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    Clinical Trial Results:
    Axitinib (AG-013736) As Second Line Therapy For Metastatic Renal Cell Cancer: Axis Trial

    Summary
    EudraCT number
    		 2008-001451-21
    Trial protocol
    		 SE   ES   AT   FR   GB   IE   DE   IT   PL   GR   SK  
    Global end of trial date
    25 Feb 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 Mar 2017
    First version publication date
    16 Mar 2017
    Other versions
    Summary report(s)
    		 A4061032 EU Posting

    Trial information

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    Trial identification
    Sponsor protocol code
    A4061032
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00678392
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pfizer, Inc.
    Sponsor organisation address
    235 E 42nd Street, New York, United States, NY 10017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 800-718-1021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 800-718-1021, ClinicalTrials.gov_Inquiries@pfizer.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
    09 Jun 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Feb 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Compare the progression-free survival (PFS) of subjects with mRCC receiving AG-013736 vs sorafenib following failure of one prior systemic first-line regimen containing one or more of the following: sunitinib, bevacizumab + IFN alpha, temsirolimus, or cytokine(s).
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Council for Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trials subjects were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Sep 2008
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 11
    Country: Number of subjects enrolled
    Austria: 6
    Country: Number of subjects enrolled
    Brazil: 17
    Country: Number of subjects enrolled
    Canada: 17
    Country: Number of subjects enrolled
    China: 26
    Country: Number of subjects enrolled
    France: 67
    Country: Number of subjects enrolled
    Germany: 22
    Country: Number of subjects enrolled
    Greece: 4
    Country: Number of subjects enrolled
    India: 23
    Country: Number of subjects enrolled
    Ireland: 2
    Country: Number of subjects enrolled
    Italy: 40
    Country: Number of subjects enrolled
    Japan: 54
    Country: Number of subjects enrolled
    Korea, Republic of: 25
    Country: Number of subjects enrolled
    Poland: 56
    Country: Number of subjects enrolled
    Russian Federation: 81
    Country: Number of subjects enrolled
    Singapore: 4
    Country: Number of subjects enrolled
    Slovakia: 7
    Country: Number of subjects enrolled
    Spain: 21
    Country: Number of subjects enrolled
    Sweden: 3
    Country: Number of subjects enrolled
    Taiwan: 20
    Country: Number of subjects enrolled
    United Kingdom: 48
    Country: Number of subjects enrolled
    United States: 169
    Worldwide total number of subjects
    723
    EEA total number of subjects
    276
    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)
    476
    From 65 to 84 years
    247
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 This study was conducted at multiple sites in United Kingdom. Study started on 03 September 2008 and completed on 25 February 2016.

    Period 1
    Period 1 title
    Over All (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Axitinib 5 mg
    Arm description
    		 Axitinib (AG-013736) 5 milligram (mg) tablet administered orally twice daily in cycles of 4 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Axitinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received Axitinib (AG-013736) 5 mg tablet orally twice daily in cycles of 4 weeks.

    Arm title
    		 Sorafenib 400 mg
    Arm description
    		 Sorafenib 400 mg tablet administered orally twice daily in cycles of 4 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Sorafenib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received Sorafenib 400 mg tablet orally twice daily in cycles of 4 weeks.

    Number of subjects in period 1
    		Axitinib 5 mg Sorafenib 400 mg
    Started
    361
    362
    Completed
    0
    0
    Not completed
    361
    362
         Consent withdrawn by subject
    4
    4
         Adverse Event
    -
    6
         Objective Progression or Relapse
    3
    8
         Death
    280
    269
         Sponsor Decision
    1
    2
         Randomized But Not Treated
    2
    7
         Unspecified
    56
    53
         Lost to follow-up
    15
    13

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Axitinib 5 mg
    Reporting group description
    		 Axitinib (AG-013736) 5 milligram (mg) tablet administered orally twice daily in cycles of 4 weeks.

    Reporting group title
    Sorafenib 400 mg
    Reporting group description
    		 Sorafenib 400 mg tablet administered orally twice daily in cycles of 4 weeks.

    Reporting group values
    		 Axitinib 5 mg Sorafenib 400 mg Total
    Number of subjects
    		 361 362 723
    Age Categorical
    Units: Subjects
        Adults (18-64 years)
    		 238 238 476
        From 65-84 years
    		 123 124 247
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 59.7 ( 10.5 ) 60 ( 10.1 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 96 104 200
        Male
    		 265 258 523

    End points

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    End points reporting groups
    Reporting group title
    Axitinib 5 mg
    Reporting group description
    		 Axitinib (AG-013736) 5 milligram (mg) tablet administered orally twice daily in cycles of 4 weeks.

    Reporting group title
    Sorafenib 400 mg
    Reporting group description
    		 Sorafenib 400 mg tablet administered orally twice daily in cycles of 4 weeks.

    Primary: Progression-Free Survival (PFS)

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    End point title
    		 Progression-Free Survival (PFS)
    End point description
    PFS was defined as the time in months from start of study treatment to the first documentation of objective tumor progression of disease (PD) or to death due to any cause, whichever occurs first. PD was assessed by response evaluation criteria in solid tumors (RECIST) version 1.0. PD = greater than or equal to (>=) 20 percent (%) increase in the sum of the longest dimensions (LD) of the target lesions taking as a reference the smallest sum of the LD recorded since the start of treatment or unequivocal progression in non-target lesions or the appearance of 1 or more new lesions. Occurrence of a pleural effusion or ascites was also considered PD if demonstrated by cytological investigation and it was not previously documented. New bone lesions not previously documented were considered PD if confirmed by computed tomography/magnetic resonance imaging or X-ray. Full analysis set (FAS).
    End point type
    Primary
    End point timeframe
    From initiation of treatment up to follow-up period (up to 3 years)
    End point values
    		 Axitinib 5 mg Sorafenib 400 mg
    Number of subjects analysed
    361
    362
    Units: Months
        median (confidence interval 95%)
    6.7 (6.3 to 8.6)
    4.7 (4.6 to 5.6)
    Statistical analysis title
    		 Axitinib vs Sorafenib
    Comparison groups
    Sorafenib 400 mg v Axitinib 5 mg
    Number of subjects included in analysis
    723
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [1]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.665
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.544
         upper limit
    		 0.812
    Notes
    [1] - P-value was obtained from 1-sided log rank test, stratified by eastern cooperative oncology group (ECOG) and prior treatment. One-sided log-rank test at 0.025 level of significance was used to compare PFS between the 2 treatment arms.

