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    Clinical Trial Results:
    Phase III randomized sequential open-label study to evaluate the efficacy and safety of sorafenib followed by pazopanib versus pazopanib followed by sorafenib in the treatment of advanced / metastatic renal cell carcinoma (SWITCH 2)

    Summary
    EudraCT number
    2011-004396-36
    Trial protocol
    DE   AT   NL  
    Global end of trial date
    14 Nov 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    04 Jan 2018
    First version publication date
    04 Jan 2018
    Other versions
    Summary report(s)
    SWITCH-2 ICH-E3 Synopsis

    Trial information

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    Trial identification
    Sponsor protocol code
    16037
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00439636
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    AUO study code number: AN 33/11
    Sponsors
    Sponsor organisation name
    Technical University Munich
    Sponsor organisation address
    Ismaninger Str. 22, Munich, Germany, 81675
    Public contact
    Clinical Research Organisation, iOMEDICO AG, 0049 0761152420, info@iomedico.com
    Scientific contact
    Clinical Research Organisation, iOMEDICO AG, 0049 0761152420, info@iomedico.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
    20 Oct 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 Nov 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Nov 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate if progression -free survival from randomization to progression or death during second -line therapy (total PFS) of sorafenib followed by pazopanib ist non-inferior compared to pazopanib followed by sorafenib
    Protection of trial subjects
    Informed consent of patient has been obtained in accordance with § 40 I 3 No. 3 Lit. b), II 1 AMG and § 40 I 3 No. 3 Lit. c). IIa 1&2 AMG by each investigator prior to inclusion of each patient to the study. In addition, informed consent of patients had been obtained in accordance with the respective legal obligations in Austria and the Netherlands. The nature, objective and importance of the study, the possible benefits and disadvantages or risks, and the study procedures were explained to each patient orally and in writing. The patients were informed that their participation was voluntary, that they were free to withdraw from the study at any time, and that choosing not to participate would not impact on the patient’s care or future treatment. The patients were also informed that, by signing the Informed Consent Form, they explicitly permitted authorized representatives of the sponsor and the regulatory authorities access to study-related personal data to the extent permitted by the applicable law(s) and/or regulations without violating the confidentiality of the patient, to the extent permitted by the applicable law(s) and/or regulations. The patients were also informed that their consent to access their data might not be revoked. Each patient was given sufficient time to read and discuss the ICF with the investigator prior to giving his/her written consent. Before entry to the study and prior to the conduct of any study-related procedure consent was recorded by means of the patient’s dated signature.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    14 Jun 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 45
    Country: Number of subjects enrolled
    Austria: 14
    Country: Number of subjects enrolled
    Germany: 318
    Worldwide total number of subjects
    377
    EEA total number of subjects
    377
    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)
    149
    From 65 to 84 years
    227
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    The investigators enrolled patients based on previously defined inclusion and exclusion criteria. All patients, who fulfilled all of the inclusion criteria and none of the exclusion criteria, were randomized centrally in a ratio of 1:1 to either Pazopanib or Sorafenib as first-line treatment.

    Pre-assignment
    Screening details
    Screening: starting on day -28 prior to randomization. This study was a sequential, randomized, open-label (1:1), multicenter phase III study starting in first-line of metastatic / advanced RCC using in the experimental arm sorafenib until progression followed by pazopanib and in the control arm pazopanib until progression followed by sorafenib.

    Pre-assignment period milestones
    Number of subjects started
    377
    Intermediate milestone: Number of subjects
    Screening and Randomization: 377
    Number of subjects completed
    377

    Period 1
    Period 1 title
    Treatment Period - Switch Design (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded
    Blinding implementation details
    Not applicable in this open label randomized study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Group A Sorafenib - Pazopanib (S-P)
    Arm description
    Group A First-line: Sorafenib 800 mg (daily total dose) 2*400 mg Second-line: Pazopanib 800 mg (daily total dose) 1*800 mg
    Arm type
    Experimental

    Investigational medicinal product name
    Sorafenib followed by Pazopanib
    Investigational medicinal product code
    L01XE05 followed by L01XE11
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Sorafenib 800 mg (daily dose) 2*400mg Pazopanib 800 mg (daily dose) 1*800 mg

    Arm title
    Group B Pazopanib - Sorafenib (P-S)
    Arm description
    Group B First-line: Pazopanib 800 mg (daily total dose) 1*800 mg Second-line: Sorafenib 800 mg (daily total dose) 2*400 mg
    Arm type
    Active comparator

    Investigational medicinal product name
    Pazopanib followed by Sorafenib
    Investigational medicinal product code
    L01XE11 followed by L01XE05
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Sorafenib 800 mg (daily dose) 2*400mg Pazopanib 800 mg (daily dose) 1*800 mg

    Number of subjects in period 1
    Group A Sorafenib - Pazopanib (S-P) Group B Pazopanib - Sorafenib (P-S)
    Started
    189
    188
    Completed
    153
    146
    Not completed
    36
    42
         other reason
    4
    5
         Screening Failure
    4
    4
         No Follow-up participation
    7
    8
         Consent withdrawn by subject
    11
    16
         Lost to follow-up
    10
    9

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group A Sorafenib - Pazopanib (S-P)
    Reporting group description
    Group A First-line: Sorafenib 800 mg (daily total dose) 2*400 mg Second-line: Pazopanib 800 mg (daily total dose) 1*800 mg

