33.8 to 59.9)
    No statistical analyses for this end point

    Secondary: Overall Survival

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    End point title
    Overall Survival
    End point description
    The time from the date of first dose to the date of death from any cause. Subjects who had not died by the analysis data cutoff date were censored at their last date known to be alive. Overall survival was analyzed using the Kaplan-Meier method.
    End point type
    Secondary
    End point timeframe
    The median follow-up time was 69.1 weeks for cohort A and 44.6 weeks for cohort B.
    End point values
    Trebananib 10 mg/kg + Sorafenib Trebananib 15 mg/kg + Sorafenib
    Number of subjects analysed
    30
    30
    Units: months
        median (confidence interval 80%)
    17 (9.8 to 22.5)
    13.2 (7.3 to 16.9)
    No statistical analyses for this end point

    Secondary: Number of Participants who Developed Anti-trebananib Antibodies

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    End point title
    Number of Participants who Developed Anti-trebananib Antibodies
    End point description
    Samples were first tested in an electrochemiluminescence (ECL) immunoassay to detect antibodies capable of binding specifically to trebananib. Samples confirmed positive in the immunoassay were then tested in an ECL receptor-binding neutralizing antibody assay to measure the neutralizing or inhibitory effects of the antibodies in vitro. if a sample was positive in the immunoassay, but negative in the neutralizing assay, the subject was defined as positive for binding antibodies. If a sample was positive in both assays, a subject was defined as positive for neutralizing antibodies. Developing antibody incidence is defined as subjects with a negative or no result at or before baseline and a positive result at a post-baseline time point.
    End point type
    Secondary
    End point timeframe
    Blood samples were taken predose on day 1 of weeks 1, 5, and 9, and every 16 weeks thereafter until the safety follow-up visit.
    End point values
    Trebananib 10 mg/kg + Sorafenib Trebananib 15 mg/kg + Sorafenib
    Number of subjects analysed
    27 [2]
    26 [3]
    Units: participants
        Developed Binding Antibodies
    2
    1
        Developed Neutralizing Antibodies
    0
    0
    Notes
    [2] - Subjects with at least one post-baseline immunoassay result
    [3] - Subjects with at least one post-baseline immunoassay result
    No statistical analyses for this end point

    Secondary: Maximum Observed Serum Concentration (Cmax) of Trebananib

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    End point title
    Maximum Observed Serum Concentration (Cmax) of Trebananib
    End point description
    Serum samples were analyzed for trebananib concentration using a validated enzyme linked immunosorbent assay (ELISA). The lower limit of quantification (LLOQ) of the serum assay was 20 ng/mL.
    End point type
    Secondary
    End point timeframe
    Week 1, week 5, and week 9, at the end of infusion
    End point values
    Trebananib 10 mg/kg + Sorafenib Trebananib 15 mg/kg + Sorafenib
    Number of subjects analysed
    25
    30
    Units: µg/mL
    arithmetic mean (standard deviation)
        Week 1 (N = 25, 30)
    201 ± 89.3
    260 ± 122
        Week 5 (N = 20, 19)
    323 ± 115
    350 ± 135
        Week 9 (N = 14, 19)
    275 ± 105
    344 ± 104
    No statistical analyses for this end point

    Secondary: Minimum Observed Serum Concentration (Cmin) of Trebananib

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    End point title
    Minimum Observed Serum Concentration (Cmin) of Trebananib
    End point description
    End point type
    Secondary
    End point timeframe
    Predose at week 2, week 5 and week 9
    End point values
    Trebananib 10 mg/kg + Sorafenib Trebananib 15 mg/kg + Sorafenib
    Number of subjects analysed
    27
    25
    Units: µg/mL
    arithmetic mean (standard deviation)
        Week 2 (N = 27, 25)
    10.2 ± 8.37
    12.7 ± 7.35
        Week 5 (N = 20, 20)
    18.2 ± 11.1
    25.5 ± 19.5
        Week 9 (N = 15, 20)
    15.7 ± 8.04
    31.5 ± 27.3
    No statistical analyses for this end point

