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    Clinical Trial Results:
    A Randomized Phase 3 Open Label Study of Nivolumab versus Bevacizumab and a Safety Study of Nivolumab or Nivolumab in Combination with Ipilimumab in Adult Subjects with Recurrent Glioblastoma (GBM) (CheckMate 143: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 143).

    Summary
    EudraCT number
    2013-003738-34
    Trial protocol
    DE   IT   ES   BE   DK   PL   FR   NL  
    Global end of trial date
    21 Jun 2024

    Results information
    Results version number
    v1(current)
    This version publication date
    02 Apr 2025
    First version publication date
    02 Apr 2025
    Other versions

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    CA209-143
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Bristol-Myers Squibb
    Sponsor organisation address
    Chaussee de la Hulpe 185, Brussels, Belgium, 1170
    Public contact
    Global Submission Management, Clinical Trials, Bristol-Myers Squibb, mg-gsm-ct@bms.com
    Scientific contact
    Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, mg-gsm-ct@bms.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
    18 Jul 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Jun 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Cohort 1 and 1b (Safety Lead-in): To evaluate the safety and tolerability of nivolumab and nivolumab in combination with ipilimumab Cohort 2: To compare the overall survival (OS) of nivolumab versus bevacizumab.
    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 Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial participants were followed.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    07 Feb 2014
    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: 24
    Country: Number of subjects enrolled
    Belgium: 7
    Country: Number of subjects enrolled
    Denmark: 4
    Country: Number of subjects enrolled
    France: 10
    Country: Number of subjects enrolled
    Germany: 44
    Country: Number of subjects enrolled
    Italy: 75
    Country: Number of subjects enrolled
    Netherlands: 10
    Country: Number of subjects enrolled
    Poland: 9
    Country: Number of subjects enrolled
    Spain: 20
    Country: Number of subjects enrolled
    Switzerland: 13
    Country: Number of subjects enrolled
    United Kingdom: 12
    Country: Number of subjects enrolled
    United States: 301
    Worldwide total number of subjects
    529
    EEA total number of subjects
    179
    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)
    414
    From 65 to 84 years
    115
    85 years and over
    0

    Subject disposition

    Close Top of page
    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    529 participants participated in the study. 4 (81 directly treated, 423 randomized and treated). GBM = Glioblastoma MGMT = O6-methylguanin-DNA-methyltransferase

    Period 1
    Period 1 title
    Before treatment period
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Cohort 1: Arm N1+I3
    Arm description
    Nivolumab 1 mg/kg administered as a 60-minute intravenous (IV) infusion followed by ipilimumab 3 mg/kg 90-minute IV infusion every 3 weeks for 4 cycles, then nivolumab 3 mg/kg 60-minute IV every 2 weeks thereafter
    Arm type
    Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    1 mg/kg

    Investigational medicinal product name
    Ipilimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    3 mg/kg

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    3 mg/kg

    Arm title
    Cohort 1: Arm N3
    Arm description
    Nivolumab 3 mg/kg dosed as 60-minute IV infusion every 2 weeks
    Arm type
    Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    3 mg/kg

    Arm title
    Cohort 1b: Arm N3+I1
    Arm description
    Nivolumab 3 mg/kg administered as a 60-minute IV infusion followed by ipilimumab 1 mg/kg 90-minute IV infusion every 3 weeks for 4 cycles, then nivolumab 3 mg/kg 60-minute IV every 2 weeks thereafter
    Arm type
    Experimental

    Investigational medicinal product name
    Ipilimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    1 mg/kg

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    3 mg/kg

    Arm title
    Part A Cohort 1c: Arm N3+RT+TMZ
    Arm description
    Participants with newly diagnosed GBM: Nivolumab 3 mg/kg dosed as 60-minute IV infusion every 2 weeks with standard of care treatment including surgical resection and chemoradiation followed by 6 or more cycles of maintenance temozolomide
    Arm type
    Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    3 mg/kg

    Arm title
    Part A Cohort 1d: Arm N3+RT
    Arm description
    Participants with newly diagnosed unmethylated MGMT GBM: Nivolumab 3 mg/kg dosed as 60-minute IV infusion every 2 weeks with standard of care treatment including surgical resection and radiation therapy
    Arm type
    Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    3 mg/kg

    Arm title
    Part B Cohort 1c: Arm N3+RT+TMZ
    Arm description
    Participants with newly diagnosed GBM: Nivolumab 3 mg/kg dosed as 60-minute IV infusion every 2 weeks with standard of care treatment including surgical resection and chemoradiation followed by 6 or more cycles of maintenance temozolomide
    Arm type
    Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    3 mg/kg

    Arm title
    Part B Cohort 1d: Arm N3+RT
    Arm description
    Participants with newly diagnosed unmethylated MGMT GBM: Nivolumab 3 mg/kg dosed as 60-minute IV infusion every 2 weeks with standard of care treatment including surgical resection and radiation therapy
    Arm type
    Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    3 mg/kg

    Arm title
    Cohort 2: Arm N3
    Arm description
    Nivolumab 3 mg/kg dosed as 60-minute IV infusion every 2 weeks
    Arm type
    Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    3 mg/kg

    Arm title
    Cohort 2: Arm B
    Arm description
    Bevacizumab 10 mg/kg dosed every 2 weeks as 90-minute IV infusion for the first dose and 60-minute IV infusions for subsequent doses if the first infusion is tolerated
    Arm type
    Active comparator

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    10 mg/kg

    Number of subjects in period 1
    Cohort 1: Arm N1+I3 Cohort 1: Arm N3 Cohort 1b: Arm N3+I1 Part A Cohort 1c: Arm N3+RT+TMZ Part A Cohort 1d: Arm N3+RT Part B Cohort 1c: Arm N3+RT+TMZ Part B Cohort 1d: Arm N3+RT Cohort 2: Arm N3 Cohort 2: Arm B
    Started
    10
    10
    20
    31
    30
    29
    30
    184
    185
    Randomized
    10
    10
    0 [1]
    0 [2]
    0 [3]
    29
    30
    184
    185
    Completed
    10
    10
    20
    31
    30
    28
    28
    182
    165
    Not completed
    0
    0
    0
    0
    0
    1
    2
    2
    20
         Participant no longer met criteria
    -
    -
    -
    -
    -
    1
    -
    1
    2
         Adverse Event unrelated to study drug
    -
    -
    -
    -
    -
    -
    -
    1
    -
         Participant withdrew consent
    -
    -
    -
    -
    -
    -
    2
    -
    11
         Participant request to stop therapy
    -
    -
    -
    -
    -
    -
    -
    -
    5
         Lost to follow-up
    -
    -
    -
    -
    -
    -
    -
    -
    1
         other reason
    -
    -
    -
    -
    -
    -
    -
    -
    1
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: 81 participants were not randomized but directly treated.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: 81 participants were not randomized but directly treated.
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: 81 participants were not randomized but directly treated.
    Period 2
    Period 2 title
    Treatment period
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Cohort 1: Arm N1+I3
    Arm description
    Nivolumab 1 mg/kg administered as a 60-minute intravenous (IV) infusion followed by ipilimumab 3 mg/kg 90-minute IV infusion every 3 weeks for 4 cycles, then nivolumab 3 mg/kg 60-minute IV every 2 weeks thereafter
    Arm type
    Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    1 mg/kg

    Investigational medicinal product name
    Ipilimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    3 mg/kg

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    1 mg/kg

    Arm title
    Cohort 1: Arm N3
    Arm description
    Nivolumab 3 mg/kg dosed as 60-minute IV infusion every 2 weeks
    Arm type
    Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    3 mg/kg

    Arm title
    Cohort 1b: Arm N3+I1
    Arm description
    Nivolumab 3 mg/kg administered as a 60-minute IV infusion followed by ipilimumab 1 mg/kg 90-minute IV infusion every 3 weeks for 4 cycles, then nivolumab 3 mg/kg 60-minute IV every 2 weeks thereafter
    Arm type
    Experimental

    Investigational medicinal product name
    Ipilimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    1 mg/kg

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    3 mg/kg

    Arm title
    Part A Cohort 1c: Arm N3+RT+TMZ
    Arm description
    Participants with newly diagnosed GBM: Nivolumab 3 mg/kg dosed as 60-minute IV infusion every 2 weeks with standard of care treatment including surgical resection and chemoradiation followed by 6 or more cycles of maintenance temozolomide
    Arm type
    Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    3 mg/kg

    Arm title
    Part A Cohort 1d: Arm N3+RT
    Arm description
    Participants with newly diagnosed unmethylated MGMT GBM: Nivolumab 3 mg/kg dosed as 60-minute IV infusion every 2 weeks with standard of care treatment including surgical resection and radiation therapy
    Arm type
    Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    3 mg/kg

    Arm title
    Part B Cohort 1c: Arm N3+RT+TMZ
    Arm description
    Participants with newly diagnosed GBM: Nivolumab 3 mg/kg dosed as 60-minute IV infusion every 2 weeks with standard of care treatment including surgical resection and chemoradiation followed by 6 or more cycles of maintenance temozolomide
    Arm type
    Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    3 mg/kg

    Arm title
    Part B Cohort 1d: Arm N3+RT
    Arm description
    Participants with newly diagnosed unmethylated MGMT GBM: Nivolumab 3 mg/kg dosed as 60-minute IV infusion every 2 weeks with standard of care treatment including surgical resection and radiation therapy
    Arm type
    Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    3 mg/kg

    Arm title
    Cohort 2: Arm N3
    Arm description
    Nivolumab 3 mg/kg dosed as 60-minute IV infusion every 2 weeks
    Arm type
    Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    3 mg/kg

    Arm title
    Cohort 2: Arm B
    Arm description
    Bevacizumab 10 mg/kg dosed every 2 weeks as 90-minute IV infusion for the first dose and 60-minute IV infusions for subsequent doses if the first infusion is tolerated
    Arm type
    Active comparator