    Reporting group title
    Group B Pazopanib - Sorafenib (P-S)
    Reporting group description
    Group B First-line: Pazopanib 800 mg (daily total dose) 1*800 mg Second-line: Sorafenib 800 mg (daily total dose) 2*400 mg

    Reporting group values
    Group A Sorafenib - Pazopanib (S-P) Group B Pazopanib - Sorafenib (P-S) Total
    Number of subjects
    189 188 377
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        median (full range (min-max))
    67.5 (31.3 to 83.7) 68.4 (25.6 to 85.6) -
    Gender categorical
    Units: Subjects
        Female
    53 51 104
        Male
    136 137 273
    Karnofsky Performance Status at Screening
    Karnofsky Performance Status at Screening in categories (100, 90, 80, 70, missing)
    Units: Subjects
        KPS Screen 100
    96 85 181
        KPS Screen 90
    32 46 78
        KPS Screen 80
    52 44 96
        KPS Screen 70
    9 12 21
        KPS Screen missing
    0 1 1
    MSKCC
    MSKCC score at enrolment
    Units: Subjects
        High
    4 5 9
        Intermediate
    90 89 179
        Low
    95 91 186
        Unknown
    0 2 2
        Missing
    0 1 1
    Renal insufficiency
    Chronic renal insuffiency
    Units: Subjects
        Yes
    26 29 55
        No
    156 149 305
        Unknown
    7 10 17
    Weight
    Median weight at screening
    Units: kg
        median (full range (min-max))
    80.3 (49 to 130) 81.7 (43.6 to 129) -
    BMI
    Median Body Mass Index
    Units: kg/m²
        median (full range (min-max))
    27.2 (19.4 to 44.6) 26.5 (15.5 to 38.1) -
    Time from diagnosis to randomization
    Median Time from Diagnosis to Randomization
    Units: months
        median (full range (min-max))
    6.3 (0.22 to 221.4) 8.7 (0.2 to 245.6) -
    Time from first relapse/metastatic disease to randomization
    Median time from first relapse/metastatic disease to randomization
    Units: months
        median (full range (min-max))
    1.9 (0.1 to 123.1) 2.2 (0.1 to 155.7) -
    Number of disease sites
    Median number of disease sites
    Units: number
        median (full range (min-max))
    2 (1 to 6) 3 (1 to 5) -

    End points

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    End points reporting groups
    Reporting group title
    Group A Sorafenib - Pazopanib (S-P)
    Reporting group description
    Group A First-line: Sorafenib 800 mg (daily total dose) 2*400 mg Second-line: Pazopanib 800 mg (daily total dose) 1*800 mg

    Reporting group title
    Group B Pazopanib - Sorafenib (P-S)
    Reporting group description
    Group B First-line: Pazopanib 800 mg (daily total dose) 1*800 mg Second-line: Sorafenib 800 mg (daily total dose) 2*400 mg

    Subject analysis set title
    ITT
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    All subjects who were assigned a subject number at randomization are considered randomized subjects, even if they did not receive any trial treatment. All randomized subjects will be included in the Intention-to-treat (ITT) population. This population is the primary analysis population. In analyses of the ITT population, subjects will be assigned to the treatment to which they were randomized. The Safety analysis population consists of n=366 patients.

    Primary: Total Progression-free survival

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    End point title
    Total Progression-free survival
    End point description
    The goal was to demonstrate that the PFS time in the experimental arm (Sorafenib first in sequence) was not inferior to the PFS time in the control arm (Pazopanib first in sequence). Primary analysis population: Intent to Treat (ITT).
    End point type
    Primary
    End point timeframe
    Total PFS is defined as the time interval from randomization to progression or death (whichever comes first) during second-line therapy.
    End point values
    Group A Sorafenib - Pazopanib (S-P) Group B Pazopanib - Sorafenib (P-S)
    Number of subjects analysed
    189
    188
    Units: months
        median (confidence interval 95%)
    8.6 (7.7 to 10.2)
    12.9 (10.8 to 15.2)
    Attachments
    Total PFS (ITT)
    Statistical analysis title
    Analysis of primary endpoint
    Statistical analysis description
    To demonstrate total PFS time in the experimental arm (Sorafenib first) not inferior to total PFS time in the control arm. Definition non-inferiority: in the experimental arm, upper limit of the one-sided 95% CI of the hazard ratio is not above 1.225 (corresponding to a decrease to 13.1 months compared to an assumed median total PFS in the control group of 16 months). 383 events needed to be observed to have 80% power to reject the null hypotheses of inferiority (HR >=1.225), when true HR=0.95.
    Comparison groups
    Group A Sorafenib - Pazopanib (S-P) v Group B Pazopanib - Sorafenib (P-S)
    Number of subjects included in analysis
    377
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    Method
    Parameter type
    Cox proportional hazard
    Point estimate
    1.36
    Confidence interval
         level
    95%
         sides
    1-sided
         lower limit
    -
         upper limit
    1.68

    Secondary: Time to Progression (TTP)

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    End point title
    Time to Progression (TTP)
    End point description
    Patients without tumor progression at the time of analysis will be censored at their last date of tumor evaluation.
    End point type
    Secondary
    End point timeframe
    Total TTP is defined as the time interval from randomization to the date of progression during second-line therapy.
    End point values
    Group A Sorafenib - Pazopanib (S-P) Group B Pazopanib - Sorafenib (P-S)
    Number of subjects analysed
    189
    188
    Units: months
        median (confidence interval 95%)
    8.5 (7.4 to 10.2)
    12.9 (10.7 to 15.3)
    Attachments
    Total Time to Progression (TTP - ITT)
    No statistical analyses for this end point