    Secondary: Minimum Observed Serum Concentration (Cmin) of Sorafenib

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    End point title
    Minimum Observed Serum Concentration (Cmin) of Sorafenib
    End point description
    Blood samples for sorafenib pharmacokinetics were taken from a subgroup of subjects at selected sites outside of Europe. Plasma concentrations of sorafenib were measured by a validated liquid chromatography–mass spectrometry ( LC-MS/MS) method. The LLOQ was 10 ng/mL.
    End point type
    Secondary
    End point timeframe
    Predose at weeks 2, 5 and 9
    End point values
    Trebananib 10 mg/kg + Sorafenib Trebananib 15 mg/kg + Sorafenib
    Number of subjects analysed
    5
    9
    Units: µg/mL
    arithmetic mean (standard deviation)
        Week 2 (N = 5, 9)
    5.85 ± 6.31
    5.25 ± 3.28
        Week 5 (N = 4, 8)
    8.11 ± 6.37
    2.8 ± 2.09
        Week 9 (n = 3, 5)
    6.26 ± 2.29
    3.35 ± 1.02
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose until 30 days after last dose.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Trebananib 15 mg/kg + Sorafenib
    Reporting group description
    Participants received 15 mg/kg trebananib administered by intravenous infusion once a week in combination with sorafenib starting at 400 mg orally twice daily until disease progression, clinical progression, unacceptable toxicity, the subject withdrew consent or died.

    Reporting group title
    Trebananib 10 mg/kg + Sorafenib
    Reporting group description
    Participants received 10 mg/kg trebananib administered by intravenous infusion once a week in combination with sorafenib starting at 400 mg orally twice daily until disease progression, clinical progression, unacceptable toxicity, the subject withdrew consent or died.