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    10 mg/kg

    Number of subjects in period 2
    Cohort 1: Arm N1+I3 Cohort 1: Arm N3 Cohort 1b: Arm N3+I1 Part A Cohort 1c: Arm N3+RT+TMZ Part A Cohort 1d: Arm N3+RT Part B Cohort 1c: Arm N3+RT+TMZ Part B Cohort 1d: Arm N3+RT Cohort 2: Arm N3 Cohort 2: Arm B
    Started
    10
    10
    20
    31
    30
    28
    28
    182
    165
    Completed
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Not completed
    10
    10
    20
    31
    30
    28
    28
    182
    165
         Adverse event, serious fatal
    -
    -
    1
    -
    -
    2
    -
    -
    -
         Participant no longer met criteria
    -
    -
    -
    -
    -
    -
    -
    -
    1
         Disease progression
    7
    9
    12
    20
    26
    16
    22
    165
    135
         Adverse Event unrelated to study drug
    -
    -
    2
    -
    -
    -
    1
    4
    5
         Participant withdrew consent
    -
    -
    1
    -
    -
    2
    -
    1
    4
         Study drug toxicity
    3
    -
    1
    4
    4
    5
    3
    7
    11
         Not reported
    -
    1
    -
    -
    -
    -
    -
    -
    -
         Maximum clinical benefit
    -
    -
    -
    -
    -
    -
    -
    -
    1
         Other reasons
    -
    -
    -
    1
    -
    1
    1
    1
    1
         Participant request to stop therapy
    -
    -
    3
    6
    -
    2
    1
    4
    7

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1: Arm N1+I3
    Reporting group description
    Nivolumab 1 mg/kg administered as a 60-minute intravenous (IV) infusion followed by ipilimumab 3 mg/kg 90-minute IV infusion every 3 weeks for 4 cycles, then nivolumab 3 mg/kg 60-minute IV every 2 weeks thereafter

    Reporting group title
    Cohort 1: Arm N3
    Reporting group description
    Nivolumab 3 mg/kg dosed as 60-minute IV infusion every 2 weeks

    Reporting group title
    Cohort 1b: Arm N3+I1
    Reporting group description
    Nivolumab 3 mg/kg administered as a 60-minute IV infusion followed by ipilimumab 1 mg/kg 90-minute IV infusion every 3 weeks for 4 cycles, then nivolumab 3 mg/kg 60-minute IV every 2 weeks thereafter

    Reporting group title
    Part A Cohort 1c: Arm N3+RT+TMZ
    Reporting group description
    Participants with newly diagnosed GBM: Nivolumab 3 mg/kg dosed as 60-minute IV infusion every 2 weeks with standard of care treatment including surgical resection and chemoradiation followed by 6 or more cycles of maintenance temozolomide

    Reporting group title
    Part A Cohort 1d: Arm N3+RT
    Reporting group description
    Participants with newly diagnosed unmethylated MGMT GBM: Nivolumab 3 mg/kg dosed as 60-minute IV infusion every 2 weeks with standard of care treatment including surgical resection and radiation therapy

    Reporting group title
    Part B Cohort 1c: Arm N3+RT+TMZ
    Reporting group description
    Participants with newly diagnosed GBM: Nivolumab 3 mg/kg dosed as 60-minute IV infusion every 2 weeks with standard of care treatment including surgical resection and chemoradiation followed by 6 or more cycles of maintenance temozolomide

    Reporting group title
    Part B Cohort 1d: Arm N3+RT
    Reporting group description
    Participants with newly diagnosed unmethylated MGMT GBM: Nivolumab 3 mg/kg dosed as 60-minute IV infusion every 2 weeks with standard of care treatment including surgical resection and radiation therapy

    Reporting group title
    Cohort 2: Arm N3
    Reporting group description
    Nivolumab 3 mg/kg dosed as 60-minute IV infusion every 2 weeks

    Reporting group title
    Cohort 2: Arm B
    Reporting group description
    Bevacizumab 10 mg/kg dosed every 2 weeks as 90-minute IV infusion for the first dose and 60-minute IV infusions for subsequent doses if the first infusion is tolerated

    Reporting group values
    Cohort 1: Arm N1+I3 Cohort 1: Arm N3 Cohort 1b: Arm N3+I1 Part A Cohort 1c: Arm N3+RT+TMZ Part A Cohort 1d: Arm N3+RT Part B Cohort 1c: Arm N3+RT+TMZ Part B Cohort 1d: Arm N3+RT Cohort 2: Arm N3 Cohort 2: Arm B Total
    Number of subjects
    10 10 20 31 30 29 30 184 185 529
    Age Categorical
    Units: Participants
        < 65
    7 6 17 23 22 22 19 142 156 414
        >= 65
    3 4 3 8 8 7 11 42 29 115
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    54.5 ( 11.3 ) 58.6 ( 10.9 ) 55.0 ( 11.9 ) 56.5 ( 11.3 ) 58.2 ( 10.2 ) 57.3 ( 12.7 ) 58.8 ( 10.5 ) 55.0 ( 11.3 ) 54.2 ( 10.7 ) -
    Sex: Female, Male
    Units: Participants
        Female
    4 5 6 11 8 10 9 68 66 187
        Male
    6 5 14 20 22 19 21 116 119 342
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    0 0 0 2 2 1 0 4 1 10
        Not Hispanic or Latino
    10 10 20 29 27 28 29 86 88 327
        Unknown or Not Reported
    0 0 0 0 1 0 1 94 96 192
    Race/Ethnicity, Customized
    Race only
    Units: Subjects
        American Indian or Alaska Native
    0 0 0 0 1 0 0 0 0 1
        Asian
    0 0 1 1 0 1 1 2 1 7
        Black or African American
    0 2 0 2 0 0 0 2 2 8
        White
    10 8 18 26 28 27 28 176 181 502
        Other
    0 0 1 2 1 1 0 4 1 10
        Not Reported
    0 0 0 0 0 0 1 0 0 1

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1: Arm N1+I3
    Reporting group description
    Nivolumab 1 mg/kg administered as a 60-minute intravenous (IV) infusion followed by ipilimumab 3 mg/kg 90-minute IV infusion every 3 weeks for 4 cycles, then nivolumab 3 mg/kg 60-minute IV every 2 weeks thereafter

    Reporting group title
    Cohort 1: Arm N3
    Reporting group description
    Nivolumab 3 mg/kg dosed as 60-minute IV infusion every 2 weeks

    Reporting group title
    Cohort 1b: Arm N3+I1
    Reporting group description
    Nivolumab 3 mg/kg administered as a 60-minute IV infusion followed by ipilimumab 1 mg/kg 90-minute IV infusion every 3 weeks for 4 cycles, then nivolumab 3 mg/kg 60-minute IV every 2 weeks thereafter

    Reporting group title
    Part A Cohort 1c: Arm N3+RT+TMZ
    Reporting group description
    Participants with newly diagnosed GBM: Nivolumab 3 mg/kg dosed as 60-minute IV infusion every 2 weeks with standard of care treatment including surgical resection and chemoradiation followed by 6 or more cycles of maintenance temozolomide

    Reporting group title
    Part A Cohort 1d: Arm N3+RT
    Reporting group description
    Participants with newly diagnosed unmethylated MGMT GBM: Nivolumab 3 mg/kg dosed as 60-minute IV infusion every 2 weeks with standard of care treatment including surgical resection and radiation therapy

    Reporting group title
    Part B Cohort 1c: Arm N3+RT+TMZ
    Reporting group description
    Participants with newly diagnosed GBM: Nivolumab 3 mg/kg dosed as 60-minute IV infusion every 2 weeks with standard of care treatment including surgical resection and chemoradiation followed by 6 or more cycles of maintenance temozolomide

    Reporting group title
    Part B Cohort 1d: Arm N3+RT
    Reporting group description
    Participants with newly diagnosed unmethylated MGMT GBM: Nivolumab 3 mg/kg dosed as 60-minute IV infusion every 2 weeks with standard of care treatment including surgical resection and radiation therapy

    Reporting group title
    Cohort 2: Arm N3
    Reporting group description
    Nivolumab 3 mg/kg dosed as 60-minute IV infusion every 2 weeks

    Reporting group title
    Cohort 2: Arm B
    Reporting group description
    Bevacizumab 10 mg/kg dosed every 2 weeks as 90-minute IV infusion for the first dose and 60-minute IV infusions for subsequent doses if the first infusion is tolerated
    Reporting group title
    Cohort 1: Arm N1+I3
    Reporting group description
    Nivolumab 1 mg/kg administered as a 60-minute intravenous (IV) infusion followed by ipilimumab 3 mg/kg 90-minute IV infusion every 3 weeks for 4 cycles, then nivolumab 3 mg/kg 60-minute IV every 2 weeks thereafter

    Reporting group title
    Cohort 1: Arm N3
    Reporting group description
    Nivolumab 3 mg/kg dosed as 60-minute IV infusion every 2 weeks

    Reporting group title
    Cohort 1b: Arm N3+I1
    Reporting group description
    Nivolumab 3 mg/kg administered as a 60-minute IV infusion followed by ipilimumab 1 mg/kg 90-minute IV infusion every 3 weeks for 4 cycles, then nivolumab 3 mg/kg 60-minute IV every 2 weeks thereafter

    Reporting group title
    Part A Cohort 1c: Arm N3+RT+TMZ
    Reporting group description
    Participants with newly diagnosed GBM: Nivolumab 3 mg/kg dosed as 60-minute IV infusion every 2 weeks with standard of care treatment including surgical resection and chemoradiation followed by 6 or more cycles of maintenance temozolomide

    Reporting group title
    Part A Cohort 1d: Arm N3+RT
    Reporting group description
    Participants with newly diagnosed unmethylated MGMT GBM: Nivolumab 3 mg/kg dosed as 60-minute IV infusion every 2 weeks with standard of care treatment including surgical resection and radiation therapy

    Reporting group title
    Part B Cohort 1c: Arm N3+RT+TMZ
    Reporting group description
    Participants with newly diagnosed GBM: Nivolumab 3 mg/kg dosed as 60-minute IV infusion every 2 weeks with standard of care treatment including surgical resection and chemoradiation followed by 6 or more cycles of maintenance temozolomide

    Reporting group title
    Part B Cohort 1d: Arm N3+RT
    Reporting group description
    Participants with newly diagnosed unmethylated MGMT GBM: Nivolumab 3 mg/kg dosed as 60-minute IV infusion every 2 weeks with standard of care treatment including surgical resection and radiation therapy

    Reporting group title
    Cohort 2: Arm N3
    Reporting group description
    Nivolumab 3 mg/kg dosed as 60-minute IV infusion every 2 weeks