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    Overall survival was defined as the duration from start of study treatment to date of death due to any cause. OS was calculated as (months) = (date of death minus the date of first dose of study medication plus 1) divided by 30.4. For subjects who were alive, overall survival was censored on last date the subjects were known to be alive. FAS included all subjects who were randomized, with study drug assignment designated according to initial randomization, regardless of whether subjects received study drug or receive a different drug from that to which they were randomized.
    End point type
    Secondary
    End point timeframe
    From initiation of treatment up to follow-up period (up to 3 years)
    End point values
    		 Axitinib 5 mg Sorafenib 400 mg
    Number of subjects analysed
    361
    362
    Units: Months
        median (confidence interval 95%)
    20.1 (16.7 to 23.4)
    19.2 (17.5 to 22.3)
    Statistical analysis title
    		 Axitinib vs Sorafenib
    Comparison groups
    Axitinib 5 mg v Sorafenib 400 mg
    Number of subjects included in analysis
    723
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3744 [2]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.969
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 1.174
    Notes
    [2] - P-value was obtained from a 1-sided log-rank test of treatment stratified by ECOG performance status and prior treatment.

    Secondary: Objective Response Rate (ORR)

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    End point title
    		 Objective Response Rate (ORR)
    End point description
    ORR = percentage of subjects with confirmed complete response (CR) or confirmed partial response (PR) according to the RECIST version 1.0 recorded from first dose of study treatment until PD or death due to any cause. CR: disappearance of all target, non target lesions and no appearance of new lesions, documented on 2 occasions separated by at least 4 weeks. PR: at least 30 % decrease in sum of LD of target lesions taking as reference baseline sum of LD, without progression of non target lesions, no appearance of new lesions. PD: >=20% increase in sum of LD of the target lesions taking as a reference smallest sum of LD recorded since the start of treatment or unequivocal progression in non-target lesions or appearance of 1 or more new lesions. Occurrence of pleural effusion or ascites if demonstrated by cytological investigation, not previously documented. New bone lesions not previously documented if confirmed by computed tomography/magnetic resonance imaging or X-ray. FAS.
    End point type
    Secondary
    End point timeframe
    From initiation of treatment up to follow-up period (up to 3 years)
    End point values
    		 Axitinib 5 mg Sorafenib 400 mg
    Number of subjects analysed
    361
    362
    Units: Percentage of Subjects
        number (confidence interval 95%)
    19.4 (15.4 to 23.9)
    9.4 (6.6 to 12.9)
    Statistical analysis title
    		 Axitinib vs Sorafenib
    Comparison groups
    Axitinib 5 mg v Sorafenib 400 mg
    Number of subjects included in analysis
    723
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0001 [3]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    2.056
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.408
         upper limit
    		 3.003
    Notes
    [3] - P-value was obtained from a 1-sided Cochran-Mantel-Haenszel test of treatment stratified by ECOG performance status and prior treatment.

    Secondary: Duration of Response (DR)

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    End point title
    		 Duration of Response (DR)
    End point description
    DR: time from first documentation of objective tumor response (CR or PR), that was subsequently confirmed, to first documentation of PD or to death due to any cause, whichever occurred first as per RECIST version 1.0, a) CR: disappearance of all target, non target lesions and no appearance of new lesions, documented on 2 occasions separated by at least 4 weeks, b) PR: at least 30 % decrease in sum of LD of target lesions taking as reference baseline sum of LD, without progression of non target lesions, no appearance of new lesions, c) PD: >=20% increase in sum of LD of the target lesions taking as a reference smallest sum of LD recorded since the start of treatment or unequivocal progression in non-target lesions or appearance of 1 or more new lesions. Occurrence of pleural effusion or ascites if demonstrated by cytological investigation, not previously documented. New bone lesions not previously documented if confirmed by computed tomography/magnetic resonance imaging or X-ray. FAS.
    End point type
    Secondary
    End point timeframe
    From initiation of treatment up to follow-up period (up to 3 years)
    End point values
    		 Axitinib 5 mg Sorafenib 400 mg
    Number of subjects analysed
    361 [4]
    362
    Units: Months
        median (confidence interval 95%)
    11 (7.4 to 99999)
    10.6 (8.8 to 11.5)
    Notes
    [4] - 99999: upper limit of 95% confidence interval was not reached at time of data cut-off.
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    		 Percentage of Subjects With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
    End point description
    An AE was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. A treatment emergent AE was defined as an event that emerged during the treatment period that was absent before treatment, or worsened during the treatment period relative to the pretreatment state. AEs included both serious and nonserious AEs. Safety population included all subjects who received at least 1 dose of study medication with treatment assignments designated according to actual study treatment received.
    End point type
    Secondary
    End point timeframe
    From initiation of treatment up to follow-up period (up to 3 years)
    End point values
    		 Axitinib 5 mg Sorafenib 400 mg
    Number of subjects analysed
    359
    355
    Units: Percentage of Subjects
    number (not applicable)
        AEs
    96.1
    98
        SAEs
    40.7
    35.8
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Adverse Events (AEs) by Severity

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    End point title
    		 Percentage of Subjects With Adverse Events (AEs) by Severity
    End point description
    An AE was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. Severity of the AEs was graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Grade 1= mild; Grade 2= moderate; Grade 3= severe; Grade 4= life-threatening or disabling; Grade 5= death related to AE. Safety population included all subjects who received at least 1 dose of study medication with treatment assignments designated according to actual study treatment received.
    End point type
    Secondary
    End point timeframe
    From initiation of treatment up to follow-up period (up to 3 years)
    End point values
    		 Axitinib 5 mg Sorafenib 400 mg
    Number of subjects analysed
    359
    355
    Units: Percentage of Subjects
    number (not applicable)
        Grade 1
    3.9
    3.1
        Grade 2
    20.1
    21.7
        Grade 3
    47.6
    52.4
        Grade 4
    10.6
    11.5
        Grade 5
    13.9
    9.3
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Treatment-Related Adverse Events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    		 Percentage of Subjects With Treatment-Related Adverse Events (AEs) and Serious Adverse Events (SAEs)
    End point description
    An AE was any untoward medical occurrence attributed to study drug in a subject who received study drug. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. AEs included both serious and non serious AEs. Safety population included all subjects who received at least 1 dose of study medication with treatment assignments designated according to actual study treatment received.
    End point type
    Secondary
    End point timeframe
    From initiation of treatment up to follow-up period (up to 3 years)
    End point values
    		 Axitinib 5 mg Sorafenib 400 mg
    Number of subjects analysed
    359
    355
    Units: Percentage of Subjects
    number (not applicable)
        AEs
    92.2
    95.2
        SAEs
    15.3
    13.8
    No statistical analyses for this end point

    Secondary: Number of Subjects With Clinically Significant Laboratory Abnormalities: Hematology