    Serious adverse events
    Trebananib 15 mg/kg + Sorafenib Trebananib 10 mg/kg + Sorafenib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    15 / 30 (50.00%)
    19 / 30 (63.33%)
         number of deaths (all causes)
    25
    28
         number of deaths resulting from adverse events
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 30 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Toe amputation
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colorectal cancer
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         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
    3 / 30 (10.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 30 (0.00%)
    3 / 30 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 30 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Mania
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         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 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound complication
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 30 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Choking
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Dyspnoea
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         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 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pleural effusion
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 30 (6.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         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 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         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
    1 / 30 (3.33%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Retinal vein thrombosis
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vision blurred
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (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
    2 / 30 (6.67%)
    3 / 30 (10.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocutaneous fistula
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Intestinal obstruction
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal varices haemorrhage
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Acute hepatic failure
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bile duct stone
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (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
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    4 / 30 (13.33%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 0
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    Hepatorenal syndrome
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    2 / 30 (6.67%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Exfoliative rash
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Swelling face
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 30 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 30 (6.67%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis of male external genital organ
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Trebananib 15 mg/kg + Sorafenib Trebananib 10 mg/kg + Sorafenib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    30 / 30 (100.00%)
    30 / 30 (100.00%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Haematoma
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Peripheral ischaemia
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Hypertension
         subjects affected / exposed
    8 / 30 (26.67%)
    10 / 30 (33.33%)
         occurrences all number
    13
    14
    Subclavian vein thrombosis
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Venous thrombosis
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 30 (3.33%)
         occurrences all number
    1
    1
    Surgical and medical procedures
    Cataract operation
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Benign neoplasm
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Metastatic pain
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Colorectal cancer
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Papilloma
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Tumour pain
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 30 (3.33%)
         occurrences all number
    1
    1
    General disorders and administration site conditions
    Abasia
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Asthenia
         subjects affected / exposed
    0 / 30 (0.00%)
    10 / 30 (33.33%)
         occurrences all number
    0
    28
    Chest pain
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    2
    Chills
         subjects affected / exposed
    1 / 30 (3.33%)
    3 / 30 (10.00%)
         occurrences all number
    1
    3
    Face oedema
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 30 (3.33%)
         occurrences all number
    1
    1
    Extravasation
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Fatigue
         subjects affected / exposed
    14 / 30 (46.67%)
    16 / 30 (53.33%)
         occurrences all number
    21
    46
    Feeling cold
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Gait disturbance
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    General physical health deterioration
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Generalised oedema
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 30 (6.67%)
         occurrences all number
    1
    7
    Influenza like illness
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Localised oedema
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 30 (6.67%)
         occurrences all number
    1
    2
    Malaise
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Mucosal inflammation
         subjects affected / exposed
    2 / 30 (6.67%)
    5 / 30 (16.67%)
         occurrences all number
    2
    7
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Oedema
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Oedema peripheral
         subjects affected / exposed
    8 / 30 (26.67%)
    8 / 30 (26.67%)
         occurrences all number
    10
    12
    Pain
         subjects affected / exposed
    2 / 30 (6.67%)
    1 / 30 (3.33%)
         occurrences all number
    3
    1
    Pyrexia
         subjects affected / exposed
    4 / 30 (13.33%)
    8 / 30 (26.67%)
         occurrences all number
    4
    8
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Anxiety
         subjects affected / exposed
    4 / 30 (13.33%)
    6 / 30 (20.00%)
         occurrences all number
    4
    6
    Bipolar disorder
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Confusional state
         subjects affected / exposed
    2 / 30 (6.67%)
    2 / 30 (6.67%)
         occurrences all number
    4
    3
    Delirium
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Depression
         subjects affected / exposed
    0 / 30 (0.00%)
    6 / 30 (20.00%)
         occurrences all number
    0
    6
    Insomnia
         subjects affected / exposed
    3 / 30 (10.00%)
    6 / 30 (20.00%)
         occurrences all number
    3
    7
    Libido decreased
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Nervousness
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Sleep disorder
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 30 (6.67%)
         occurrences all number
    1
    3
    Reproductive system and breast disorders
    Balanoposthitis
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Erectile dysfunction
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Genital lesion
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Penile pain
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Prostatitis
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Excoriation