    Reporting group title
    Cohort 2: Arm B
    Reporting group description
    Bevacizumab 10 mg/kg dosed every 2 weeks as 90-minute IV infusion for the first dose and 60-minute IV infusions for subsequent doses if the first infusion is tolerated

    Primary: Percentage of Participants with Drug-Related Adverse Events Leading to Discontinuation by Worst CTC Grade for All Treated Participants in Cohorts 1, 1b, 1c and 1d Who Permanently Discontinued Study Medication Prior to Completing Four Doses

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    End point title
    Percentage of Participants with Drug-Related Adverse Events Leading to Discontinuation by Worst CTC Grade for All Treated Participants in Cohorts 1, 1b, 1c and 1d Who Permanently Discontinued Study Medication Prior to Completing Four Doses [1] [2]
    End point description
    The percentage of participants who experienced a drug-related adverse event leading to drug discontinuation by worst grade (grade 5 being the worst) prior to complete four-dose treatment. Toxicities were graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. MedDRA Version: 24.1
    End point type
    Primary
    End point timeframe
    Includes events reported between first dose and 30 days after last dose of study therapy (up to 3 doses, up to approximately 2 months)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Prespecified to be collected for Cohorts 1, 1b, 1c, and 1d only.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Prespecified to be collected for Cohorts 1, 1b, 1c, and 1d only.
    End point values
    Cohort 1: Arm N1+I3 Cohort 1: Arm N3 Cohort 1b: Arm N3+I1 Part A Cohort 1c: Arm N3+RT+TMZ Part A Cohort 1d: Arm N3+RT Part B Cohort 1c: Arm N3+RT+TMZ Part B Cohort 1d: Arm N3+RT
    Number of subjects analysed
    6
    4
    7
    3
    1
    4
    4
    Units: Percentage of participants
    number (not applicable)
        Grade 1
    0
    0
    0
    0
    0
    0
    0
        Grade 2
    0
    0
    0
    0
    0
    0
    0
        Grade 3
    16.7
    0
    0
    66.7
    0
    0
    50.0
        Grade 4
    33.3
    0
    0
    0
    0
    0
    0
        Grade 5
    0
    0
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Percentage of Participants with Adverse Events (Worst Grade) in Cohorts 1, 1b, 1c and 1d

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    End point title
    Percentage of Participants with Adverse Events (Worst Grade) in Cohorts 1, 1b, 1c and 1d [3] [4]
    End point description
    The percentage of participants who experienced an adverse event by worst grade in each treatment arm. Toxicities were graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. MedDRA Version: 24.1
    End point type
    Primary
    End point timeframe
    From first dose to 30 days post last dose (up to approximately 34 months).
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Prespecified to be collected for Cohorts 1, 1b, 1c, and 1d only.
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Prespecified to be collected for Cohorts 1, 1b, 1c, and 1d only.
    End point values
    Cohort 1: Arm N1+I3 Cohort 1: Arm N3 Cohort 1b: Arm N3+I1 Part A Cohort 1c: Arm N3+RT+TMZ Part A Cohort 1d: Arm N3+RT Part B Cohort 1c: Arm N3+RT+TMZ Part B Cohort 1d: Arm N3+RT
    Number of subjects analysed
    10
    10
    20
    31
    30
    28
    28
    Units: Percentage of participants
    number (not applicable)
        Grade 1
    0
    20.0
    5.0
    6.5
    13.3
    3.6
    17.9
        Grade 2
    10.0
    30.0
    25.0
    12.9
    26.7
    28.6
    25.0
        Grade 3
    70.0
    40.0
    50.0
    58.1
    33.3
    50.0
    35.7
        Grade 4
    20.0
    10.0
    20.0
    22.6
    20.0
    10.7
    21.4
        Grade 5
    0
    0
    0
    0
    3.3
    3.6
    0
    No statistical analyses for this end point

    Primary: Percentage of Participants with Serious Adverse Events (Worst Grade) in Cohorts 1, 1b, 1c and 1d

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    End point title
    Percentage of Participants with Serious Adverse Events (Worst Grade) in Cohorts 1, 1b, 1c and 1d [5] [6]
    End point description
    The percentage of participants who experienced a serious adverse event by worst grade in each treatment arm. Toxicities were graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. MedDRA Version: 24.1
    End point type
    Primary
    End point timeframe
    From first dose to 30 days post last dose (up to approximately 34 months).
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Prespecified to be collected for Cohorts 1, 1b, 1c, and 1d only.
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Prespecified to be collected for Cohorts 1, 1b, 1c, and 1d only.
    End point values
    Cohort 1: Arm N1+I3 Cohort 1: Arm N3 Cohort 1b: Arm N3+I1 Part A Cohort 1c: Arm N3+RT+TMZ Part A Cohort 1d: Arm N3+RT Part B Cohort 1c: Arm N3+RT+TMZ Part B Cohort 1d: Arm N3+RT
    Number of subjects analysed
    10
    10
    20
    31
    30
    28
    28
    Units: Percentage of participants
    number (not applicable)
        Grade 1
    0
    0
    0
    3.2
    0
    0
    0
        Grade 2
    0
    10.0
    5.0
    0
    16.7
    3.6
    10.7
        Grade 3
    60.0
    40.0
    35.0
    45.2
    16.7
    35.7
    32.1
        Grade 4
    20.0
    0
    15.0
    16.1
    16.7
    3.6
    14.3
        Grade 5
    0
    0
    0
    0
    3.3
    3.6
    0
    No statistical analyses for this end point

    Primary: Percentage of Participants with Specific Laboratory Abnormalities in Liver Tests in Cohorts 1, 1b, 1c and 1d

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    End point title
    Percentage of Participants with Specific Laboratory Abnormalities in Liver Tests in Cohorts 1, 1b, 1c and 1d [7] [8]
    End point description
    The percentage of participants who experienced a laboratory abnormality of the liver in each treatment arm. MedDRA Version: 24.1 Aspartate aminotransferase (AST) Alanine aminotransferase (ALT) Upper Limit of Normal (ULN) Denominator corresponds to participants with at least on one treatment measurement of the corresponding laboratory parameter. Includes laboratory results reported after the first dose and within 30 days of last dose of study therapy.
    End point type
    Primary
    End point timeframe
    From first dose to 30 days post last dose (up to approximately 34 months).
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Prespecified to be collected for Cohorts 1, 1b, 1c, and 1d only.
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Prespecified to be collected for Cohorts 1, 1b, 1c, and 1d only.
    End point values
    Cohort 1: Arm N1+I3 Cohort 1: Arm N3 Cohort 1b: Arm N3+I1 Part A Cohort 1c: Arm N3+RT+TMZ Part A Cohort 1d: Arm N3+RT Part B Cohort 1c: Arm N3+RT+TMZ Part B Cohort 1d: Arm N3+RT
    Number of subjects analysed
    10
    10
    19
    31
    30
    27
    27
    Units: Percentage of participants
    number (not applicable)
        ALT OR AST > 3*ULN
    30.0
    0.0
    15.8
    22.6
    10.0
    18.5
    14.8
        ALT OR AST > 5*ULN
    20.0
    0.0
    10.5
    12.9
    3.3
    11.1
    3.7
        ALT OR AST > 10*ULN
    10.0
    0.0
    5.3
    6.5
    3.3
    3.7
    3.7
        ALT OR AST > 20*ULN
    10.0
    0.0
    5.3
    3.2
    3.3
    0.0
    3.7
        TOTAL BILIRUBIN (Tbili) > 2*ULN
    10.0
    0.0
    0.0
    0.0
    0.0
    7.4
    0.0
        ALP > 1.5*ULN
    10.0
    10.0
    0.0
    0.0
    3.3
    0.0
    3.7
        ALT or AST > 3xULN w/ Tbili > 1.5*ULN in 1 day
    10.0
    0.0
    0.0
    0.0
    0.0
    3.7
    0.0
        ALT or AST > 3*ULN w/ Tbili > 1.5*ULN in 30 days
    10.0
    0.0
    0.0
    0.0
    0.0
    3.7
    0.0
        ALT or AST > 3xULN w/ Tbili > 2*ULN in 1 day
    10.0
    0.0
    0.0
    0.0
    0.0
    3.7
    0.0
        ALT or AST > 3*ULN w/ Tbili > 2*ULN in 30 days
    10.0
    0.0
    0.0
    0.0
    0.0
    3.7
    0.0
    No statistical analyses for this end point

    Primary: Percentage of Participants with Specific Laboratory Abnormalities in Thyroid Tests in Cohorts 1, 1b, 1c and 1d

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    End point title
    Percentage of Participants with Specific Laboratory Abnormalities in Thyroid Tests in Cohorts 1, 1b, 1c and 1d [9] [10]
    End point description
    The percentage of participants who experienced a laboratory abnormality of the thyroid in each treatment arm. MedDRA Version: 24.1 Free T3 (FT3) Free T4 (FT4) Lower Limit of Normal (LLN) (A) Within a 2-week window after the abnormal TSH test date. (B) Includes participants with TSH abnormality and with no FT3/FT4 test values in the 2-week window or with non-abnormal value(s) from only one of the two tests and no value from the other test.
    End point type
    Primary
    End point timeframe
    From first dose to 30 days post last dose (up to approximately 34 months).
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Prespecified to be collected for Cohorts 1, 1b, 1c, and 1d only.
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Prespecified to be collected for Cohorts 1, 1b, 1c, and 1d only.
    End point values
    Cohort 1: Arm N1+I3 Cohort 1: Arm N3 Cohort 1b: Arm N3+I1 Part A Cohort 1c: Arm N3+RT+TMZ Part A Cohort 1d: Arm N3+RT Part B Cohort 1c: Arm N3+RT+TMZ Part B Cohort 1d: Arm N3+RT
    Number of subjects analysed
    10
    10
    19
    30
    30
    27
    27
    Units: Percentage of participants
    number (not applicable)
        TSH > ULN
    20.0
    50.0
    10.5
    23.3
    16.7
    11.1
    7.4
        TSH > ULN, WITH TSH <= ULN AT BASELINE
    20.0
    30.0
    10.5
    20.0
    16.7
    11.1
    7.4
        TSH > ULN, WITH AT LEAST ONE FT3/FT4 TEST < LLN
    20.0
    30.0
    10.5
    13.3
    13.3
    7.4
    0.0
        TSH > ULN, WITH ALL OTHER FT3/FT4 TEST >= LLN
    0.0
    10.0
    0.0
    6.7
    0.0
    3.7
    7.4
        TSH > ULN, WITH FT3/FT4 TEST MISSING
    0.0
    10.0
    0.0
    3.3
    3.3
    0.0
    0.0
        TSH < LLN
    60.0
    30.0
    31.6
    43.3
    40.0
    22.2
    33.3
        TSH < LLN, WITH TSH >= LLN AT BASELINE
    60.0
    30.0
    31.6
    33.3
    40.0
    18.5
    18.5
        TSH<LLN, LLN WITH AT LEAST ONE FT3/FT4 TEST>ULN
    30.0
    10.0
    15.8
    10.0
    13.3
    11.1
    0.0
        TSH < LLN, WITH ALL OTHER FT3/FT4 TEST <= ULN
    20.0
    20.0
    10.5
    30.0
    16.7
    11.1
    29.6
        TSH < LLN, WITH FT3/FT4 TEST MISSING
    10.0
    0.0
    5.3
    3.3
    10.0
    0.0
    3.7
    No statistical analyses for this end point