    Secondary: Time to first-line treatment failure (TTF)

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    End point title
    Time to first-line treatment failure (TTF)
    End point description
    Reasons for end of treatment that count for an event (treatment failure) are adverse event, death, patient non-compliance, investigator’s decision, progression of disease and use of illicit drugs. Patients with all other reasons will be censored at the end date of first-line treatment.
    End point type
    Secondary
    End point timeframe
    TTF is defined by the time interval between the date of randomization and the date of stopping first-line treatment due to treatment failure.
    End point values
    Group A Sorafenib - Pazopanib (S-P) Group B Pazopanib - Sorafenib (P-S)
    Number of subjects analysed
    189
    188
    Units: months
        median (confidence interval 95%)
    5.5 (3.9 to 5.8)
    7.8 (5.8 to 9.6)
    Attachments
    Time to first-line treatment failure (ITT)
    No statistical analyses for this end point

    Secondary: PFS first-line

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    End point title
    PFS first-line
    End point description
    PFS in first line therapy is defined as the time from randomization to first progression or death from any cause, whatever occurs first. The primary analysis of PFS in first-line will be performed with the ITT population.
    End point type
    Secondary
    End point timeframe
    Time from randomization to first progression or death from any cause, whatever occurs first.
    End point values
    Group A Sorafenib - Pazopanib (S-P) Group B Pazopanib - Sorafenib (P-S)
    Number of subjects analysed
    189
    188
    Units: months
        median (confidence interval 95%)
    5.6 (4.7 to 6.3)
    9.3 (7.4 to 10.6)
    Attachments
    First-line PFS
    No statistical analyses for this end point

    Secondary: PFS-Second-line

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    End point title
    PFS-Second-line
    End point description
    PFS in second-line therapy is defined as the time from start of second-line therapy to progression or death from any cause, whatever occurs first, during second line therapy. The primary analysis of PFS in second line will be performed with the ITT population.
    End point type
    Secondary
    End point timeframe
    Time from start of second-line therapy to progression or death from any cause, whatever occurs first.
    End point values
    Group A Sorafenib - Pazopanib (S-P) Group B Pazopanib - Sorafenib (P-S)
    Number of subjects analysed
    189
    188
    Units: months
        median (confidence interval 95%)
    2.9 (2 to 3.7)
    2.1 (1.8 to 3.5)
    Attachments
    Second-line PFS
    No statistical analyses for this end point

    Secondary: Overall Survival

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    End point title
    Overall Survival
    End point description
    Overall survival is defined as the time from randomization to death of any cause. The primary analysis of OS will be performed with the ITT population. Time to last observation will be used if a patient has no documented date of death and OS for the patient will be considered censored.
    End point type
    Secondary
    End point timeframe
    Time from randomization to death of any cause.
    End point values
    Group A Sorafenib - Pazopanib (S-P) Group B Pazopanib - Sorafenib (P-S)
    Number of subjects analysed
    189
    188
    Units: months
        median (confidence interval 95%)
    22.7 (17.4 to 28.6)
    28.0 (22.6 to 34.1)
    Attachments
    Overall Survival (ITT)
    No statistical analyses for this end point

    Secondary: PRO FKSI change from BL to last available value - first-line

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    End point title
    PRO FKSI change from BL to last available value - first-line
    End point description
    Patient-reported outcome (PRO) FKSI Score, change from baseline to last available value in first-line. If no worsening happens, patients will be censored with the date of last available questionnaire per treatment line.
    End point type
    Secondary
    End point timeframe
    The time to health state deterioration is defined as the time from baseline questionnaire to the date of first worsening of 4 points compared to baseline in the total score per treatment line.
    End point values
    Group A Sorafenib - Pazopanib (S-P) Group B Pazopanib - Sorafenib (P-S)
    Number of subjects analysed
    136
    132
    Units: points
        median (inter-quartile range (Q1-Q3))
    -2.0 (-6.1 to 0.0)
    -3.0 (-8 to 0)
    No statistical analyses for this end point

    Secondary: PRO FACIT-F change from BL to last available value - first-line

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    End point title
    PRO FACIT-F change from BL to last available value - first-line
    End point description
    Patient-reported outcomes (PROs) of FACIT-F subscores, total score and single items are summarized per visit and treatment arm. Following Cella et al (Cella, Eton, Lai, Peterman, & Merkel, 2002), the minimal important difference (MID) indicating clinically important QoL changes in cancer clinical trials is assumed to be 3 points for the Fatigue Scale and 4 points for the FACT-G respectively. If no worsening happens, patients will be censored with the date of last available questionnaire per treatment line.
    End point type
    Secondary
    End point timeframe
    The time to health state deterioration is defined as the time from baseline questionnaire to the date of first worsening of MID compared to baseline in the total score per treatment line.
    End point values
    Group A Sorafenib - Pazopanib (S-P) Group B Pazopanib - Sorafenib (P-S)
    Number of subjects analysed
    136
    131
    Units: points
        median (inter-quartile range (Q1-Q3))
    -1 (-19.4 to 1.2)
    -7.4 (-24.8 to 5)
    No statistical analyses for this end point