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    End point title
    		 Number of Subjects With Clinically Significant Laboratory Abnormalities: Hematology
    End point description
    Hematology laboratory test included hemoglobin, platelet count, white blood cells count, neutrophils and Lymphocytes. Abnormalities were assessed by CTCAE Grade Version 2 for severity: Grade 1= mild; Grade 2= moderate; Grade 3= severe and Grade 4= life-threatening or disabling. Safety population included all subjects who received at least 1 dose of study medication with treatment assignments designated according to actual study treatment received. Here, "n" signifies number of subjects available for specified categories for each arm respectively.
    End point type
    Secondary
    End point timeframe
    From initiation of treatment up to follow-up period (up to 3 years)
    End point values
    		 Axitinib 5 mg Sorafenib 400 mg
    Number of subjects analysed
    359
    355
    Units: Subjects
    number (not applicable)
        Hemoglobin: Grade 1 (n =320, 316)
    93
    112
        Hemoglobin: Grade 2 (n =320, 316)
    19
    41
        Hemoglobin: Grade 3 (n =320, 316)
    1
    11
        Hemoglobin: Grade 4 (n =320, 316)
    0
    1
        Lymphocytes: Grade 1 (n =317, 309)
    7
    7
        Lymphocytes: Grade 2 (n =317, 309)
    89
    93
        Lymphocytes: Grade 3 (n =317, 309)
    10
    11
        Lymphocytes: Grade 4 (n =317, 309)
    0
    0
        Neutrophils: Grade 1 (n =316, 308)
    13
    20
        Neutrophils: Grade 2 (n =316, 308)
    4
    4
        Neutrophils: Grade 3 (n =316, 308)
    2
    2
        Neutrophils: Grade 4 (n =316, 308)
    0
    0
        Platelets: Grade 1 (n =312, 310)
    47
    41
        Platelets: Grade 2 (n =312, 310)
    0
    3
        Platelets: Grade 3 (n =312, 310)
    1
    0
        Platelets: Grade 4 (n =312, 310)
    0
    0
        White blood cells: Grade 1 (n =320, 315)
    32
    36
        White blood cells: Grade 2 (n =320, 315)
    4
    12
        White blood cells: Grade 3 (n =320, 315)
    0
    1
        White blood cells: Grade 4 (n =320, 315)
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Clinically Significant Laboratory Abnormalities: Biochemistry

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    End point title
    		 Number of Subjects With Clinically Significant Laboratory Abnormalities: Biochemistry
    End point description
    Biochemistry laboratory test included parameters: alanine aminotransferase, alkaline phosphatase, amylase, aspartate aminotransferase, bicarbonate, bilirubin, creatinine, hypercalcemia, hyperglycemia, hyperkalemia, hypernatremia, hypoalbuminemia, hypocalcemia, hypoglycemia, hypokalemia, hyponatremia, hypophosphatemia and lipase. Abnormalities were assessed by CTCAE Grade Version 2 for severity: Grade 1= mild; Grade 2= moderate; Grade 3= severe and Grade 4= life-threatening or disabling. Safety population included all subjects who received at least 1 dose of study medication with treatment assignments designated according to actual study treatment received. Here, "n" signifies number of subjects available for specified categories for each arm respectively.
    End point type
    Secondary
    End point timeframe
    From initiation of treatment up to follow-up period (up to 3 years)
    End point values
    		 Axitinib 5 mg Sorafenib 400 mg
    Number of subjects analysed
    359
    355
    Units: Subjects
    number (not applicable)
        Alanine aminotransferase: Grade 1 (n =331, 313)
    65
    57
        Alanine aminotransferase: Grade 2 (n =331, 313)
    8
    6
        Alanine aminotransferase: Grade 3 (n =331, 313)
    1
    2
        Alanine aminotransferase: Grade 4 (n =331, 313)
    0
    3
        Alkaline phosphatase: Grade 1 (n =336, 319)
    88
    92
        Alkaline phosphatase: Grade 2 (n =336, 319)
    8
    15
        Alkaline phosphatase: Grade 3 (n =336, 319)
    4
    3
        Alkaline phosphatase: Grade 4 (n =336, 319)
    0
    0
        Amylase: Grade 1 (n =338, 319)
    64
    76
        Amylase: Grade 2 (n =338, 319)
    12
    21
        Amylase: Grade 3 (n =338, 319)
    7
    6
        Amylase: Grade 4 (n =338, 319)
    0
    1
        Aspartate aminotransferase: Grade 1 (n =331, 311)
    59
    67
        Aspartate aminotransferase: Grade 2 (n =331, 311)
    5
    7
        Aspartate aminotransferase: Grade 3 (n =331, 311)
    1
    4
        Aspartate aminotransferase: Grade 4 (n =331, 311)
    0
    0
        Bicarbonate: Grade 1 (n =314, 291)
    127
    115
        Bicarbonate: Grade 2 (n =314, 291)
    11
    10
        Bicarbonate: Grade 3 (n =314, 291)
    0
    0
        Bicarbonate: Grade 4 (n =314, 291)
    1
    0
        Bilirubin: Grade 1 (n =336, 318)
    16
    12
        Bilirubin: Grade 2 (n =336, 318)
    8
    2
        Bilirubin: Grade 3 (n =336, 318)
    1
    1
        Bilirubin: Grade 4 (n =336, 318)
    0
    0
        Creatinine: Grade 1 (n =336, 318)
    155
    121
        Creatinine: Grade 2 (n =336, 318)
    30
    9
        Creatinine: Grade 3 (n =336, 318)
    0
    1
        Creatinine: Grade 4 (n =336, 318)
    0
    0
        Hypercalcemia: Grade 1 (n =336, 319)
    92
    22
        Hypercalcemia: Grade 2 (n =336, 319)
    8
    1
        Hypercalcemia: Grade 3 (n =336, 319)
    1
    0
        Hypercalcemia: Grade 4 (n =336, 319)
    0
    0
        Hyperglycemia: Grade 1 (n =336, 319)
    41
    28
        Hyperglycemia: Grade 2 (n =336, 319)
    45
    37
        Hyperglycemia: Grade 3 (n =336, 319)
    7
    7
        Hyperglycemia: Grade 4 (n =336, 319)
    0
    0
        Hyperkalemia: Grade 1 (n =333, 314)
    0
    0
        Hyperkalemia: Grade 2 (n =333, 314)
    42
    22
        Hyperkalemia: Grade 3 (n =333, 314)
    9
    8
        Hyperkalemia: Grade 4 (n =333, 314)
    0
    0
        Hypernatremia: Grade 1 (n =338, 319)
    34
    23
        Hypernatremia: Grade 2 (n =338, 319)
    19
    14
        Hypernatremia: Grade 3 (n =338, 319)
    3
    1
        Hypernatremia: Grade 4 (n =338, 319)
    0
    2
        Hypoalbuminemia: Grade 1 (n =337, 319)
    37
    25
        Hypoalbuminemia: Grade 2 (n =337, 319)
    11
    31
        Hypoalbuminemia: Grade 3 (n =337, 319)
    1
    2
        Hypoalbuminemia: Grade 4 (n =337, 319)
    0
    0
        Hypocalcemia: Grade 1 (n =336, 319)
    25
    67
        Hypocalcemia: Grade 2 (n =336, 319)
    4
    18
        Hypocalcemia: Grade 3 (n =336, 319)
    2
    2
        Hypocalcemia: Grade 4 (n =336, 319)
    1
    2
        Hypoglycemia: Grade 1 (n =336, 319)
    23
    9
        Hypoglycemia: Grade 2 (n =336, 319)
    12
    16
        Hypoglycemia: Grade 3 (n =336, 319)
    1
    1
        Hypoglycemia: Grade 4 (n =336, 319)
    0
    0
        Hypokalemia: Grade 1 (n =333, 314)
    22
    21
        Hypokalemia: Grade 2 (n =333, 314)
    0
    0
        Hypokalemia: Grade 3 (n =333, 314)
    0
    5
        Hypokalemia: Grade 4 (n =333, 314)
    0
    0
        Hyponatremia: Grade 1 (n =338, 319)
    33
    27
        Hyponatremia: Grade 2 (n =338, 319)
    0
    0
        Hyponatremia: Grade 3 (n =338, 319)
    11
    6
        Hyponatremia: Grade 4 (n =338, 319)
    1
    1
        Hypophosphatemia: Grade 1 (n =336, 318)
    4
    8
        Hypophosphatemia: Grade 2 (n =336, 318)
    33
    99
        Hypophosphatemia: Grade 3 (n =336, 318)
    6
    51
        Hypophosphatemia: Grade 4 (n =336, 318)
    0
    0
        Lipase: Grade 1 (n =338, 319)
    53
    76
        Lipase: Grade 2 (n =338, 319)
    22
    25
        Lipase: Grade 3 (n =338, 319)
    14
    40
        Lipase: Grade 4 (n =338, 319)
    2
    7
    No statistical analyses for this end point