    Primary: Overall Survival (OS) for Cohort 2

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    End point title
    Overall Survival (OS) for Cohort 2 [11]
    End point description
    OS was measured in months from the time of randomization to the event date (death) due to any cause. A participant who has not died will be censored at the last known alive date. Based on Kaplan-Meier Estimates. Hazard ratio from Cox proportional hazard model stratified by presence of measurable lesions at baseline per IVRS. P-value from log-rank test stratified by presence of measurable lesions at baseline per IVRS.
    End point type
    Primary
    End point timeframe
    Time between the date of randomization and the date of death due to any cause (up to up to 17Jun2019, approximately 5 years)
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Prespecified to be collected for Cohort 2 only.
    End point values
    Cohort 2: Arm N3 Cohort 2: Arm B
    Number of subjects analysed
    184
    185
    Units: Months
        median (confidence interval 95%)
    9.77 (8.21 to 11.83)
    10.05 (9.00 to 11.99)
    Statistical analysis title
    Overall Survival (OS) Cohort 2
    Comparison groups
    Cohort 2: Arm N3 v Cohort 2: Arm B
    Number of subjects included in analysis
    369
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.3791
    Method
    log-rank test stratified
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.89
         upper limit
    1.36

    Secondary: Overall Survival (OS) at 12 Months for Cohort 2

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    End point title
    Overall Survival (OS) at 12 Months for Cohort 2 [12]
    End point description
    OS(12) is measured as the percentage of participants alive at 12 months per Kaplan-Meier curve of OS. Z test with variance estimation based on Greenwood formula using log(-log) transformation.
    End point type
    Secondary
    End point timeframe
    From randomization to 12 months following randomization
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Prespecified to be collected for Cohort 2 only.
    End point values
    Cohort 2: Arm N3 Cohort 2: Arm B
    Number of subjects analysed
    184
    185
    Units: Percentage of Participants
        number (confidence interval 95%)
    41.8 (34.7 to 48.8)
    42.4 (34.9 to 49.6)
    Statistical analysis title
    Overall Survival (OS) at 12 months - Cohort 2
    Comparison groups
    Cohort 2: Arm N3 v Cohort 2: Arm B
    Number of subjects included in analysis
    369
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.9208
    Method
    Z test with variance estimation based on
    Parameter type
    Difference of OS rates at 12 months
    Point estimate
    -0.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -10.8
         upper limit
    9.7

    Secondary: Overall Survival (OS) for Cohorts 1c and 1d

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    End point title
    Overall Survival (OS) for Cohorts 1c and 1d [13]
    End point description
    OS was measured in months from the time of randomization (Part B) or time of treatment (Part A) to the event date (death) due to any cause. A participant who has not died will be censored at the last known alive date. Based on Kaplan-Meier Estimates.
    End point type
    Secondary
    End point timeframe
    Time between the date of randomization and the date of death due to any cause (up to approximately 10 years and 5 months)
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Prespecified to be collected for Cohorts 1c, and 1d only.
    End point values
    Part A Cohort 1c: Arm N3+RT+TMZ Part A Cohort 1d: Arm N3+RT Part B Cohort 1c: Arm N3+RT+TMZ Part B Cohort 1d: Arm N3+RT
    Number of subjects analysed
    31
    30
    28
    28
    Units: Months
        median (confidence interval 95%)
    22.08 (16.13 to 32.39)
    14.41 (12.55 to 17.31)
    15.95 (10.35 to 18.30)
    13.96 (10.81 to 18.14)
    No statistical analyses for this end point

    Secondary: Progression Free Survival (PFS) for Cohort 2

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    End point title
    Progression Free Survival (PFS) for Cohort 2 [14]
    End point description
    PFS was measured in months from the time of randomization to the date of the first documented tumor progression or death due to any cause. Based on Kaplan-Meier Estimates. Hazard ratio from Cox proportional hazard model stratified by presence of measurable lesions at baseline per IVRS.
    End point type
    Secondary
    End point timeframe
    Time from randomization to the date of the first documented tumor progression or death due to any cause (up to approximately 10 years and 5 months)
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Prespecified to be collected for Cohort 2 only.
    End point values
    Cohort 2: Arm N3 Cohort 2: Arm B
    Number of subjects analysed
    184
    185
    Units: Months
        median (confidence interval 95%)
    1.51 (1.48 to 1.61)
    3.61 (2.99 to 4.60)
    Statistical analysis title
    Progression Free Survival (PFS) for Cohort 2
    Comparison groups
    Cohort 2: Arm N3 v Cohort 2: Arm B
    Number of subjects included in analysis
    369
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.88
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.5
         upper limit
    2.35

    Secondary: Objective Response Rate (ORR) for Cohort 2

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    End point title
    Objective Response Rate (ORR) for Cohort 2 [15]
    End point description
    ORR was measured by the percentage of participants whose best overall response (BOR) is confirmed Complete Response (CR) or Partial Response (PR) divided by response evaluable participants. The best overall response (BOR) is determined once all the data for the participant is known. BOR is defined as the best response designation, as determined by investigators, recorded between the date of randomization and the date of objectively documented progression per RANO criteria, the date of subsequent therapy, or date of surgical resection, whichever occurs first. Confidence interval based on the Clopper and Pearson method. For the comparison of the odds ratio of Nivolumab over Bevacizumab, the Cochran-Mantel-Haenszel (CMH) method of weighting was utilized.
    End point type
    Secondary
    End point timeframe
    Time from randomization to the date of the first documented tumor progression or death due to any cause (up to approximately 10 years and 5 months)
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Prespecified to be collected for Cohort 2 only.
    End point values
    Cohort 2: Arm N3 Cohort 2: Arm B
    Number of subjects analysed
    153
    156
    Units: Percentage of participants
        number (confidence interval 95%)
    7.8 (4.1 to 13.3)
    23.1 (16.7 to 30.5)
    Statistical analysis title
    Objective Response Rate (ORR) for Cohort 2
    Comparison groups
    Cohort 2: Arm N3 v Cohort 2: Arm B
    Number of subjects included in analysis
    309
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.29
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.15
         upper limit
    0.59

    Post-hoc: Post-hoc Overall Survival (OS) for Cohort 2

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    End point title
    Post-hoc Overall Survival (OS) for Cohort 2 [16]
    End point description
    OS was measured in months from the time of randomization to the event date (death) due to any cause. A participant who has not died will be censored at the last known alive date. Based on Kaplan-Meier Estimates. Hazard ratio from Cox proportional hazard model stratified by presence of measurable lesions at baseline per IVRS. P-value from log-rank test stratified by presence of measurable lesions at baseline per IVRS.
    End point type
    Post-hoc
    End point timeframe
    Time between the date of randomization and the date of death due to any cause (up to approximately 10 years and 5 months)
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Prespecified to be collected for Cohorts 1, 1b, 1c, and 1d only.
    End point values
    Cohort 2: Arm N3 Cohort 2: Arm B
    Number of subjects analysed
    184
    185
    Units: Months
        median (confidence interval 95%)
    9.77 (8.21 to 11.83)
    10.05 (9.00 to 11.99)
    Statistical analysis title
    Post-hoc Overall Survival (OS) for Cohort 2
    Comparison groups
    Cohort 2: Arm N3 v Cohort 2: Arm B
    Number of subjects included in analysis
    369
    Analysis specification
    Post-hoc
    Analysis type
    P-value
    = 0.3791
    Method
    log-rank test stratified
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.89
         upper limit
    1.36

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    SAEs and NSAEs: From first dose (SAEs and NSAEs) to 100 days post last dose (up to approximately 113 months).
    Adverse event reporting additional description
    SAEs and NSAEs (Other Adverse Events) = treated participant population
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    27.0
    Reporting groups
    Reporting group title
    Cohort 1: Arm N3
    Reporting group description
    Nivolumab 3 mg/kg dosed as 60-minute IV infusion every 2 weeks.

    Reporting group title
    Cohort 1: Arm N1+I3
    Reporting group description
    Nivolumab 1 mg/kg administered as a 60-minute intravenous (IV) infusion followed by ipilimumab 3 mg/kg 90-minute IV infusion every 3 weeks for 4 cycles, then nivolumab 3 mg/kg 60-minute IV every 2 weeks thereafter.

    Reporting group title
    Cohort 1b: Arm N3+I1
    Reporting group description
    Nivolumab 3 mg/kg administered as a 60-minute IV infusion followed by ipilimumab 1 mg/kg 90-minute IV infusion every 3 weeks for 4 cycles, then nivolumab 3 mg/kg 60-minute IV every 2 weeks thereafter.

    Reporting group title
    Cohort 2: Arm B
    Reporting group description
    Bevacizumab 10 mg/kg dosed every 2 weeks as 90-minute IV infusion for the first dose and 60-minute IV infusions for subsequent doses if the first infusion is tolerated.