    Secondary: PRO FKSI change from BL to last available value - second-line

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    End point title
    PRO FKSI change from BL to last available value - second-line
    End point description
    Patient-reported outcome (PRO) FKSI Score, change from baseline to last available value in second-line. If no worsening happens, patients will be censored with the date of last available questionnaire per treatment line.
    End point type
    Secondary
    End point timeframe
    The time to health state deterioration is defined as the time from baseline questionnaire to the date of first worsening of 4 points compared to baseline in the total score per treatment line.
    End point values
    Group A Sorafenib - Pazopanib (S-P) Group B Pazopanib - Sorafenib (P-S)
    Number of subjects analysed
    80
    67
    Units: points
        median (inter-quartile range (Q1-Q3))
    0 (-3 to 1)
    0 (-5 to 1.7)
    No statistical analyses for this end point

    Secondary: PRO FACIT-F change from BL to last available value - second-line

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    End point title
    PRO FACIT-F change from BL to last available value - second-line
    End point description
    Patient-reported outcome (PRO) FACIT-F Score, change from Baseline to last available value in second-line. If no worsening happens, patients will be censored with the date of last available questionnaire per treatment line.
    End point type
    Secondary
    End point timeframe
    The time to health state deterioration is defined as the time from baseline questionnaire to the date of first worsening of MID compared to baseline in the total score per treatment line.
    End point values
    Group A Sorafenib - Pazopanib (S-P) Group B Pazopanib - Sorafenib (P-S)
    Number of subjects analysed
    76
    62
    Units: points
        median (inter-quartile range (Q1-Q3))
    0 (-7.2 to 3.3)
    -1.2 (-14.9 to 0.8)
    No statistical analyses for this end point

    Secondary: Overall Response Rate - First-line (ORR-1)

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    End point title
    Overall Response Rate - First-line (ORR-1)
    End point description
    The sum of rates of complete response and partial response as best response.
    End point type
    Secondary
    End point timeframe
    Relevant response evaluations for first-line treatment are all evaluations before start of second-line therapy.
    End point values
    Group A Sorafenib - Pazopanib (S-P) Group B Pazopanib - Sorafenib (P-S)
    Number of subjects analysed
    189
    188
    Units: Number
    54
    87
    No statistical analyses for this end point

    Secondary: Overall Response Rate - Second-line (ORR-2)

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    End point title
    Overall Response Rate - Second-line (ORR-2)
    End point description
    The overall response rate (ORR) is defined as the sum of rates of complete response and partial response as best response.
    End point type
    Secondary
    End point timeframe
    Relevant response evaluations for second-line treatment are all evaluations after start of second-line therapy.
    End point values
    Group A Sorafenib - Pazopanib (S-P) Group B Pazopanib - Sorafenib (P-S)
    Number of subjects analysed
    106
    87
    Units: Number
    21
    8
    No statistical analyses for this end point

    Secondary: Disease Control Rate - First-line (DCR-1)

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    End point title
    Disease Control Rate - First-line (DCR-1)
    End point description
    The disease control rate (DCR) is defined as the sum of rates of complete response, partial response and stable disease based on the best response.
    End point type
    Secondary
    End point timeframe
    Relevant response evaluations for first-line treatment are all evaluations before start of second-line therapy.
    End point values
    Group A Sorafenib - Pazopanib (S-P) Group B Pazopanib - Sorafenib (P-S)
    Number of subjects analysed
    189
    188
    Units: Number
    128
    146
    No statistical analyses for this end point

    Secondary: Disease Control Rate - Second-line (DCR-2)

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    End point title
    Disease Control Rate - Second-line (DCR-2)
    End point description
    The disease control rate (DCR) is defined as the sum of rates of complete response, partial response and stable disease based on the best response.
    End point type
    Secondary
    End point timeframe
    Relevant response evaluations for second-line treatment are all evaluations after start of second-line therapy.
    End point values
    Group A Sorafenib - Pazopanib (S-P) Group B Pazopanib - Sorafenib (P-S)
    Number of subjects analysed
    106
    87
    Units: Number
    60
    38
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    On-treatment period: from day of first dose of study medication to 30 days after last dose of study medication.
    Adverse event reporting additional description
    Adverse Events (AEs) will be graded according to the CTCAE, version 4.03.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Arm A: S-P First-line
    Reporting group description
    Arm A: Sorafenib - Pazopanib First-line (Note: Only fatal TEAE were analysed per reporting group, in total 94 patients died in Arm A upon study completion (LPLV).

    Reporting group title
    Arm B: P-S First-line
    Reporting group description
    Pazopanib - Sorafenib First-line (Note: Only fatal TEAE were analysed per reporting group, in total 82 patients died in Arm B upon study completion (LPLV)).

    Reporting group title
    Arm A: S-P Second-line
    Reporting group description
    Sorafenib - Pazopanib Second-line (Note: Only fatal TEAE were analysed per reporting group, in total 94 patients died in Arm A upon study completion (LPLV)).

    Reporting group title
    Arm B: P-S Second-line
    Reporting group description
    Arm B: Pazopanib - Sorafenib Second-line (Note: Only fatal TEAE were analysed per reporting group, in total 82 patients died in Arm B upon study completion (LPLV)).