    Secondary: Number of Subjects With Clinically Significant Laboratory Abnormalities: Urinalysis

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    End point title
    		 Number of Subjects With Clinically Significant Laboratory Abnormalities: Urinalysis
    End point description
    Urinalysis included urine blood/ hemoglobin, glucose and protein. Abnormalities were assessed by CTCAE Grade Version 2 for severity: Grade 1= mild; Grade 2= moderate; Grade 3= severe and Grade 4= life-threatening or disabling. Safety population included all subjects who received at least 1 dose of study medication with treatment assignments designated according to actual study treatment received. Here, "n" signifies number of subjects available for specified categories for each arm respectively.
    End point type
    Secondary
    End point timeframe
    From initiation of treatment up to follow-up period (up to 3 years)
    End point values
    		 Axitinib 5 mg Sorafenib 400 mg
    Number of subjects analysed
    359
    355
    Units: Subjects
    number (not applicable)
        Urine blood/ hemoglobin: Grade 1 (n =304, 272)
    45
    35
        Urine blood/ hemoglobin: Grade 2 (n =304, 272)
    1
    0
        Urine blood/ hemoglobin: Grade 3 (n =304, 272)
    0
    0
        Urine blood/ hemoglobin: Grade 4 (n =304, 272)
    0
    0
        Urine glucose: Grade 1 (n =322, 286)
    12
    13
        Urine glucose: Grade 2 (n =322, 286)
    0
    3
        Urine glucose: Grade 3 (n =322, 286)
    0
    0
        Urine glucose: Grade 4 (n =322, 286)
    1
    1
        Urine protein: Grade 1 (n =326, 289)
    105
    91
        Urine protein: Grade 2 (n =326, 289)
    31
    27
        Urine protein: Grade 3 (n =326, 289)
    27
    21
        Urine protein: Grade 4 (n =326, 289)
    9
    7
    No statistical analyses for this end point

    Secondary: Functional Assessment of Cancer Therapy Kidney Symptom Index-15 (FKSI-15) Score

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    End point title
    		 Functional Assessment of Cancer Therapy Kidney Symptom Index-15 (FKSI-15) Score
    End point description
    FKSI was used to assess quality of life (QoL) for those diagnosed with renal cell cancer and consisted of 15 items (lack of energy, side effects, pain, losing weight, bone pain, fatigue, enjoying life, short of breath, worsened condition, appetite, coughing, bothered by fevers, ability to work, hematuria and sleep). Each of the 15 items was answered on a 5-point Likert-type scale ranging from 0 to 4 (0= not at all, 1= a little bit, 2= somewhat, 3= quite a bit, 4= very much). Total FKSI score = sum of the 15 item scores; total range: 0 - 60; 0 (no symptoms) to 60 (very much); higher scores indicate greater presence of symptoms. FAS. Here, "n" signifies those subjects who were evaluable for the specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline (Predose on Cycle 1 Day 1) , Day 1 of each cycle until Cycle 21, End of treatment (Day 670) and Follow-up visit (Day 698)
    End point values
    		 Axitinib 5 mg Sorafenib 400 mg
    Number of subjects analysed
    361
    362
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Baseline (n =346, 342)
    43.199 ( 8.416 )
    43.339 ( 8.162 )
        Cycle 2/Day1 (n =319, 296)
    42.351 ( 8.305 )
    41.688 ( 7.696 )
        Cycle 3/Day1 (n =279, 246)
    42.59 ( 7.729 )
    42.424 ( 7.888 )
        Cycle 4/Day1 (n =257, 221)
    42.791 ( 8.18 )
    43.424 ( 7.345 )
        Cycle 5/Day1 (n =238, 203)
    42.968 ( 8.152 )
    42.907 ( 7.255 )
        Cycle 6/Day1 (n =213, 179)
    42.949 ( 7.842 )
    43.057 ( 7.724 )
        Cycle 7/Day1 (n =206, 158)
    42.747 ( 7.621 )
    43.578 ( 7.621 )
        Cycle 8/Day1 (n =177, 136)
    43.58 ( 7.578 )
    44.074 ( 7.757 )
        Cycle 9/Day1 (n =163, 118)
    43.191 ( 8.3 )
    44.518 ( 6.511 )
        Cycle 10/Day1 (n =146, 96)
    43.312 ( 8.564 )
    44.771 ( 7.155 )
        Cycle 11/Day1 (n =122, 85)
    44.119 ( 8.306 )
    44.438 ( 7.388 )
        Cycle 12/Day1 (n =110, 70)
    44.517 ( 8.212 )
    44.357 ( 7.247 )
        Cycle 13/Day1 (n =92, 58)
    44.492 ( 7.972 )
    45.261 ( 7.84 )
        Cycle 14/Day1 (n =81, 54)
    44.485 ( 8.204 )
    44.898 ( 7.495 )
        Cycle 15/Day1 (n =61, 38)
    45.291 ( 7.095 )
    45.053 ( 6.682 )
        Cycle 16/Day1 (n =52, 34)
    45.217 ( 7.656 )
    44.445 ( 7.16 )
        Cycle 17/Day1 (n =47, 28)
    45.242 ( 7.344 )
    44.438 ( 7.683 )
        Cycle 18/Day1 (n =36, 22)
    44.861 ( 7.769 )
    44.182 ( 7.228 )
        Cycle 19/Day1 (n =29, 14)
    45.379 ( 6.662 )
    45.026 ( 7.705 )
        Cycle 20/Day1 (n =20, 12)
    47.05 ( 5.375 )
    44.78 ( 6.689 )
        Cycle 21/Day1 (n =15, 7)
    45.85 ( 5.209 )
    44.494 ( 6.153 )
        End of treatment (n=163, 191)
    38.328 ( 9.472 )
    38.457 ( 8.787 )
        Follow up (n =80, 110)
    41.919 ( 8.318 )
    40.028 ( 9.048 )
    No statistical analyses for this end point