    Reporting group title
    Part B Cohort 1c: Arm N3+RT+TMZ
    Reporting group description
    Participants with newly diagnosed GBM: Nivolumab 3 mg/kg dosed as 60-minute IV infusion every 2 weeks with standard of care treatment including surgical resection and chemoradiation followed by 6 or more cycles of maintenance temozolomide.

    Reporting group title
    Cohort 2: Arm N3
    Reporting group description
    Nivolumab 3 mg/kg dosed as 60-minute IV infusion every 2 weeks.

    Reporting group title
    Part B Cohort 1d: Arm N3+RT
    Reporting group description
    Participants with newly diagnosed unmethylated MGMT GBM: Nivolumab 3 mg/kg dosed as 60-minute IV infusion every 2 weeks with standard of care treatment including surgical resection and radiation therapy.

    Reporting group title
    Part A Cohort 1c: Arm N3+RT+TMZ
    Reporting group description
    Participants with newly diagnosed GBM: Nivolumab 3 mg/kg dosed as 60-minute IV infusion every 2 weeks with standard of care treatment including surgical resection and chemoradiation followed by 6 or more cycles of maintenance temozolomide.

    Reporting group title
    Part A Cohort 1d: Arm N3+RT
    Reporting group description
    Participants with newly diagnosed unmethylated MGMT GBM: Nivolumab 3 mg/kg dosed as 60-minute IV infusion every 2 weeks with standard of care treatment including surgical resection and radiation therapy.