    Serious adverse events
    Arm A: S-P First-line Arm B: P-S First-line Arm A: S-P Second-line Arm B: P-S Second-line
    Total subjects affected by serious adverse events
         subjects affected / exposed
    96 / 183 (52.46%)
    97 / 183 (53.01%)
    51 / 106 (48.11%)
    32 / 87 (36.78%)
         number of deaths (all causes)
    19
    23
    19
    9
         number of deaths resulting from adverse events
    19
    23
    19
    9
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
    1 / 106 (0.94%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    0 / 183 (0.00%)
    0 / 183 (0.00%)
    1 / 106 (0.94%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 183 (0.55%)
    2 / 183 (1.09%)
    0 / 106 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 183 (0.55%)
    4 / 183 (2.19%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vena cava thrombosis
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Cancer surgery
         subjects affected / exposed
    2 / 183 (1.09%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meniscus removal
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephrectomy
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin lesion removal
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Brain neoplasm
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cancer pain
         subjects affected / exposed
    0 / 183 (0.00%)
    0 / 183 (0.00%)
    1 / 106 (0.94%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lip and/or oral cavity cancer
         subjects affected / exposed
    0 / 183 (0.00%)
    0 / 183 (0.00%)
    1 / 106 (0.94%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymphangiosis carcinomatosa
         subjects affected / exposed
    0 / 183 (0.00%)
    0 / 183 (0.00%)
    1 / 106 (0.94%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    11 / 183 (6.01%)
    10 / 183 (5.46%)
    7 / 106 (6.60%)
    6 / 87 (6.90%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 10
    1 / 7
    0 / 6
         deaths causally related to treatment / all
    0 / 11
    0 / 8
    1 / 7
    0 / 5
    Malignant pleural effusion
         subjects affected / exposed
    1 / 183 (0.55%)
    3 / 183 (1.64%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Metastases to bone
         subjects affected / exposed
    1 / 183 (0.55%)
    2 / 183 (1.09%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    0 / 183 (0.00%)
    0 / 183 (0.00%)
    2 / 106 (1.89%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Metastases to perineum
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Metastases to skin
         subjects affected / exposed
    0 / 183 (0.00%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasm
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasm progression
         subjects affected / exposed
    1 / 183 (0.55%)
    1 / 183 (0.55%)
    0 / 106 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    Non-small cell lung cancer
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal adenocarcinoma
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal cancer metastatic
         subjects affected / exposed
    0 / 183 (0.00%)
    0 / 183 (0.00%)
    1 / 106 (0.94%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Contrast media allergy
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 183 (0.00%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
    1 / 106 (0.94%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    Fatigue
         subjects affected / exposed
    3 / 183 (1.64%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    3 / 183 (1.64%)
    2 / 183 (1.09%)
    5 / 106 (4.72%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 2
    1 / 5
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Impaired healing
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
    1 / 106 (0.94%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 183 (0.55%)
    3 / 183 (1.64%)
    1 / 106 (0.94%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Performance status decreased
         subjects affected / exposed
    0 / 183 (0.00%)
    0 / 183 (0.00%)
    1 / 106 (0.94%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 183 (1.09%)
    2 / 183 (1.09%)
    2 / 106 (1.89%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Unevaluable event
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    0 / 183 (0.00%)
    2 / 183 (1.09%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Personality change
         subjects affected / exposed
    0 / 183 (0.00%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Alcohol poisoning
         subjects affected / exposed
    0 / 183 (0.00%)
    0 / 183 (0.00%)
    1 / 106 (0.94%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cervical vertebral fracture
         subjects affected / exposed
    2 / 183 (1.09%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
    1 / 106 (0.94%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 183 (0.55%)
    1 / 183 (0.55%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    0 / 183 (0.00%)
    0 / 183 (0.00%)
    1 / 106 (0.94%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Patella fracture
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radiation proctitis
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 183 (0.00%)
    6 / 183 (3.28%)
    3 / 106 (2.83%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    6 / 6
    3 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 183 (0.00%)
    2 / 183 (1.09%)
    1 / 106 (0.94%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood creatine phosphokinase MB increased
         subjects affected / exposed
    0 / 183 (0.00%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eastern Cooperative Oncology Group performance status worsened
         subjects affected / exposed
    1 / 183 (0.55%)
    1 / 183 (0.55%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fibrin D dimer increased
         subjects affected / exposed
    0 / 183 (0.00%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General physical condition abnormal
         subjects affected / exposed
    0 / 183 (0.00%)
    0 / 183 (0.00%)
    4 / 106 (3.77%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 183 (0.00%)
    4 / 183 (2.19%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 6
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Liver function test increased
         subjects affected / exposed
    0 / 183 (0.00%)
    2 / 183 (1.09%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial necrosis marker increased