    Secondary: Functional Assessment of Cancer Therapy Kidney Symptom Index-Disease Related Symptoms (FKSI-DRS) Score

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    End point title
    		 Functional Assessment of Cancer Therapy Kidney Symptom Index-Disease Related Symptoms (FKSI-DRS) Score
    End point description
    FKSI-DRS was used to assess quality of life for those diagnosed with renal cell cancer and consisted of 9 items (lack of energy, pain, losing weight, bone pain, fatigue, short of breath, coughing, bothered by fevers, and hematuria). Each of the 9 items was answered on a 5-point Likert-type scale ranging from 0 to 4 (0= not at all, 1= a little bit, 2= somewhat, 3= quite a bit, 4= very much). Total FKSI-DRS score = sum of the 9 item scores; total range: 0 - 36; 0 (no symptoms) to 36 (very much); higher scores indicate greater presence of symptoms. FAS. Here, "n" signifies those subjects who were evaluable for the specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline (Predose on Cycle 1 Day 1) , Day 1 of each cycle until Cycle 21, End of treatment (Day 670) and Follow-up visit (Day 698)
    End point values
    		 Axitinib 5 mg Sorafenib 400 mg
    Number of subjects analysed
    361
    362
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Baseline (n =346, 341)
    28.874 ( 5.187 )
    28.975 ( 5.193 )
        Cycle 2/Day1 (n =319, 295)
    28.211 ( 4.92 )
    28.399 ( 5.064 )
        Cycle 3/Day1 (n =279, 244)
    28.64 ( 4.837 )
    28.64 ( 4.868 )
        Cycle 4/Day1 (n =257, 220)
    28.822 ( 4.952 )
    29.13 ( 4.322 )
        Cycle 5/Day1 (n =238, 202)
    28.869 ( 4.88 )
    29.007 ( 4.379 )
        Cycle 6/Day1 (n =213, 178)
    29.159 ( 4.462 )
    29.098 ( 4.697 )
        Cycle 7/Day1 (n =206, 157)
    29.042 ( 4.581 )
    29.361 ( 4.558 )
        Cycle 8/Day1 (n =177, 135)
    29.52 ( 4.346 )
    29.619 ( 4.386 )
        Cycle 9/Day1 (n =163, 117)
    29.194 ( 4.937 )
    29.884 ( 3.838 )
        Cycle 10/Day1 (n =146, 96)
    29.343 ( 4.907 )
    29.604 ( 3.959 )
        Cycle 11/Day1 (n =122, 85)
    29.762 ( 4.943 )
    29.366 ( 4.404 )
        Cycle 12/Day1 (n =110, 70)
    29.764 ( 4.507 )
    29.257 ( 4.299 )
        Cycle 13/Day1 (n =92, 58)
    29.594 ( 4.205 )
    29.666 ( 4.71 )
        Cycle 14/Day1 (n =81, 54)
    29.711 ( 4.313 )
    29.82 ( 4.333 )
        Cycle 15/Day1 (n =61, 38)
    30.324 ( 3.582 )
    29.5 ( 3.454 )
        Cycle 16/Day1 (n =52, 34)
    30.43 ( 3.443 )
    29.474 ( 4.146 )
        Cycle 17/Day1 (n =47, 28)
    30.551 ( 3.331 )
    28.737 ( 4.93 )
        Cycle 18/Day1 (n =36, 22)
    30.194 ( 3.992 )
    29.045 ( 4.52 )
        Cycle 19/Day1 (n =29, 14)
    30.13 ( 3.636 )
    29.286 ( 4.795 )
        Cycle 20/Day1 (n =20, 12)
    31.3 ( 2.736 )
    29.25 ( 4.025 )
        Cycle 21/Day1 (n =15, 7)
    31.067 ( 3.173 )
    30.143 ( 4.1 )
        End of Treatment (n =163, 191)
    26.288 ( 5.806 )
    26.517 ( 5.614 )
        Follow up (n =80, 110)
    28.263 ( 4.802 )
    27.516 ( 5.577 )
    No statistical analyses for this end point

    Secondary: Euro Quality of Life Questionnaire-5 Dimension (EQ-5D): Health State Profile Utility Score