    Serious adverse events
    Cohort 1: Arm N3 Cohort 1: Arm N1+I3 Cohort 1b: Arm N3+I1 Cohort 2: Arm B Part B Cohort 1c: Arm N3+RT+TMZ Cohort 2: Arm N3 Part B Cohort 1d: Arm N3+RT Part A Cohort 1c: Arm N3+RT+TMZ Part A Cohort 1d: Arm N3+RT
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 10 (70.00%)
    8 / 10 (80.00%)
    15 / 20 (75.00%)
    94 / 165 (56.97%)
    16 / 28 (57.14%)
    117 / 182 (64.29%)
    19 / 28 (67.86%)
    24 / 31 (77.42%)
    19 / 30 (63.33%)
         number of deaths (all causes)
    9
    10
    20
    156
    28
    178
    28
    29
    30
         number of deaths resulting from adverse events
    2
    2
    8
    48
    5
    48
    6
    2
    6
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    1 / 182 (0.55%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colorectal adenoma
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    1 / 182 (0.55%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Glioblastoma
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    1 / 28 (3.57%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Glioblastoma multiforme
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    1 / 182 (0.55%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intraductal proliferative breast lesion
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    1 / 31 (3.23%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    2 / 10 (20.00%)
    2 / 10 (20.00%)
    8 / 20 (40.00%)
    53 / 165 (32.12%)
    4 / 28 (14.29%)
    64 / 182 (35.16%)
    7 / 28 (25.00%)
    12 / 31 (38.71%)
    9 / 30 (30.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 9
    0 / 55
    0 / 4
    0 / 66
    0 / 8
    1 / 12
    0 / 9
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    0 / 6
    0 / 47
    0 / 2
    0 / 46
    0 / 4
    0 / 2
    0 / 6
    Metastases to spine
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    1 / 31 (3.23%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasm malignant
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    1 / 182 (0.55%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    1 / 28 (3.57%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour flare
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    0 / 165 (0.00%)
    3 / 28 (10.71%)
    2 / 182 (1.10%)
    2 / 28 (7.14%)
    3 / 31 (9.68%)
    2 / 30 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    3 / 3
    2 / 2
    2 / 2
    1 / 3
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    1 / 182 (0.55%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    2 / 182 (1.10%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    1 / 165 (0.61%)
    1 / 28 (3.57%)
    1 / 182 (0.55%)
    1 / 28 (3.57%)
    0 / 31 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Flushing
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    1 / 28 (3.57%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    1 / 28 (3.57%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    1 / 165 (0.61%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 10 (20.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    1 / 28 (3.57%)
    0 / 31 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    1 / 182 (0.55%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    0 / 165 (0.00%)
    1 / 28 (3.57%)
    1 / 182 (0.55%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    2 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    2 / 20 (10.00%)
    1 / 165 (0.61%)
    0 / 28 (0.00%)
    1 / 182 (0.55%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Necrosis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    4 / 165 (2.42%)
    0 / 28 (0.00%)
    2 / 182 (1.10%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 4
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Impaired healing
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    2 / 182 (1.10%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gait disturbance
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    1 / 28 (3.57%)
    0 / 31 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    1 / 28 (3.57%)
    1 / 182 (0.55%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oedema
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    1 / 182 (0.55%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    2 / 165 (1.21%)
    1 / 28 (3.57%)
    3 / 182 (1.65%)
    2 / 28 (7.14%)
    4 / 31 (12.90%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 2
    0 / 1
    0 / 3
    1 / 2
    3 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    1 / 28 (3.57%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Performance status decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    1 / 182 (0.55%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    1 / 182 (0.55%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Contrast media allergy
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    1 / 165 (0.61%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Uterine prolapse
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    1 / 165 (0.61%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    1 / 182 (0.55%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Granulomatous pneumonitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    1 / 182 (0.55%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    1 / 165 (0.61%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    2 / 28 (7.14%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    1 / 31 (3.23%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspiration
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hiccups
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    1 / 182 (0.55%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    1 / 165 (0.61%)
    0 / 28 (0.00%)
    4 / 182 (2.20%)
    1 / 28 (3.57%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 1
    0 / 0
    3 / 4
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    1 / 28 (3.57%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax spontaneous
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    1 / 165 (0.61%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    2 / 20 (10.00%)
    5 / 165 (3.03%)
    0 / 28 (0.00%)
    3 / 182 (1.65%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    5 / 5
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    1 / 28 (3.57%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    1 / 28 (3.57%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    2 / 10 (20.00%)
    2 / 10 (20.00%)
    2 / 20 (10.00%)
    0 / 165 (0.00%)
    1 / 28 (3.57%)
    3 / 182 (1.65%)
    1 / 28 (3.57%)
    4 / 31 (12.90%)
    3 / 30 (10.00%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 3
    0 / 2
    0 / 0
    0 / 1
    0 / 3
    0 / 1
    1 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Delirium
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    1 / 28 (3.57%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hallucination
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    1 / 28 (3.57%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    1 / 165 (0.61%)
    0 / 28 (0.00%)
    1 / 182 (0.55%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Agitation
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    1 / 165 (0.61%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    1 / 165 (0.61%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 10 (20.00%)
    1 / 20 (5.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    1 / 182 (0.55%)
    1 / 28 (3.57%)
    2 / 31 (6.45%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    2 / 2
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    3 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    1 / 165 (0.61%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    1 / 20 (5.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    1 / 182 (0.55%)
    0 / 28 (0.00%)
    2 / 31 (6.45%)
    2 / 30 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    2 / 2
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    3 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza B virus test positive
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lipase increased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    0 / 165 (0.00%)
    1 / 28 (3.57%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    1 / 182 (0.55%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    1 / 182 (0.55%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    2 / 20 (10.00%)
    1 / 165 (0.61%)
    1 / 28 (3.57%)
    3 / 182 (1.65%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 3
    0 / 1
    0 / 1
    0 / 3
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Fracture
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    1 / 182 (0.55%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    1 / 165 (0.61%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    1 / 28 (3.57%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Procedural haemorrhage
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    1 / 165 (0.61%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    1 / 182 (0.55%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    1 / 28 (3.57%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Amnesia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    1 / 165 (0.61%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aphasia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    1 / 28 (3.57%)
    4 / 182 (2.20%)
    0 / 28 (0.00%)
    1 / 31 (3.23%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    1 / 5
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Brain oedema
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    1 / 20 (5.00%)
    1 / 165 (0.61%)
    1 / 28 (3.57%)
    5 / 182 (2.75%)
    0 / 28 (0.00%)
    1 / 31 (3.23%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
    0 / 1
    0 / 1
    1 / 5
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ataxia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    1 / 28 (3.57%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    1 / 165 (0.61%)
    0 / 28 (0.00%)
    1 / 182 (0.55%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrospinal fluid leakage
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    1 / 182 (0.55%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    2 / 165 (1.21%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cognitive disorder
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    2 / 165 (1.21%)
    0 / 28 (0.00%)
    1 / 182 (0.55%)
    2 / 28 (7.14%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    2 / 165 (1.21%)
    0 / 28 (0.00%)
    1 / 182 (0.55%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    3 / 3
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Demyelination
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    1 / 182 (0.55%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    2 / 20 (10.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    1 / 182 (0.55%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysarthria
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    1 / 28 (3.57%)
    2 / 31 (6.45%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Epilepsy
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    3 / 165 (1.82%)
    0 / 28 (0.00%)
    2 / 182 (1.10%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Facial paralysis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    1 / 28 (3.57%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    5 / 182 (2.75%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 5
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 10 (10.00%)
    3 / 20 (15.00%)
    2 / 165 (1.21%)
    5 / 28 (17.86%)
    10 / 182 (5.49%)
    1 / 28 (3.57%)
    2 / 31 (6.45%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    1 / 3
    0 / 2
    0 / 6
    3 / 11
    0 / 1
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hemianopia homonymous
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    1 / 28 (3.57%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    2 / 182 (1.10%)
    0 / 28 (0.00%)
    1 / 31 (3.23%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    1 / 20 (5.00%)
    3 / 165 (1.82%)
    1 / 28 (3.57%)
    5 / 182 (2.75%)
    1 / 28 (3.57%)
    0 / 31 (0.00%)
    2 / 30 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 3
    0 / 1
    0 / 5
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    2 / 165 (1.21%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorder
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    1 / 165 (0.61%)
    0 / 28 (0.00%)
    1 / 182 (0.55%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Memory impairment
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lethargy
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    1 / 28 (3.57%)
    1 / 31 (3.23%)
    2 / 30 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Neurological decompensation
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    1 / 165 (0.61%)
    0 / 28 (0.00%)
    1 / 182 (0.55%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Parkinson's disease
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    1 / 182 (0.55%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    1 / 182 (0.55%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyramidal tract syndrome
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    1 / 31 (3.23%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 10 (10.00%)
    1 / 20 (5.00%)
    11 / 165 (6.67%)
    4 / 28 (14.29%)
    17 / 182 (9.34%)
    2 / 28 (7.14%)
    5 / 31 (16.13%)
    4 / 30 (13.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
    0 / 12
    0 / 5
    4 / 25
    0 / 2
    1 / 6
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Slow speech
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    1 / 165 (0.61%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    1 / 28 (3.57%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    2 / 20 (10.00%)
    1 / 165 (0.61%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    1 / 28 (3.57%)
    1 / 31 (3.23%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    1 / 182 (0.55%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    1 / 182 (0.55%)
    1 / 28 (3.57%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Vasogenic cerebral oedema
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    2 / 182 (1.10%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    2 / 28 (7.14%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    1 / 31 (3.23%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 4
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    1 / 28 (3.57%)
    1 / 182 (0.55%)
    0 / 28 (0.00%)
    1 / 31 (3.23%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    1 / 165 (0.61%)
    0 / 28 (0.00%)
    2 / 182 (1.10%)
    0 / 28 (0.00%)
    1 / 31 (3.23%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 2
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    2 / 31 (6.45%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    1 / 31 (3.23%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Visual impairment
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    1 / 28 (3.57%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye movement disorder
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    1 / 28 (3.57%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    2 / 28 (7.14%)
    1 / 182 (0.55%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Autoimmune pancreatitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    1 / 182 (0.55%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    3 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 10 (20.00%)
    1 / 20 (5.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 10 (20.00%)
    2 / 20 (10.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