         subjects affected / exposed
    0 / 183 (0.00%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial strain
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 183 (0.00%)
    0 / 183 (0.00%)
    1 / 106 (0.94%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    1 / 183 (0.55%)
    1 / 183 (0.55%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
    1 / 106 (0.94%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    3 / 183 (1.64%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    2 / 183 (1.09%)
    4 / 183 (2.19%)
    2 / 106 (1.89%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 4
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 183 (0.55%)
    1 / 183 (0.55%)
    0 / 106 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocarditis
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 183 (0.55%)
    1 / 183 (0.55%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 183 (0.00%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 183 (0.55%)
    3 / 183 (1.64%)
    2 / 106 (1.89%)
    3 / 87 (3.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 0
    Haemoptysis
         subjects affected / exposed
    2 / 183 (1.09%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperventilation
         subjects affected / exposed
    0 / 183 (0.00%)
    2 / 183 (1.09%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    7 / 183 (3.83%)
    5 / 183 (2.73%)
    6 / 106 (5.66%)
    2 / 87 (2.30%)
         occurrences causally related to treatment / all
    1 / 8
    0 / 5
    0 / 10
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 1
    Pneumonitis
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax spontaneous
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 183 (0.55%)
    5 / 183 (2.73%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
    0 / 106 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Pulmonary mass
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 183 (0.00%)
    0 / 183 (0.00%)
    1 / 106 (0.94%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebellar infarction
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 183 (0.55%)
    2 / 183 (1.09%)
    0 / 106 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 183 (0.55%)
    1 / 183 (0.55%)
    0 / 106 (0.00%)
    2 / 87 (2.30%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug withdrawal headache
         subjects affected / exposed
    0 / 183 (0.00%)
    0 / 183 (0.00%)
    1 / 106 (0.94%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 183 (0.55%)
    2 / 183 (1.09%)
    1 / 106 (0.94%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 183 (0.00%)
    0 / 183 (0.00%)
    1 / 106 (0.94%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    0 / 183 (0.00%)
    0 / 183 (0.00%)
    1 / 106 (0.94%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hemiplegia
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intracranial pressure increased
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    IVth nerve paralysis
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nerve compression
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
    1 / 106 (0.94%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paralysis
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paraplegia
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
    1 / 106 (0.94%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Paresis
         subjects affected / exposed
    0 / 183 (0.00%)
    0 / 183 (0.00%)
    1 / 106 (0.94%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 183 (0.00%)
    0 / 183 (0.00%)
    1 / 106 (0.94%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
    1 / 106 (0.94%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Retinal detachment
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retinal haemorrhage
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 183 (0.00%)
    2 / 183 (1.09%)
    0 / 106 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 183 (0.55%)
    2 / 183 (1.09%)
    1 / 106 (0.94%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute abdomen
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Anal fissure
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 183 (0.55%)
    1 / 183 (0.55%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    5 / 183 (2.73%)
    5 / 183 (2.73%)
    0 / 106 (0.00%)
    2 / 87 (2.30%)
         occurrences causally related to treatment / all
    5 / 5
    3 / 5
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Diverticular perforation
         subjects affected / exposed
    2 / 183 (1.09%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulum intestinal haemorrhagic
         subjects affected / exposed
    0 / 183 (0.00%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 183 (0.00%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Faecaloma
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    2 / 183 (1.09%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis erosive
         subjects affected / exposed
    0 / 183 (0.00%)
    0 / 183 (0.00%)
    1 / 106 (0.94%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis haemorrhagic
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 183 (0.00%)
    2 / 183 (1.09%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Gastrointestinal perforation
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 183 (0.00%)
    0 / 183 (0.00%)
    1 / 106 (0.94%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    3 / 183 (1.64%)
    0 / 183 (0.00%)
    1 / 106 (0.94%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
    0 / 106 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mallory-Weiss syndrome
         subjects affected / exposed
    0 / 183 (0.00%)
    0 / 183 (0.00%)
    1 / 106 (0.94%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 183 (1.09%)
    1 / 183 (0.55%)
    0 / 106 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    4 / 183 (2.19%)
    3 / 183 (1.64%)
    0 / 106 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    1 / 5
    2 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 183 (0.55%)
    2 / 183 (1.09%)
    0 / 106 (0.00%)
    2 / 87 (2.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 2
    Haematuria
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
    1 / 106 (0.94%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Proteinuria
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Renal pain
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tubulointerstitial nephritis