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    End point title
    		 Euro Quality of Life Questionnaire-5 Dimension (EQ-5D): Health State Profile Utility Score
    End point description
    EQ-5D: subject rated questionnaire to assess health-related quality of life in terms of a single utility or index score. Health state profile component assesses level of health for 5 domains: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each domain was rated on a 3-point response scale (1= no problems, 2= some/moderate problems and 3= extreme problems). Scoring formula developed by EuroQol Group assigned a utility value for each domain in the profile. Score were transformed and resulted in a total score range of 0 to 1, with higher scores indicating better health. FAS. Here, "n" signifies those subjects who were evaluable for the specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline (Predose on Cycle 1 Day 1) , Day 1 of each cycle until Cycle 21, End of treatment (Day 670) and Follow-up visit (Day 698)
    End point values
    		 Axitinib 5 mg Sorafenib 400 mg
    Number of subjects analysed
    361
    362
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Baseline (n =347, 341)
    0.732 ( 0.275 )
    0.731 ( 0.257 )
        Cycle 2/Day1 (n =326, 307)
    0.716 ( 0.267 )
    0.696 ( 0.237 )
        Cycle 3/Day1 (n =287, 248)
    0.722 ( 0.243 )
    0.709 ( 0.239 )
        Cycle 4/Day1 (n =262, 226)
    0.73 ( 0.236 )
    0.716 ( 0.248 )
        Cycle 5/Day1 (n =244, 207)
    0.73 ( 0.237 )
    0.711 ( 0.243 )
        Cycle 6/Day1 (n =221, 178)
    0.734 ( 0.23 )
    0.704 ( 0.246 )
        Cycle 7/Day1 (n =213, 163)
    0.718 ( 0.267 )
    0.728 ( 0.228 )
        Cycle 8/Day1 (n =181, 136)
    0.756 ( 0.236 )
    0.702 ( 0.259 )
        Cycle 9/Day1 (n =169, 120)
    0.76 ( 0.227 )
    0.73 ( 0.229 )
        Cycle 10/Day1 (n =151, 98)
    0.734 ( 0.243 )
    0.73 ( 0.233 )
        Cycle 11/Day1 (n =126, 87)
    0.764 ( 0.235 )
    0.724 ( 0.25 )
        Cycle 12/Day1 (n =110, 73)
    0.744 ( 0.244 )
    0.734 ( 0.232 )
        Cycle 13/Day1 (n =96, 61)
    0.76 ( 0.211 )
    0.753 ( 0.232 )
        Cycle 14/Day1 (n =80, 57)
    0.723 ( 0.239 )
    0.752 ( 0.211 )
        Cycle 15/Day1 (n =63, 41)
    0.73 ( 0.255 )
    0.758 ( 0.191 )
        Cycle 16/Day1 (n =54, 37)
    0.749 ( 0.22 )
    0.785 ( 0.158 )
        Cycle 17/Day1 (n =48, 29)
    0.779 ( 0.186 )
    0.764 ( 0.193 )
        Cycle 18/Day1 (n =37, 20)
    0.755 ( 0.204 )
    0.755 ( 0.208 )
        Cycle 19/Day1 (n =29, 14)
    0.734 ( 0.253 )
    0.804 ( 0.184 )
        Cycle 20/Day1 (n =21, 12)
    0.794 ( 0.22 )
    0.771 ( 0.182 )
        Cycle 21/Day1 (n =16, 7)
    0.7 ( 0.273 )
    0.771 ( 0.186 )
        End of Treatment (n =169, 196)
    0.608 ( 0.316 )
    0.612 ( 0.31 )
        Follow up (n =76, 106)
    0.682 ( 0.294 )
    0.666 ( 0.295 )
    No statistical analyses for this end point

    Secondary: Euro Quality of Life Questionnaire-5 Dimension (EQ-5D): Visual Analog Scale (VAS)

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    End point title
    		 Euro Quality of Life Questionnaire-5 Dimension (EQ-5D): Visual Analog Scale (VAS)
    End point description
    EQ-5D: subject rated questionnaire to assess health-related quality of life in terms of a single index value. VAS component: subjects rated their current health state on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state); higher scores indicate a better health. FAS. Here, "n" signifies those subjects who were evaluable for the specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline (Predose on Cycle 1 Day 1) , Day 1 of each cycle until Cycle 21, End of treatment (Day 670) and Follow-up visit (Day 698)
    End point values
    		 Axitinib 5 mg Sorafenib 400 mg
    Number of subjects analysed
    361
    362
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Baseline (n =341, 339)
    70.56 ( 19.187 )
    70.351 ( 17.403 )
        Cycle 2/Day1 (n =317, 302)
    69.003 ( 20.195 )
    67.606 ( 18.265 )
        Cycle 3/Day1 (n =280, 250)
    69.843 ( 17.927 )
    69.712 ( 18.429 )
        Cycle 4/Day1 (n =261, 224)
    69.18 ( 18.636 )
    70.759 ( 17.189 )
        Cycle 5/Day1 (n =244, 205)
    69.705 ( 18.33 )
    71.888 ( 16.999 )
        Cycle 6/Day1 (n =220, 178)
    69.9 ( 18.168 )
    71.365 ( 17.019 )
        Cycle 7/Day1 (n =209, 163)
    69.919 ( 18.063 )
    72.282 ( 17.521 )
        Cycle 8/Day1 (n =180, 139)
    70.756 ( 19.183 )
    71.475 ( 18.523 )
        Cycle 9/Day1 (n =168, 121)
    70.667 ( 18.556 )
    73.38 ( 17.473 )
        Cycle 10/Day1 (n =151, 98)
    70.629 ( 18.68 )
    75.102 ( 14.854 )
        Cycle 11/Day1 (n =126, 87)
    72.103 ( 18.064 )
    74.586 ( 15.161 )
        Cycle 12/Day1 (n =111, 73)
    71.73 ( 17.276 )
    73.959 ( 15.852 )
        Cycle 13/Day1 (n =94, 61)
    70.723 ( 19.147 )
    75.693 ( 14.571 )
        Cycle 14/Day1 (n =81, 58)
    69.42 ( 20.286 )
    75.362 ( 15.875 )
        Cycle 15/Day1 (n =62, 42)
    73.016 ( 15.325 )
    75.357 ( 15.368 )
        Cycle 16/Day1 (n =52, 37)
    70.629 ( 19.272 )
    73.676 ( 15.699 )
        Cycle 17/Day1 (n =48, 30)
    71.357 ( 17.84 )
    73.676 ( 16.298 )
        Cycle 18/Day1 (n =37, 23)
    70.459 ( 18.853 )
    73.87 ( 16.904 )
        Cycle 19/Day1 (n =29, 14)
    71.034 ( 16.963 )
    70.571 ( 17.956 )
        Cycle 20/Day1 (n =21, 12)
    73.143 ( 15.347 )
    66.917 ( 17.758 )
        Cycle 21/Day1 (n =16, 7)
    74.563 ( 16.054 )
    64.714 ( 16.183 )
        End of Treatment (n =166, 197)
    61.759 ( 21.668 )
    61.69 ( 20.973 )
        Follow up (n =76, 109)
    64.382 ( 21.392 )
    66.037 ( 19.754 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From initiation of treatment up to follow-up period (up to 3 years)
    Adverse event reporting additional description
    Same event may appear as both AE and SAE, what is presented are distinct event. Event may be classified as serious in 1 subject, nonserious in other, or 1 subject may have experienced both serious, nonserious event during study.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Axitinib 5 mg
    Reporting group description
    		 Axitinib (AG-013736) 5 mg tablet administered orally twice daily in cycles of 4 weeks.