    2 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal pain
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    1 / 31 (3.23%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    1 / 28 (3.57%)
    1 / 31 (3.23%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    1 / 182 (0.55%)
    0 / 28 (0.00%)
    1 / 31 (3.23%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    1 / 28 (3.57%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    1 / 165 (0.61%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    1 / 182 (0.55%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    1 / 165 (0.61%)
    1 / 28 (3.57%)
    2 / 182 (1.10%)
    1 / 28 (3.57%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 1
    0 / 1
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    1 / 31 (3.23%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    1 / 165 (0.61%)
    1 / 28 (3.57%)
    1 / 182 (0.55%)
    1 / 28 (3.57%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    1 / 165 (0.61%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertransaminasaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    1 / 28 (3.57%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Portal vein thrombosis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    1 / 165 (0.61%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune-mediated hepatitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    1 / 28 (3.57%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis bullous
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug reaction with eosinophilia and systemic symptoms
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    1 / 28 (3.57%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lichen planus
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psoriasis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    1 / 182 (0.55%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    1 / 31 (3.23%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash erythematous
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    1 / 28 (3.57%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    1 / 28 (3.57%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stevens-Johnson syndrome
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Tubulointerstitial nephritis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    1 / 182 (0.55%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    1 / 28 (3.57%)
    1 / 182 (0.55%)
    1 / 28 (3.57%)
    0 / 31 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Endocrine disorders
    Autoimmune hypothyroidism
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    1 / 182 (0.55%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Autoimmune thyroiditis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperthyroidism
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    1 / 31 (3.23%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypothyroidism
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 10 (20.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    1 / 165 (0.61%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    1 / 31 (3.23%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mobility decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    2 / 165 (1.21%)
    0 / 28 (0.00%)
    1 / 182 (0.55%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematoma muscle
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    3 / 20 (15.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    2 / 30 (6.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Neck pain
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    1 / 28 (3.57%)
    1 / 182 (0.55%)
    1 / 28 (3.57%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Brain abscess
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    1 / 182 (0.55%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    1 / 182 (0.55%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    1 / 31 (3.23%)
    2 / 30 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    1 / 31 (3.23%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    1 / 165 (0.61%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    1 / 182 (0.55%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalitis herpes
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    1 / 28 (3.57%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    1 / 28 (3.57%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Groin abscess
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    1 / 165 (0.61%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes simplex encephalitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    1 / 28 (3.57%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Graft infection
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    1 / 182 (0.55%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophageal infection
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    1 / 28 (3.57%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    2 / 165 (1.21%)
    1 / 28 (3.57%)
    4 / 182 (2.20%)
    3 / 28 (10.71%)
    5 / 31 (16.13%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    0 / 1
    0 / 4
    0 / 4
    2 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    1 / 28 (3.57%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural infection
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    1 / 182 (0.55%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    1 / 165 (0.61%)
    0 / 28 (0.00%)
    2 / 182 (1.10%)
    2 / 28 (7.14%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 2
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    1 / 182 (0.55%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    1 / 165 (0.61%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    1 / 31 (3.23%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    1 / 165 (0.61%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    1 / 28 (3.57%)
    1 / 182 (0.55%)
    0 / 28 (0.00%)
    1 / 31 (3.23%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    1 / 20 (5.00%)
    0 / 165 (0.00%)
    1 / 28 (3.57%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    1 / 28 (3.57%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    1 / 182 (0.55%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    2 / 31 (6.45%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypovolaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    1 / 165 (0.61%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    1 / 165 (0.61%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    1 / 31 (3.23%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    1 / 31 (3.23%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Cohort 1: Arm N3 Cohort 1: Arm N1+I3 Cohort 1b: Arm N3+I1 Cohort 2: Arm B Part B Cohort 1c: Arm N3+RT+TMZ Cohort 2: Arm N3 Part B Cohort 1d: Arm N3+RT Part A Cohort 1c: Arm N3+RT+TMZ Part A Cohort 1d: Arm N3+RT
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 10 (100.00%)
    10 / 10 (100.00%)
    20 / 20 (100.00%)
    148 / 165 (89.70%)
    27 / 28 (96.43%)
    168 / 182 (92.31%)
    27 / 28 (96.43%)
    31 / 31 (100.00%)
    29 / 30 (96.67%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    2 / 165 (1.21%)
    1 / 28 (3.57%)
    3 / 182 (1.65%)
    2 / 28 (7.14%)
    1 / 31 (3.23%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    2
    1
    3
    2
    1
    1
    Hypertension
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    1 / 20 (5.00%)
    50 / 165 (30.30%)
    3 / 28 (10.71%)
    12 / 182 (6.59%)
    1 / 28 (3.57%)
    5 / 31 (16.13%)
    6 / 30 (20.00%)
         occurrences all number
    0
    1
    1
    63
    3
    18
    1
    7
    6
    Deep vein thrombosis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    2 / 165 (1.21%)
    1 / 28 (3.57%)
    2 / 182 (1.10%)
    2 / 28 (7.14%)
    1 / 31 (3.23%)
    1 / 30 (3.33%)
         occurrences all number
    1
    0
    1
    2
    1
    2
    2
    1
    1
    Pelvic venous thrombosis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    2 / 182 (1.10%)
    1 / 28 (3.57%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    2
    1
    0
    0
    Asthenia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    2 / 20 (10.00%)
    9 / 165 (5.45%)
    3 / 28 (10.71%)
    14 / 182 (7.69%)
    1 / 28 (3.57%)
    1 / 31 (3.23%)
    1 / 30 (3.33%)
         occurrences all number
    1
    0
    3
    11
    3
    15
    1
    1
    1
    Oedema
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    1 / 20 (5.00%)
    2 / 165 (1.21%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    0
    1
    1
    2
    0
    0
    0
    0
    0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    4 / 165 (2.42%)
    3 / 28 (10.71%)
    1 / 182 (0.55%)
    1 / 28 (3.57%)
    1 / 31 (3.23%)
    1 / 30 (3.33%)
         occurrences all number
    2
    0
    0
    5
    3
    1
    1
    1
    1
    Mucosal inflammation
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    2 / 165 (1.21%)
    1 / 28 (3.57%)
    2 / 182 (1.10%)
    2 / 28 (7.14%)
    1 / 31 (3.23%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    0
    2
    2
    2
    2
    1
    0
    Influenza like illness
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    5 / 165 (3.03%)
    2 / 28 (7.14%)
    2 / 182 (1.10%)
    2 / 28 (7.14%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    0
    5
    2
    2
    3
    0
    0
    Gait disturbance
         subjects affected / exposed
    2 / 10 (20.00%)
    3 / 10 (30.00%)
    6 / 20 (30.00%)
    7 / 165 (4.24%)
    2 / 28 (7.14%)
    16 / 182 (8.79%)
    0 / 28 (0.00%)
    5 / 31 (16.13%)
    3 / 30 (10.00%)
         occurrences all number
    2
    3
    6
    7
    2
    18
    0
    5
    3
    Chills
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    2 / 165 (1.21%)
    2 / 28 (7.14%)
    3 / 182 (1.65%)
    1 / 28 (3.57%)
    2 / 31 (6.45%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    2
    2
    2
    3
    2
    2
    2
    Face oedema
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    1 / 28 (3.57%)
    1 / 182 (0.55%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    0
    1
    0
    0
    2
    1
    0
    0
    0
    Fatigue
         subjects affected / exposed
    5 / 10 (50.00%)
    8 / 10 (80.00%)
    14 / 20 (70.00%)
    45 / 165 (27.27%)
    20 / 28 (71.43%)
    69 / 182 (37.91%)
    18 / 28 (64.29%)
    25 / 31 (80.65%)
    16 / 30 (53.33%)
         occurrences all number
    5
    8
    18
    56
    24
    84
    19
    29
    19
    Pain
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    5 / 165 (3.03%)
    5 / 28 (17.86%)
    4 / 182 (2.20%)
    2 / 28 (7.14%)
    1 / 31 (3.23%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    1
    5
    5
    4
    2
    1
    0
    Oedema peripheral
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 10 (20.00%)
    2 / 20 (10.00%)
    15 / 165 (9.09%)
    0 / 28 (0.00%)
    16 / 182 (8.79%)
    2 / 28 (7.14%)
    4 / 31 (12.90%)
    2 / 30 (6.67%)
         occurrences all number
    0
    2
    3
    15
    0
    18
    2
    5
    2
    Pyrexia
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 10 (20.00%)
    2 / 20 (10.00%)
    8 / 165 (4.85%)
    3 / 28 (10.71%)
    13 / 182 (7.14%)
    6 / 28 (21.43%)
    3 / 31 (9.68%)
    3 / 30 (10.00%)
         occurrences all number
    0
    2
    3
    9
    3
    21
    6
    3
    5
    Reproductive system and breast disorders
    Erectile dysfunction
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    1 / 165 (0.61%)
    0 / 28 (0.00%)
    1 / 182 (0.55%)
    0 / 28 (0.00%)
    1 / 31 (3.23%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    1
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    10 / 165 (6.06%)
    0 / 28 (0.00%)
    2 / 182 (1.10%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    0
    11
    0
    2
    0
    0
    0
    Nasal congestion
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 10 (10.00%)
    4 / 20 (20.00%)
    3 / 165 (1.82%)
    2 / 28 (7.14%)
    7 / 182 (3.85%)
    3 / 28 (10.71%)
    4 / 31 (12.90%)
    2 / 30 (6.67%)
         occurrences all number
    1
    1
    5
    3
    2
    7
    3
    5
    2
    Oropharyngeal pain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    7 / 165 (4.24%)
    3 / 28 (10.71%)
    7 / 182 (3.85%)
    0 / 28 (0.00%)
    3 / 31 (9.68%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    0
    7
    4
    9
    0
    3
    0
    Pneumonitis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    1 / 20 (5.00%)
    2 / 165 (1.21%)
    0 / 28 (0.00%)
    3 / 182 (1.65%)
    0 / 28 (0.00%)
    1 / 31 (3.23%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    1
    2
    0
    3
    0
    1
    1
    Cough
         subjects affected / exposed
    1 / 10 (10.00%)
    3 / 10 (30.00%)
    9 / 20 (45.00%)
    12 / 165 (7.27%)
    3 / 28 (10.71%)
    23 / 182 (12.64%)
    5 / 28 (17.86%)
    5 / 31 (16.13%)
    5 / 30 (16.67%)
         occurrences all number
    2
    3
    11
    13
    4
    26
    6
    6
    5
    Dysphonia
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 10 (20.00%)
    1 / 20 (5.00%)
    10 / 165 (6.06%)
    0 / 28 (0.00%)
    2 / 182 (1.10%)
    1 / 28 (3.57%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    0
    2
    1
    10
    0
    3
    1
    0
    0
    Dyspnoea
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 10 (10.00%)
    2 / 20 (10.00%)
    9 / 165 (5.45%)
    1 / 28 (3.57%)
    5 / 182 (2.75%)
    2 / 28 (7.14%)
    3 / 31 (9.68%)
    1 / 30 (3.33%)
         occurrences all number
    1
    1
    2
    10
    1
    5
    2
    3
    1
    Dyspnoea exertional
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    2 / 165 (1.21%)
    0 / 28 (0.00%)
    1 / 182 (0.55%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    0
    1
    0
    2
    0
    1
    0
    0
    0
    Tonsillar erythema
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Upper-airway cough syndrome
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    4 / 165 (2.42%)
    2 / 28 (7.14%)
    5 / 182 (2.75%)
    1 / 28 (3.57%)
    1 / 31 (3.23%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    0
    4
    2
    5
    1
    1
    0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    10 / 165 (6.06%)
    6 / 28 (21.43%)
    6 / 182 (3.30%)
    1 / 28 (3.57%)
    1 / 31 (3.23%)
    3 / 30 (10.00%)
         occurrences all number
    1
    0
    1
    10
    6
    6
    1
    1
    3
    Delusion
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Confusional state
         subjects affected / exposed
    3 / 10 (30.00%)
    3 / 10 (30.00%)
    9 / 20 (45.00%)
    10 / 165 (6.06%)
    6 / 28 (21.43%)
    15 / 182 (8.24%)
    3 / 28 (10.71%)
    2 / 31 (6.45%)
    3 / 30 (10.00%)
         occurrences all number
    4
    3
    11
    10
    6
    15
    4
    4
    6
    Anxiety
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    2 / 20 (10.00%)
    6 / 165 (3.64%)
    1 / 28 (3.57%)
    6 / 182 (3.30%)
    4 / 28 (14.29%)
    4 / 31 (12.90%)
    5 / 30 (16.67%)
         occurrences all number
    1
    0
    2
    6
    1
    6
    4
    4
    5
    Agitation
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    2 / 20 (10.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    5 / 182 (2.75%)
    1 / 28 (3.57%)
    1 / 31 (3.23%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    5
    1
    1
    0
    Irritability
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    2 / 165 (1.21%)
    0 / 28 (0.00%)
    2 / 182 (1.10%)
    0 / 28 (0.00%)
    1 / 31 (3.23%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    0
    2
    0
    2
    0
    1
    1
    Insomnia
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 10 (10.00%)
    1 / 20 (5.00%)
    15 / 165 (9.09%)