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urethral haemorrhage
         subjects affected / exposed
    0 / 183 (0.00%)
    0 / 183 (0.00%)
    1 / 106 (0.94%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 183 (0.55%)
    1 / 183 (0.55%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
    1 / 106 (0.94%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    0 / 183 (0.00%)
    2 / 183 (1.09%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    0 / 183 (0.00%)
    8 / 183 (4.37%)
    3 / 106 (2.83%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    8 / 8
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Jaundice
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
    0 / 106 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis allergic
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Erythema
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain of skin
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    3 / 183 (1.64%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
    1 / 106 (0.94%)
    2 / 87 (2.30%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 183 (1.09%)
    0 / 183 (0.00%)
    2 / 106 (1.89%)
    2 / 87 (2.30%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 183 (0.00%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteolysis
         subjects affected / exposed
    2 / 183 (1.09%)
    0 / 183 (0.00%)
    1 / 106 (0.94%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteonecrosis of jaw
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
    0 / 106 (0.00%)
    2 / 87 (2.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal instability
         subjects affected / exposed
    0 / 183 (0.00%)
    2 / 183 (1.09%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    0 / 183 (0.00%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    2 / 183 (1.09%)
    2 / 183 (1.09%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    3 / 183 (1.64%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 183 (0.55%)
    2 / 183 (1.09%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 183 (0.55%)
    1 / 183 (0.55%)
    0 / 106 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
    1 / 106 (0.94%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal abscess
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abscess intestinal
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abscess jaw
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacterial infection
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Candida infection
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
    0 / 106 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Empyema
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epididymitis
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 183 (0.00%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 183 (0.00%)
    2 / 183 (1.09%)
    0 / 106 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    2 / 183 (1.09%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed
    0 / 183 (0.00%)
    0 / 183 (0.00%)
    1 / 106 (0.94%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Medical device site infection
         subjects affected / exposed
    0 / 183 (0.00%)
    2 / 183 (1.09%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Necrotising fasciitis
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 183 (0.00%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    7 / 183 (3.83%)
    5 / 183 (2.73%)
    1 / 106 (0.94%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 7
    0 / 5
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 183 (0.00%)
    0 / 183 (0.00%)
    1 / 106 (0.94%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    1 / 183 (0.55%)
    1 / 183 (0.55%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 183 (0.55%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 183 (0.55%)
    1 / 183 (0.55%)
    0 / 106 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 183 (0.00%)
    0 / 106 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Arm A: S-P First-line Arm B: P-S First-line Arm A: S-P Second-line Arm B: P-S Second-line
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    172 / 183 (93.99%)
    178 / 183 (97.27%)
    91 / 106 (85.85%)
    77 / 87 (88.51%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    48 / 183 (26.23%)
    81 / 183 (44.26%)
    15 / 106 (14.15%)
    9 / 87 (10.34%)
         occurrences all number
    59
    97
    18
    9
    Immune system disorders
    Aspartate aminotransferase increased
         subjects affected / exposed
    4 / 183 (2.19%)
    19 / 183 (10.38%)
    1 / 106 (0.94%)
    1 / 87 (1.15%)
         occurrences all number
    7
    31
    2
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    66 / 183 (36.07%)
    82 / 183 (44.81%)
    16 / 106 (15.09%)
    9 / 87 (10.34%)
         occurrences all number
    71
    96
    19
    10
    Oedema peripheral
         subjects affected / exposed
    6 / 183 (3.28%)
    18 / 183 (9.84%)
    7 / 106 (6.60%)
    5 / 87 (5.75%)
         occurrences all number
    8
    19
    7
    5
    Pain
         subjects affected / exposed
    18 / 183 (9.84%)
    21 / 183 (11.48%)
    4 / 106 (3.77%)
    1 / 87 (1.15%)
         occurrences all number
    20
    23
    4
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 183 (1.64%)
    21 / 183 (11.48%)
    3 / 106 (2.83%)
    1 / 87 (1.15%)
         occurrences all number
    7
    30
    2
    1
    Weight decreased
         subjects affected / exposed
    30 / 183 (16.39%)
    14 / 183 (7.65%)
    4 / 106 (3.77%)
    5 / 87 (5.75%)
         occurrences all number
    33
    17
    4
    7
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    7 / 183 (3.83%)
    10 / 183 (5.46%)
    1 / 106 (0.94%)
    6 / 87 (6.90%)
         occurrences all number
    7
    12
    3
    7
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    18 / 183 (9.84%)
    17 / 183 (9.29%)
    2 / 106 (1.89%)
    3 / 87 (3.45%)
         occurrences all number
    20
    20
    2
    3
    Dyspnoea
         subjects affected / exposed
    16 / 183 (8.74%)
    14 / 183 (7.65%)
    6 / 106 (5.66%)
    1 / 87 (1.15%)
         occurrences all number
    18
    16
    6
    1
    Epistaxis
         subjects affected / exposed
    12 / 183 (6.56%)
    17 / 183 (9.29%)
    6 / 106 (5.66%)
    4 / 87 (4.60%)
         occurrences all number
    14
    21
    9
    4
    Nervous system disorders
    Ageusia