    Reporting group title
    Sorafenib 400 mg
    Reporting group description
    		 Sorafenib 400 mg tablet administered orally twice daily in cycles of 4 weeks.

    Serious adverse events
    		 Axitinib 5 mg Sorafenib 400 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    146 / 359 (40.67%)
    127 / 355 (35.77%)
         number of deaths (all causes)
    55
    42
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Metastasis
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastatic pain
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasm progression
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cell carcinoma
         subjects affected / exposed
    1 / 359 (0.28%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour associated fever
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Accelerated hypertension
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 359 (0.28%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 359 (0.28%)
    2 / 355 (0.56%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 359 (0.28%)
    4 / 355 (1.13%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infarction
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jugular vein thrombosis
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subclavian vein thrombosis
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Pain management
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertebroplasty
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 359 (0.56%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Chest pain
         subjects affected / exposed
    2 / 359 (0.56%)
    2 / 355 (0.56%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    3 / 359 (0.84%)
    6 / 355 (1.69%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    3 / 3
    4 / 6
    Device dislocation
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    32 / 359 (8.91%)
    18 / 355 (5.07%)
         occurrences causally related to treatment / all
    0 / 33
    0 / 19
         deaths causally related to treatment / all
    0 / 29
    0 / 18
    Fatigue
         subjects affected / exposed
    4 / 359 (1.11%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    3 / 359 (0.84%)
    5 / 355 (1.41%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Hernia
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Impaired healing
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inflammation
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    2 / 359 (0.56%)
    3 / 355 (0.85%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    7 / 359 (1.95%)
    5 / 355 (1.41%)
         occurrences causally related to treatment / all
    3 / 8
    6 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
    Additional description: This event was gender specific.
         subjects affected / exposed [1]
    1 / 265 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Menometrorrhagia
    Additional description: This event was gender specific.
         subjects affected / exposed [2]
    0 / 96 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vaginal polyp
    Additional description: This event was gender specific.
         subjects affected / exposed [3]
    1 / 96 (1.04%)
    0 / 104 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    7 / 359 (1.95%)
    3 / 355 (0.85%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Dyspnoea exertional
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 359 (0.28%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 359 (0.28%)
    2 / 355 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemothorax
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    3 / 359 (0.84%)
    5 / 355 (1.41%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    4 / 359 (1.11%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    1 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax spontaneous
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    7 / 359 (1.95%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    2 / 7
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    0 / 359 (0.00%)
    2 / 355 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disorientation
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    1 / 359 (0.28%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    2 / 359 (0.56%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil count abnormal
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 359 (0.28%)
    2 / 355 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal anastomotic leak
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laceration
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    2 / 359 (0.56%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiation pneumonitis
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue injury
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 359 (0.00%)
    2 / 355 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    2 / 359 (0.56%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 359 (0.00%)
    2 / 355 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia supraventricular
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriosclerosis coronary artery
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 359 (0.56%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure
         subjects affected / exposed
    2 / 359 (0.56%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    2 / 359 (0.56%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Congestive cardiomyopathy
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery insufficiency
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Haemorrhage coronary artery
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    6 / 359 (1.67%)
    4 / 355 (1.13%)
         occurrences causally related to treatment / all
    4 / 7
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prinzmetal angina
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Balance disorder
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Central nervous system haemorrhage
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    2 / 359 (0.56%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Dizziness
         subjects affected / exposed
    3 / 359 (0.84%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukoencephalopathy
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    2 / 359 (0.56%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningeal disorder
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Monoplegia
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    2 / 359 (0.56%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 359 (0.56%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    3 / 359 (0.84%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 359 (0.00%)
    8 / 355 (2.25%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Splenic infarction
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Diplopia
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal artery embolism
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal artery occlusion
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal vein occlusion
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal vein thrombosis
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 359 (0.28%)
    2 / 355 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal fistula
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    2 / 359 (0.56%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    8 / 359 (2.23%)
    5 / 355 (1.41%)
         occurrences causally related to treatment / all
    6 / 8
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Enterocolitis
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    2 / 359 (0.56%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 359 (0.00%)
    5 / 355 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Gastrointestinal perforation
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    3 / 359 (0.84%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    4 / 359 (1.11%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 359 (0.28%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 359 (0.28%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retroperitoneal haemorrhage
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Small intestinal obstruction
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    5 / 359 (1.39%)
    2 / 355 (0.56%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Biliary dilatation
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Budd-Chiari syndrome
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    1 / 359 (0.28%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 359 (0.28%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Erythema multiforme
         subjects affected / exposed
    0 / 359 (0.00%)
    3 / 355 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperhidrosis
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pustular psoriasis
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    0 / 359 (0.00%)
    2 / 355 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    4 / 359 (1.11%)
    2 / 355 (0.56%)
         occurrences causally related to treatment / all
    2 / 4
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute prerenal failure
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephropathy
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Oliguria
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypothyroidism
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Secondary hypothyroidism
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thyroiditis
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 359 (0.28%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    3 / 359 (0.84%)