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Limb injury
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Fall
         subjects affected / exposed
    2 / 30 (6.67%)
    1 / 30 (3.33%)
         occurrences all number
    2
    1
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Post procedural swelling
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Sunburn
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    2
    Procedural pain
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    2
    Thermal burn
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Investigations
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 30 (3.33%)
         occurrences all number
    1
    2
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Blood creatinine increased
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Blood magnesium decreased
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Blood urea decreased
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Blood pressure increased
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Blood urea increased
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Blood uric acid increased
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Blood urine present
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Breath sounds abnormal
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    C-reactive protein increased
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 30 (3.33%)
         occurrences all number
    1
    1
    International normalised ratio increased
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 30 (6.67%)
         occurrences all number
    1
    2
    Culture urine positive
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Intraocular pressure increased
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Lipase increased
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Platelet count decreased
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    2
    Transaminases increased
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Urine output decreased
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Weight decreased
         subjects affected / exposed
    3 / 30 (10.00%)
    9 / 30 (30.00%)
         occurrences all number
    6
    17
    Weight increased
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Palpitations
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Mitral valve incompetence
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Sinus bradycardia
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Tachycardia
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 30 (10.00%)
    9 / 30 (30.00%)
         occurrences all number
    4
    11
    Dysphonia
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 30 (6.67%)
         occurrences all number
    1
    2
    Dyspnoea
         subjects affected / exposed
    8 / 30 (26.67%)
    9 / 30 (30.00%)
         occurrences all number
    8
    19
    Dyspnoea at rest
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Epistaxis
         subjects affected / exposed
    4 / 30 (13.33%)
    1 / 30 (3.33%)
         occurrences all number
    5
    1
    Dyspnoea exertional
         subjects affected / exposed
    1 / 30 (3.33%)
    3 / 30 (10.00%)
         occurrences all number
    1
    3
    Oropharyngeal pain
         subjects affected / exposed
    2 / 30 (6.67%)
    2 / 30 (6.67%)
         occurrences all number
    2
    2
    Pharyngeal erythema
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Pleurisy
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Pleural effusion
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 30 (6.67%)
         occurrences all number
    1
    4
    Pleuritic pain
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Rhinorrhoea
         subjects affected / exposed
    0 / 30 (0.00%)
    3 / 30 (10.00%)
         occurrences all number
    0
    3
    Sinus congestion
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 30 (6.67%)
         occurrences all number
    8
    3
    Leukopenia
         subjects affected / exposed
    2 / 30 (6.67%)
    1 / 30 (3.33%)
         occurrences all number
    2
    1
    Neutropenia
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 30 (3.33%)
         occurrences all number
    3
    1
    Polycythaemia
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Thrombocytopenia
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Nervous system disorders
    Amnesia
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    2
    Asterixis
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Ataxia
         subjects affected / exposed
    0 / 30 (0.00%)
    3 / 30 (10.00%)
         occurrences all number
    0
    3
    Cervical radiculopathy
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Coordination abnormal
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    3
    Dizziness
         subjects affected / exposed
    5 / 30 (16.67%)
    4 / 30 (13.33%)
         occurrences all number
    5
    5
    Dysgeusia
         subjects affected / exposed
    2 / 30 (6.67%)
    3 / 30 (10.00%)
         occurrences all number
    2
    3
    Dysaesthesia
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Encephalopathy
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    6
    Headache
         subjects affected / exposed
    4 / 30 (13.33%)
    4 / 30 (13.33%)
         occurrences all number
    4
    7
    Hepatic encephalopathy
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Hyperaesthesia
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 30 (3.33%)
         occurrences all number
    2
    1
    Hypoaesthesia
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Lethargy
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Hypotonia
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Memory impairment
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 30 (6.67%)
         occurrences all number
    1
    2
    Optic neuritis
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Neuropathy peripheral
         subjects affected / exposed
    1 / 30 (3.33%)
    6 / 30 (20.00%)
         occurrences all number
    1
    8
    Orthostatic tremor
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Paraesthesia
         subjects affected / exposed
    1 / 30 (3.33%)
    3 / 30 (10.00%)
         occurrences all number
    2
    3
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Spinal cord compression
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Tremor
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Eye disorders
    Conjunctival oedema
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Eye discharge
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Eye irritation
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Eye pain
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 30 (6.67%)
         occurrences all number
    1
    2
    Eye pruritus
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    2
    Glaucoma
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Lacrimation increased
         subjects affected / exposed
    2 / 30 (6.67%)
    1 / 30 (3.33%)
         occurrences all number
    2
    1
    Periorbital oedema
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Ocular hyperaemia
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    2
    Vision blurred
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Visual impairment
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    3
    Ear and labyrinth disorders
    Deafness
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Ear congestion
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Middle ear inflammation