         subjects affected / exposed
    6 / 183 (3.28%)
    16 / 183 (8.74%)
    3 / 106 (2.83%)
    2 / 87 (2.30%)
         occurrences all number
    6
    18
    3
    2
    Dizziness
         subjects affected / exposed
    8 / 183 (4.37%)
    18 / 183 (9.84%)
    4 / 106 (3.77%)
    2 / 87 (2.30%)
         occurrences all number
    9
    26
    4
    2
    Dysgeusia
         subjects affected / exposed
    9 / 183 (4.92%)
    28 / 183 (15.30%)
    4 / 106 (3.77%)
    1 / 87 (1.15%)
         occurrences all number
    10
    31
    5
    1
    Headache
         subjects affected / exposed
    22 / 183 (12.02%)
    29 / 183 (15.85%)
    10 / 106 (9.43%)
    2 / 87 (2.30%)
         occurrences all number
    23
    34
    11
    2
    Dysphonia
         subjects affected / exposed
    19 / 183 (10.38%)
    10 / 183 (5.46%)
    1 / 106 (0.94%)
    6 / 87 (6.90%)
         occurrences all number
    20
    12
    1
    6
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    7 / 183 (3.83%)
    12 / 183 (6.56%)
    7 / 106 (6.60%)
    0 / 87 (0.00%)
         occurrences all number
    8
    13
    8
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    9 / 183 (4.92%)
    21 / 183 (11.48%)
    3 / 106 (2.83%)
    7 / 87 (8.05%)
         occurrences all number
    10
    24
    3
    7
    Abdominal pain upper
         subjects affected / exposed
    12 / 183 (6.56%)
    19 / 183 (10.38%)
    4 / 106 (3.77%)
    2 / 87 (2.30%)
         occurrences all number
    13
    22
    4
    2
    Constipation
         subjects affected / exposed
    20 / 183 (10.93%)
    21 / 183 (11.48%)
    4 / 106 (3.77%)
    9 / 87 (10.34%)
         occurrences all number
    23
    22
    4
    10
    Diarrhoea
         subjects affected / exposed
    100 / 183 (54.64%)
    107 / 183 (58.47%)
    29 / 106 (27.36%)
    25 / 87 (28.74%)
         occurrences all number
    160
    158
    40
    35
    Dry mouth
         subjects affected / exposed
    11 / 183 (6.01%)
    6 / 183 (3.28%)
    2 / 106 (1.89%)
    8 / 87 (9.20%)
         occurrences all number
    12
    6
    2
    8
    Dyspepsia
         subjects affected / exposed
    8 / 183 (4.37%)
    10 / 183 (5.46%)
    2 / 106 (1.89%)
    1 / 87 (1.15%)
         occurrences all number
    10
    12
    2
    1
    Flatulence
         subjects affected / exposed
    6 / 183 (3.28%)
    11 / 183 (6.01%)
    1 / 106 (0.94%)
    2 / 87 (2.30%)
         occurrences all number
    6
    13
    1
    2
    Nausea
         subjects affected / exposed
    44 / 183 (24.04%)
    65 / 183 (35.52%)
    27 / 106 (25.47%)
    3 / 87 (3.45%)
         occurrences all number
    47
    87
    28
    3
    Stomatitis
         subjects affected / exposed
    32 / 183 (17.49%)
    19 / 183 (10.38%)
    2 / 106 (1.89%)
    6 / 87 (6.90%)
         occurrences all number
    35
    27
    2
    7
    Vomiting
         subjects affected / exposed
    25 / 183 (13.66%)
    33 / 183 (18.03%)
    15 / 106 (14.15%)
    6 / 87 (6.90%)
         occurrences all number
    30
    45
    15
    7
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    46 / 183 (25.14%)
    11 / 183 (6.01%)
    5 / 106 (4.72%)
    9 / 87 (10.34%)
         occurrences all number
    47
    13
    5
    10
    Dry skin
         subjects affected / exposed
    17 / 183 (9.29%)
    4 / 183 (2.19%)
    0 / 106 (0.00%)
    3 / 87 (3.45%)
         occurrences all number
    17
    4
    0
    3
    Erythema
         subjects affected / exposed
    25 / 183 (13.66%)
    5 / 183 (2.73%)
    2 / 106 (1.89%)
    7 / 87 (8.05%)
         occurrences all number
    28
    6
    2
    7
    Hair colour changes
         subjects affected / exposed
    0 / 183 (0.00%)
    26 / 183 (14.21%)
    1 / 106 (0.94%)
    0 / 87 (0.00%)
         occurrences all number
    0
    26
    1
    0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    61 / 183 (33.33%)
    30 / 183 (16.39%)
    4 / 106 (3.77%)
    20 / 87 (22.99%)
         occurrences all number
    89
    38
    7
    28
    Pruritus
         subjects affected / exposed
    30 / 183 (16.39%)
    9 / 183 (4.92%)
    0 / 106 (0.00%)
    11 / 87 (12.64%)
         occurrences all number
    39
    12
    0
    12
    Rash
         subjects affected / exposed
    29 / 183 (15.85%)
    14 / 183 (7.65%)
    6 / 106 (5.66%)
    17 / 87 (19.54%)
         occurrences all number
    32
    16
    6
    24
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    15 / 183 (8.20%)
    17 / 183 (9.29%)
    2 / 106 (1.89%)
    2 / 87 (2.30%)
         occurrences all number
    21
    22
    2
    3
    Back pain
         subjects affected / exposed
    20 / 183 (10.93%)
    14 / 183 (7.65%)
    5 / 106 (4.72%)
    4 / 87 (4.60%)
         occurrences all number
    21
    16
    5
    4
    Muscle spasms
         subjects affected / exposed
    9 / 183 (4.92%)
    12 / 183 (6.56%)
    1 / 106 (0.94%)
    3 / 87 (3.45%)
         occurrences all number
    11
    13
    1
    3
    Pain in extremity
         subjects affected / exposed
    18 / 183 (9.84%)
    13 / 183 (7.10%)
    3 / 106 (2.83%)
    3 / 87 (3.45%)
         occurrences all number
    23
    16
    3
    3
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    7 / 183 (3.83%)
    25 / 183 (13.66%)
    1 / 106 (0.94%)
    3 / 87 (3.45%)
         occurrences all number
    7
    26
    1
    3
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    36 / 183 (19.67%)
    44 / 183 (24.04%)
    7 / 106 (6.60%)
    6 / 87 (6.90%)
         occurrences all number
    41
    48
    8
    8
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    9 / 183 (4.92%)
    13 / 183 (7.10%)
    3 / 106 (2.83%)
    2 / 87 (2.30%)
         occurrences all number
    10
    19
    3
    2
    Urinary tract infection
         subjects affected / exposed
    14 / 183 (7.65%)
    9 / 183 (4.92%)
    6 / 106 (5.66%)
    2 / 87 (2.30%)
         occurrences all number
    15
    11
    6
    3

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Mar 2012
    Amendment I, Germany
    27 Jun 2012
    Amendment II, Germany [Austria N/A; The Netherlands N/A]
    14 Feb 2014
    Amendment III, Germany [Austria (07-Apr-2014); The Netherlands (24-Mar-2014)]
    25 Jul 2016
    Amendment IV, Germany [Austria (07-Jul-2016); The Netherlands (08-Jul-2016)]

    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

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/20100962
    http://www.ncbi.nlm.nih.gov/pubmed/19451442
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