    2 / 355 (0.56%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    2 / 359 (0.56%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polyarthritis
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal column stenosis
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spondylolisthesis
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal abscess
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 359 (0.28%)
    2 / 355 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspergillus infection
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial diarrhoea
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    3 / 359 (0.84%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral discitis
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 359 (0.00%)
    4 / 355 (1.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection bacterial
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle abscess
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    5 / 359 (1.39%)
    4 / 355 (1.13%)
         occurrences causally related to treatment / all
    2 / 6
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia streptococcal
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 359 (0.28%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 359 (0.28%)
    2 / 355 (0.56%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Septic shock
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 359 (0.56%)
    2 / 355 (0.56%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    3 / 359 (0.84%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    10 / 359 (2.79%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    8 / 10
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 359 (0.28%)
    2 / 355 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    2 / 359 (0.56%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    2 / 359 (0.56%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 359 (0.28%)
    3 / 355 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypovolaemia
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 355 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: This event was gender specific.
    [2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: This event was gender specific.
    [3] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: This event was gender specific.
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Axitinib 5 mg Sorafenib 400 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    336 / 359 (93.59%)
    334 / 355 (94.08%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    156 / 359 (43.45%)
    107 / 355 (30.14%)
         occurrences all number
    318
    174
    Hypotension
         subjects affected / exposed
    19 / 359 (5.29%)
    6 / 355 (1.69%)
         occurrences all number
    20
    7
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    78 / 359 (21.73%)
    57 / 355 (16.06%)
         occurrences all number
    203
    120
    Chest pain
         subjects affected / exposed
    23 / 359 (6.41%)
    20 / 355 (5.63%)
         occurrences all number
    34
    24
    Fatigue
         subjects affected / exposed
    151 / 359 (42.06%)
    122 / 355 (34.37%)
         occurrences all number
    366
    210
    Mucosal inflammation
         subjects affected / exposed
    61 / 359 (16.99%)
    45 / 355 (12.68%)
         occurrences all number
    99
    83
    Oedema peripheral
         subjects affected / exposed
    22 / 359 (6.13%)
    22 / 355 (6.20%)
         occurrences all number
    25
    35
    Pain
         subjects affected / exposed
    19 / 359 (5.29%)
    17 / 355 (4.79%)
         occurrences all number
    23
    19
    Pyrexia
         subjects affected / exposed
    26 / 359 (7.24%)
    40 / 355 (11.27%)
         occurrences all number
    31
    59
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    68 / 359 (18.94%)
    70 / 355 (19.72%)
         occurrences all number
    107
    90
    Dysphonia
         subjects affected / exposed
    116 / 359 (32.31%)
    49 / 355 (13.80%)
         occurrences all number
    158
    51
    Dyspnoea
         subjects affected / exposed
    64 / 359 (17.83%)
    53 / 355 (14.93%)
         occurrences all number
    100
    78
    Dyspnoea exertional
         subjects affected / exposed
    18 / 359 (5.01%)
    11 / 355 (3.10%)
         occurrences all number
    21
    13
    Epistaxis
         subjects affected / exposed
    28 / 359 (7.80%)
    19 / 355 (5.35%)
         occurrences all number
    37
    20
    Haemoptysis
         subjects affected / exposed
    8 / 359 (2.23%)
    18 / 355 (5.07%)
         occurrences all number
    10
    21
    Oropharyngeal pain
         subjects affected / exposed
    22 / 359 (6.13%)
    21 / 355 (5.92%)
         occurrences all number
    37
    28
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    33 / 359 (9.19%)
    21 / 355 (5.92%)
         occurrences all number
    41
    24
    Investigations
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    19 / 359 (5.29%)
    11 / 355 (3.10%)
         occurrences all number
    22
    16
    Lipase increased
         subjects affected / exposed
    13 / 359 (3.62%)
    22 / 355 (6.20%)
         occurrences all number
    15
    50
    Weight decreased
         subjects affected / exposed
    111 / 359 (30.92%)
    83 / 355 (23.38%)
         occurrences all number
    216
    168
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    33 / 359 (9.19%)
    21 / 355 (5.92%)
         occurrences all number
    42
    28
    Dysgeusia
         subjects affected / exposed
    43 / 359 (11.98%)
    31 / 355 (8.73%)
         occurrences all number
    56
    32
    Headache
         subjects affected / exposed
    55 / 359 (15.32%)
    43 / 355 (12.11%)
         occurrences all number
    78
    59
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    18 / 359 (5.01%)
    44 / 355 (12.39%)
         occurrences all number
    28
    106
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    55 / 359 (15.32%)
    46 / 355 (12.96%)
         occurrences all number
    95
    69
    Abdominal pain upper
         subjects affected / exposed
    37 / 359 (10.31%)
    16 / 355 (4.51%)
         occurrences all number
    50
    20
    Constipation
         subjects affected / exposed
    79 / 359 (22.01%)
    82 / 355 (23.10%)
         occurrences all number
    116
    101
    Diarrhoea
         subjects affected / exposed
    208 / 359 (57.94%)
    195 / 355 (54.93%)
         occurrences all number
    736
    449
    Dyspepsia
         subjects affected / exposed
    39 / 359 (10.86%)
    15 / 355 (4.23%)
         occurrences all number
    46
    22
    Flatulence
         subjects affected / exposed
    20 / 359 (5.57%)
    8 / 355 (2.25%)
         occurrences all number
    22
    10
    Nausea
         subjects affected / exposed
    128 / 359 (35.65%)
    84 / 355 (23.66%)
         occurrences all number
    212
    138
    Stomatitis
         subjects affected / exposed
    60 / 359 (16.71%)
    47 / 355 (13.24%)
         occurrences all number
    113
    87
    Vomiting
         subjects affected / exposed
    95 / 359 (26.46%)
    69 / 355 (19.44%)
         occurrences all number
    161
    100
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    18 / 359 (5.01%)
    122 / 355 (34.37%)
         occurrences all number
    20
    145
    Dry skin
         subjects affected / exposed
    36 / 359 (10.03%)
    42 / 355 (11.83%)
         occurrences all number
    47
    47
    Erythema
         subjects affected / exposed
    12 / 359 (3.34%)
    39 / 355 (10.99%)
         occurrences all number
    14
    52
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    100 / 359 (27.86%)
    183 / 355 (51.55%)
         occurrences all number
    339
    484
    Pruritus
         subjects affected / exposed
    25 / 359 (6.96%)
    48 / 355 (13.52%)
         occurrences all number
    30
    59
    Rash
         subjects affected / exposed
    53 / 359 (14.76%)
    109 / 355 (30.70%)
         occurrences all number
    72
    168
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    49 / 359 (13.65%)
    32 / 355 (9.01%)
         occurrences all number
    219
    72
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    74 / 359 (20.61%)
    33 / 355 (9.30%)
         occurrences all number
    89
    36
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    62 / 359 (17.27%)
    46 / 355 (12.96%)
         occurrences all number
    111
    55
    Back pain
         subjects affected / exposed
    59 / 359 (16.43%)
    54 / 355 (15.21%)
         occurrences all number
    96
    65
    Muscle spasms
         subjects affected / exposed
    11 / 359 (3.06%)
    21 / 355 (5.92%)
         occurrences all number
    14
    30
    Musculoskeletal pain
         subjects affected / exposed
    28 / 359 (7.80%)
    27 / 355 (7.61%)
         occurrences all number
    41
    31
    Myalgia
         subjects affected / exposed
    28 / 359 (7.80%)
    12 / 355 (3.38%)
         occurrences all number
    43
    15
    Pain in extremity
         subjects affected / exposed
    49 / 359 (13.65%)
    53 / 355 (14.93%)
         occurrences all number
    82
    87
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    25 / 359 (6.96%)
    13 / 355 (3.66%)
         occurrences all number
    33
    13
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    140 / 359 (39.00%)
    112 / 355 (31.55%)
         occurrences all number
    279
    161
    Dehydration
         subjects affected / exposed
    18 / 359 (5.01%)
    10 / 355 (2.82%)
         occurrences all number
    26
    10

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

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

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

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