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Otorrhoea
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Vertigo
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Vertigo positional
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Abdominal distension
         subjects affected / exposed
    4 / 30 (13.33%)
    2 / 30 (6.67%)
         occurrences all number
    4
    2
    Abdominal pain
         subjects affected / exposed
    6 / 30 (20.00%)
    11 / 30 (36.67%)
         occurrences all number
    8
    17
    Abdominal pain upper
         subjects affected / exposed
    5 / 30 (16.67%)
    8 / 30 (26.67%)
         occurrences all number
    8
    10
    Abdominal pain lower
         subjects affected / exposed
    1 / 30 (3.33%)
    3 / 30 (10.00%)
         occurrences all number
    1
    3
    Anal fissure
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Aphthous stomatitis
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Ascites
         subjects affected / exposed
    4 / 30 (13.33%)
    10 / 30 (33.33%)
         occurrences all number
    4
    24
    Constipation
         subjects affected / exposed
    4 / 30 (13.33%)
    11 / 30 (36.67%)
         occurrences all number
    5
    16
    Diarrhoea
         subjects affected / exposed
    20 / 30 (66.67%)
    23 / 30 (76.67%)
         occurrences all number
    38
    85
    Dyspepsia
         subjects affected / exposed
    3 / 30 (10.00%)
    2 / 30 (6.67%)
         occurrences all number
    4
    3
    Dry mouth
         subjects affected / exposed
    3 / 30 (10.00%)
    4 / 30 (13.33%)
         occurrences all number
    3
    4
    Dysphagia
         subjects affected / exposed
    2 / 30 (6.67%)
    1 / 30 (3.33%)
         occurrences all number
    2
    1
    Enterocutaneous fistula
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Gastritis
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Flatulence
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Gastrointestinal pain
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Gingival bleeding
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 30 (3.33%)
    3 / 30 (10.00%)
         occurrences all number
    1
    3
    Gingival pain
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 30 (3.33%)
         occurrences all number
    1
    1
    Gingival recession
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Haemorrhoids
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Inguinal hernia
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Intestinal obstruction
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Nausea
         subjects affected / exposed
    15 / 30 (50.00%)
    18 / 30 (60.00%)
         occurrences all number
    18
    27
    Odynophagia
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    2
    Oral pain
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 30 (3.33%)
         occurrences all number
    1
    2
    Proctalgia
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Steatorrhoea
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Stomatitis
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 30 (6.67%)
         occurrences all number
    2
    2
    Tongue disorder
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Varices oesophageal
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Vomiting
         subjects affected / exposed
    9 / 30 (30.00%)
    12 / 30 (40.00%)
         occurrences all number
    12
    18
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Bladder disorder
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Enuresis
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Dysuria
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 30 (6.67%)
         occurrences all number
    1
    3
    Pollakiuria
         subjects affected / exposed
    0 / 30 (0.00%)
    3 / 30 (10.00%)
         occurrences all number
    0
    3
    Renal failure
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Proteinuria
         subjects affected / exposed
    1 / 30 (3.33%)
    3 / 30 (10.00%)
         occurrences all number
    1
    5
    Renal vein thrombosis
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Urinary hesitation
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Urinary incontinence
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Urinary retention
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Cholecystitis
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Hepatic pain
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    3
    0
    Hepatic failure
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Hyperbilirubinaemia
         subjects affected / exposed
    5 / 30 (16.67%)
    1 / 30 (3.33%)
         occurrences all number
    6
    2
    Jaundice
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Portal hypertension
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Actinic keratosis
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Blister
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Alopecia
         subjects affected / exposed
    3 / 30 (10.00%)
    5 / 30 (16.67%)
         occurrences all number
    3
    6
    Decubitus ulcer
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Dry skin
         subjects affected / exposed
    4 / 30 (13.33%)
    9 / 30 (30.00%)
         occurrences all number
    4
    10
    Ecchymosis
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Erythema
         subjects affected / exposed
    1 / 30 (3.33%)
    5 / 30 (16.67%)
         occurrences all number
    1
    5
    Exfoliative rash
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Hyperhidrosis
         subjects affected / exposed
    1 / 30 (3.33%)
    3 / 30 (10.00%)
         occurrences all number
    2
    3
    Hair texture abnormal
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 30 (3.33%)
         occurrences all number
    1
    1
    Night sweats
         subjects affected / exposed
    2 / 30 (6.67%)
    2 / 30 (6.67%)
         occurrences all number
    2
    2
    Pain of skin
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Palmar erythema
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    2
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    11 / 30 (36.67%)
    9 / 30 (30.00%)
         occurrences all number
    22
    32
    Penile ulceration
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Photosensitivity reaction
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Pruritus
         subjects affected / exposed
    5 / 30 (16.67%)
    3 / 30 (10.00%)
         occurrences all number
    5
    5
    Pruritus allergic
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Pruritus generalised
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    2
    Rash
         subjects affected / exposed
    9 / 30 (30.00%)
    5 / 30 (16.67%)
         occurrences all number
    10
    10
    Skin depigmentation
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Skin discolouration
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Skin fissures
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 30 (3.33%)
         occurrences all number
    2
    1
    Skin reaction
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Skin lesion
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 30 (3.33%)
         occurrences all number
    1
    1
    Skin ulcer
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 30 (6.67%)
         occurrences all number
    1
    2
    Swelling face
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Urticaria
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    6 / 30 (20.00%)
    8 / 30 (26.67%)
         occurrences all number
    10
    13
    Back pain
         subjects affected / exposed
    5 / 30 (16.67%)
    5 / 30 (16.67%)
         occurrences all number
    6
    5
    Bone pain
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Groin pain
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Joint stiffness
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 30 (3.33%)
         occurrences all number
    1
    1
    Muscle tightness
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Muscle spasms
         subjects affected / exposed
    3 / 30 (10.00%)
    4 / 30 (13.33%)
         occurrences all number
    3
    5
    Muscular weakness
         subjects affected / exposed
    2 / 30 (6.67%)
    1 / 30 (3.33%)
         occurrences all number
    2
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal pain
         subjects affected / exposed
    2 / 30 (6.67%)
    4 / 30 (13.33%)
         occurrences all number
    3
    5
    Myalgia
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Neck pain
         subjects affected / exposed
    2 / 30 (6.67%)
    3 / 30 (10.00%)
         occurrences all number
    2
    3
    Pain in extremity
         subjects affected / exposed
    3 / 30 (10.00%)
    5 / 30 (16.67%)
         occurrences all number
    3
    8
    Pain in jaw
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    2
    Spinal pain
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Endocrine disorders
    Hyperparathyroidism
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Hypothyroidism
         subjects affected / exposed
    2 / 30 (6.67%)
    1 / 30 (3.33%)
         occurrences all number
    2
    1
    Metabolism and nutrition disorders
    Acidosis
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Decreased appetite
         subjects affected / exposed
    9 / 30 (30.00%)
    16 / 30 (53.33%)
         occurrences all number
    12
    22
    Cachexia
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Dehydration
         subjects affected / exposed
    2 / 30 (6.67%)
    5 / 30 (16.67%)
         occurrences all number
    2
    5
    Failure to thrive
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Hypercalcaemia
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Hyperglycaemia
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 30 (3.33%)
         occurrences all number
    1
    2
    Hyperkalaemia
         subjects affected / exposed
    2 / 30 (6.67%)
    2 / 30 (6.67%)
         occurrences all number
    3
    2
    Hyperuricaemia
         subjects affected / exposed
    2 / 30 (6.67%)
    1 / 30 (3.33%)
         occurrences all number
    3
    1
    Hypoglycaemia
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 30 (3.33%)
         occurrences all number
    1
    2
    Hypocalcaemia
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Hypokalaemia
         subjects affected / exposed
    2 / 30 (6.67%)
    4 / 30 (13.33%)
         occurrences all number
    2
    5
    Hypomagnesaemia
         subjects affected / exposed
    4 / 30 (13.33%)
    1 / 30 (3.33%)
         occurrences all number
    5
    1
    Hyponatraemia
         subjects affected / exposed
    2 / 30 (6.67%)
    1 / 30 (3.33%)
         occurrences all number
    3
    2
    Hypophosphataemia
         subjects affected / exposed
    3 / 30 (10.00%)
    1 / 30 (3.33%)
         occurrences all number
    5
    1
    Malnutrition
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 30 (6.67%)
         occurrences all number
    1
    2
    Candida infection
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Cellulitis
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 30 (3.33%)
         occurrences all number
    1
    1
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Device related infection
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 30 (3.33%)
         occurrences all number
    1
    1
    Ear lobe infection
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Gastroenteritis
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    3
    Folliculitis
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    3
    Genital candidiasis
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Groin abscess
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Gingivitis
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Herpes virus infection
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Infection
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Localised infection
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Lung infection
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    1 / 30 (3.33%)
    4 / 30 (13.33%)
         occurrences all number
    2
    4
    Oesophageal candidiasis
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    2
    Oral candidiasis
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 30 (6.67%)
         occurrences all number
    2
    2
    Otitis media
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Postoperative wound infection
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Rhinitis
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    2
    Sinusitis
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Staphylococcal infection
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Skin candida
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 30 (0.00%)
    3 / 30 (10.00%)
         occurrences all number
    0
    3
    Urinary tract infection
         subjects affected / exposed
    2 / 30 (6.67%)
    2 / 30 (6.67%)
         occurrences all number
    2
    3
    Viral infection
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Dec 2009
    - Introduced a new cohort (B) (trebananib 15 mg/kg IV QW plus sorafenib 400 mg PO BID) with a planned enrollment of approximately 30 additional subjects - Extended the enrollment period to 15 months to facilitate the enrollment of the additional 30 subjects - Updated in the introduction the clinical immunogenicity data across the phase 1 trebananib program - Provided clarification regarding inclusion/exclusion criteria for consistency across the trebananib program - Provided clarification and better defined the clinical hypothesis of the study - Added thyroid function test as a required laboratory test to monitor incidence of hypothyroidism associated with tyrosine kinase inhibitors - Provided guidance regarding trebananib dosing in case of adverse event of hypertension, edema/lymphedema, and infusion reactions - Added trebananib toxicity management sections (edema/lymphedema, hypertension, infusion reactions) - Removed all specific and detailed information related to packaging and formulation of trebananib and matching placebo, and consolidated details in a pharmacy binder, which was sent to investigators with the protocol (to ensure sites always had the most accurate information). - Clarified the definition of the primary endpoint as time to progression rate at 18 weeks
    01 Mar 2011
    - Changed the primary endpoint to progression-free survival at 4 months; revised sample size section - Added an additional safety review for cohort A (after 20 subjects) - Provided an update regarding the toxicity management guidance for the adverse events of edema/lymphedema, hypertension, and hypokalemia
    18 Jul 2011
    - Added new section for the toxicity management of trebananib related pleural effusion and ascites - Decreased the radiologic scanning frequency interval after 2 years on study - Corrected the INR value for inclusion criteria to INR ≤ 2.2 per Child-Pugh Classification - Added guidelines for proscribed medications including immune modulators and strong CYP3A4 inducers during the study - Added the new pregnancy reporting section and form

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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