    6 / 28 (21.43%)
    16 / 182 (8.79%)
    3 / 28 (10.71%)
    2 / 31 (6.45%)
    5 / 30 (16.67%)
         occurrences all number
    1
    1
    1
    15
    7
    18
    3
    2
    5
    Hallucination
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    1 / 182 (0.55%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    0
    Disorientation
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    2 / 20 (10.00%)
    3 / 165 (1.82%)
    0 / 28 (0.00%)
    2 / 182 (1.10%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    2
    3
    0
    3
    0
    0
    0
    Investigations
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    1 / 20 (5.00%)
    0 / 165 (0.00%)
    2 / 28 (7.14%)
    5 / 182 (2.75%)
    0 / 28 (0.00%)
    1 / 31 (3.23%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    1
    0
    2
    5
    0
    2
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 10 (10.00%)
    4 / 10 (40.00%)
    2 / 20 (10.00%)
    3 / 165 (1.82%)
    4 / 28 (14.29%)
    6 / 182 (3.30%)
    2 / 28 (7.14%)
    9 / 31 (29.03%)
    3 / 30 (10.00%)
         occurrences all number
    1
    4
    4
    4
    4
    7
    2
    19
    5
    Amylase increased
         subjects affected / exposed
    1 / 10 (10.00%)
    3 / 10 (30.00%)
    1 / 20 (5.00%)
    3 / 165 (1.82%)
    2 / 28 (7.14%)
    4 / 182 (2.20%)
    2 / 28 (7.14%)
    4 / 31 (12.90%)
    2 / 30 (6.67%)
         occurrences all number
    4
    3
    2
    3
    3
    4
    4
    10
    3
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 10 (10.00%)
    4 / 10 (40.00%)
    3 / 20 (15.00%)
    10 / 165 (6.06%)
    5 / 28 (17.86%)
    16 / 182 (8.79%)
    2 / 28 (7.14%)
    9 / 31 (29.03%)
    5 / 30 (16.67%)
         occurrences all number
    1
    5
    6
    12
    5
    19
    3
    17
    7
    Weight decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    7 / 165 (4.24%)
    1 / 28 (3.57%)
    5 / 182 (2.75%)
    3 / 28 (10.71%)
    4 / 31 (12.90%)
    3 / 30 (10.00%)
         occurrences all number
    0
    0
    1
    7
    1
    5
    3
    5
    3
    Platelet count decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    3 / 20 (15.00%)
    5 / 165 (3.03%)
    5 / 28 (17.86%)
    7 / 182 (3.85%)
    2 / 28 (7.14%)
    8 / 31 (25.81%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    5
    5
    7
    8
    2
    27
    2
    Neutrophil count decreased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    1 / 165 (0.61%)
    1 / 28 (3.57%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    5 / 31 (16.13%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    0
    2
    1
    0
    0
    28
    0
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    3 / 20 (15.00%)
    5 / 165 (3.03%)
    3 / 28 (10.71%)
    2 / 182 (1.10%)
    2 / 28 (7.14%)
    6 / 31 (19.35%)
    3 / 30 (10.00%)
         occurrences all number
    0
    0
    4
    5
    8
    5
    2
    14
    3
    Weight increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    4 / 165 (2.42%)
    1 / 28 (3.57%)
    5 / 182 (2.75%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    1
    4
    1
    5
    0
    0
    2
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    2 / 165 (1.21%)
    0 / 28 (0.00%)
    3 / 182 (1.65%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    0
    2
    0
    3
    0
    0
    0
    Blood creatinine increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    2 / 165 (1.21%)
    3 / 28 (10.71%)
    3 / 182 (1.65%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    0
    2
    3
    4
    0
    0
    3
    Blood bilirubin increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    1 / 165 (0.61%)
    1 / 28 (3.57%)
    3 / 182 (1.65%)
    0 / 28 (0.00%)
    2 / 31 (6.45%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    1
    1
    1
    3
    0
    5
    2
    Lipase increased
         subjects affected / exposed
    2 / 10 (20.00%)
    4 / 10 (40.00%)
    2 / 20 (10.00%)
    5 / 165 (3.03%)
    2 / 28 (7.14%)
    10 / 182 (5.49%)
    1 / 28 (3.57%)
    6 / 31 (19.35%)
    5 / 30 (16.67%)
         occurrences all number
    5
    6
    2
    6
    2
    15
    2
    15
    6
    White blood cell count decreased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    3 / 165 (1.82%)
    2 / 28 (7.14%)
    2 / 182 (1.10%)
    1 / 28 (3.57%)
    6 / 31 (19.35%)
    1 / 30 (3.33%)
         occurrences all number
    1
    0
    1
    3
    4
    2
    1
    25
    1
    White blood cell count increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    2 / 28 (7.14%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    0
    Injury, poisoning and procedural complications
    Arthropod sting
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Contusion
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    1 / 165 (0.61%)
    2 / 28 (7.14%)
    4 / 182 (2.20%)
    0 / 28 (0.00%)
    2 / 31 (6.45%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    0
    1
    2
    5
    0
    2
    0
    Vaccination complication
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Radiation skin injury
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    2 / 28 (7.14%)
    0 / 182 (0.00%)
    1 / 28 (3.57%)
    1 / 31 (3.23%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    1
    1
    1
    Infusion related reaction
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    1 / 165 (0.61%)
    2 / 28 (7.14%)
    3 / 182 (1.65%)
    1 / 28 (3.57%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    0
    1
    2
    4
    1
    0
    0
    Fall
         subjects affected / exposed
    0 / 10 (0.00%)
    3 / 10 (30.00%)
    5 / 20 (25.00%)
    10 / 165 (6.06%)
    2 / 28 (7.14%)
    18 / 182 (9.89%)
    1 / 28 (3.57%)
    3 / 31 (9.68%)
    3 / 30 (10.00%)
         occurrences all number
    0
    6
    13
    14
    2
    33
    2
    5
    3
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    2 / 20 (10.00%)
    2 / 165 (1.21%)
    1 / 28 (3.57%)
    1 / 182 (0.55%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    2
    2
    1
    1
    0
    0
    0
    Palpitations
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    1 / 165 (0.61%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    1 / 28 (3.57%)
    2 / 31 (6.45%)
    0 / 30 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    1
    2
    0
    Myocardial infarction
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Atrial fibrillation
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    1 / 28 (3.57%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    1
    0
    0
    0
    1
    0
    0
    Nervous system disorders
    Balance disorder
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    0 / 165 (0.00%)
    3 / 28 (10.71%)
    7 / 182 (3.85%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    1
    0
    3
    9
    0
    0
    0
    Ataxia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    2 / 165 (1.21%)
    0 / 28 (0.00%)
    5 / 182 (2.75%)
    1 / 28 (3.57%)
    1 / 31 (3.23%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    1
    2
    0
    5
    1
    1
    0
    Aphasia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    2 / 20 (10.00%)
    21 / 165 (12.73%)
    5 / 28 (17.86%)
    28 / 182 (15.38%)
    3 / 28 (10.71%)
    6 / 31 (19.35%)
    3 / 30 (10.00%)
         occurrences all number
    0
    0
    2
    22
    5
    31
    3
    6
    3
    Amnesia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    3 / 165 (1.82%)
    0 / 28 (0.00%)
    4 / 182 (2.20%)
    0 / 28 (0.00%)
    2 / 31 (6.45%)
    1 / 30 (3.33%)
         occurrences all number
    1
    0
    1
    3
    0
    4
    0
    2
    1
    Disturbance in attention
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    2 / 165 (1.21%)
    3 / 28 (10.71%)
    9 / 182 (4.95%)
    2 / 28 (7.14%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    0
    2
    3
    9
    2
    0
    0
    Cognitive disorder
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 10 (10.00%)
    3 / 20 (15.00%)
    6 / 165 (3.64%)
    1 / 28 (3.57%)
    10 / 182 (5.49%)
    3 / 28 (10.71%)
    5 / 31 (16.13%)
    2 / 30 (6.67%)
         occurrences all number
    1
    1
    3
    6
    1
    13
    3
    5
    2
    Brain oedema
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    1 / 20 (5.00%)
    0 / 165 (0.00%)
    2 / 28 (7.14%)
    8 / 182 (4.40%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    0
    1
    1
    0
    2
    8
    0
    0
    0
    Dysgeusia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    2 / 28 (7.14%)
    1 / 182 (0.55%)
    1 / 28 (3.57%)
    2 / 31 (6.45%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    0
    0
    2
    1
    1
    3
    2
    Facial paresis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    2 / 20 (10.00%)
    2 / 165 (1.21%)
    1 / 28 (3.57%)
    1 / 182 (0.55%)
    0 / 28 (0.00%)
    2 / 31 (6.45%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    2
    2
    1
    1
    0
    2
    1
    Dysarthria
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 10 (10.00%)
    2 / 20 (10.00%)
    5 / 165 (3.03%)
    0 / 28 (0.00%)
    5 / 182 (2.75%)
    4 / 28 (14.29%)
    2 / 31 (6.45%)
    1 / 30 (3.33%)
         occurrences all number
    2
    1
    2
    5
    0
    6
    4
    2
    1
    Dizziness
         subjects affected / exposed
    4 / 10 (40.00%)
    1 / 10 (10.00%)
    4 / 20 (20.00%)
    11 / 165 (6.67%)
    2 / 28 (7.14%)
    16 / 182 (8.79%)
    3 / 28 (10.71%)
    8 / 31 (25.81%)
    5 / 30 (16.67%)
         occurrences all number
    4
    1
    4
    17
    2
    18
    3
    8
    7
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    1 / 20 (5.00%)
    1 / 165 (0.61%)
    0 / 28 (0.00%)
    1 / 182 (0.55%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    1
    0
    0
    0
    Dyspraxia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Paraesthesia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    2 / 20 (10.00%)
    5 / 165 (3.03%)
    3 / 28 (10.71%)
    9 / 182 (4.95%)
    2 / 28 (7.14%)
    3 / 31 (9.68%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    2
    5
    3
    11
    2
    3
    1
    Memory impairment
         subjects affected / exposed
    3 / 10 (30.00%)
    1 / 10 (10.00%)
    4 / 20 (20.00%)
    10 / 165 (6.06%)
    1 / 28 (3.57%)
    14 / 182 (7.69%)
    1 / 28 (3.57%)
    2 / 31 (6.45%)
    3 / 30 (10.00%)
         occurrences all number
    3
    1
    4
    10
    1
    17
    1
    2
    3
    Lethargy
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    4 / 20 (20.00%)
    1 / 165 (0.61%)
    0 / 28 (0.00%)
    1 / 182 (0.55%)
    0 / 28 (0.00%)
    1 / 31 (3.23%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    4
    1
    0
    1
    0
    1
    0
    Hypoaesthesia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    5 / 165 (3.03%)
    1 / 28 (3.57%)
    5 / 182 (2.75%)
    1 / 28 (3.57%)
    2 / 31 (6.45%)
    5 / 30 (16.67%)
         occurrences all number
    0
    0
    0
    5
    1
    6
    1
    2
    5
    Hemiparesis
         subjects affected / exposed
    3 / 10 (30.00%)
    3 / 10 (30.00%)
    7 / 20 (35.00%)
    16 / 165 (9.70%)
    4 / 28 (14.29%)
    27 / 182 (14.84%)
    3 / 28 (10.71%)
    5 / 31 (16.13%)
    2 / 30 (6.67%)
         occurrences all number
    3
    4
    7
    18
    4
    29
    3
    5
    2
    Headache
         subjects affected / exposed
    7 / 10 (70.00%)
    7 / 10 (70.00%)
    10 / 20 (50.00%)
    53 / 165 (32.12%)
    17 / 28 (60.71%)
    57 / 182 (31.32%)
    11 / 28 (39.29%)
    14 / 31 (45.16%)
    13 / 30 (43.33%)
         occurrences all number
    12
    15
    11
    85
    23
    91
    14
    25
    16
    Partial seizures
         subjects affected / exposed
    0 / 10 (0.00%)
    3 / 10 (30.00%)
    0 / 20 (0.00%)
    4 / 165 (2.42%)
    0 / 28 (0.00%)
    5 / 182 (2.75%)
    0 / 28 (0.00%)
    1 / 31 (3.23%)
    1 / 30 (3.33%)
         occurrences all number
    0
    3
    0
    6
    0
    5
    0
    1
    1
    Presyncope
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    1 / 165 (0.61%)
    0 / 28 (0.00%)
    2 / 182 (1.10%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    0
    2
    0
    1
    0
    2
    0
    0
    0
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    1 / 165 (0.61%)
    0 / 28 (0.00%)
    3 / 182 (1.65%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    0
    1
    0
    4
    0
    0
    2
    Psychomotor skills impaired
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    2 / 20 (10.00%)
    2 / 165 (1.21%)
    1 / 28 (3.57%)
    2 / 182 (1.10%)
    1 / 28 (3.57%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    2
    2
    1
    2
    1
    0
    0
    Vasogenic cerebral oedema
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    1 / 28 (3.57%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    1
    0
    0
    Tremor
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    1 / 20 (5.00%)
    4 / 165 (2.42%)
    1 / 28 (3.57%)
    4 / 182 (2.20%)
    2 / 28 (7.14%)
    2 / 31 (6.45%)
    3 / 30 (10.00%)
         occurrences all number
    0
    2
    1
    4
    1
    5
    2
    2
    3
    Syncope
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    1 / 165 (0.61%)
    0 / 28 (0.00%)
    1 / 182 (0.55%)
    0 / 28 (0.00%)
    3 / 31 (9.68%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    3
    0
    Seizure
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 10 (10.00%)
    2 / 20 (10.00%)
    17 / 165 (10.30%)
    6 / 28 (21.43%)
    33 / 182 (18.13%)
    12 / 28 (42.86%)
    3 / 31 (9.68%)
    7 / 30 (23.33%)
         occurrences all number
    2
    1
    2
    22
    7
    68
    18
    9
    8
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    1 / 165 (0.61%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    0
    1
    0
    0
    0
    0
    0
    Anaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    2 / 20 (10.00%)
    4 / 165 (2.42%)
    2 / 28 (7.14%)
    8 / 182 (4.40%)
    4 / 28 (14.29%)
    7 / 31 (22.58%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    3
    4
    2
    16
    6
    11
    1
    Lymphopenia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    4 / 165 (2.42%)
    2 / 28 (7.14%)
    6 / 182 (3.30%)
    0 / 28 (0.00%)
    3 / 31 (9.68%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    0
    4
    2
    6
    0
    5
    2
    Thrombocytopenia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    3 / 165 (1.82%)
    5 / 28 (17.86%)
    2 / 182 (1.10%)
    1 / 28 (3.57%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    0
    3
    6
    2
    1
    0
    0
    Ear and labyrinth disorders
    Ear congestion
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    1 / 28 (3.57%)
    0 / 182 (0.00%)
    1 / 28 (3.57%)
    1 / 31 (3.23%)
    2 / 30 (6.67%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    1
    1
    2
    Vertigo
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    3 / 165 (1.82%)
    1 / 28 (3.57%)
    3 / 182 (1.65%)
    2 / 28 (7.14%)
    1 / 31 (3.23%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    0
    3
    2
    3
    2
    1
    1
    Tinnitus
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    1 / 165 (0.61%)
    2 / 28 (7.14%)
    1 / 182 (0.55%)
    0 / 28 (0.00%)
    1 / 31 (3.23%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    0
    1
    2
    1
    0
    1
    1
    Eye disorders
    Visual field defect
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    3 / 165 (1.82%)
    2 / 28 (7.14%)
    3 / 182 (1.65%)
    0 / 28 (0.00%)
    3 / 31 (9.68%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    1
    3
    2
    3
    0
    3
    0
    Vision blurred
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    4 / 165 (2.42%)
    1 / 28 (3.57%)
    5 / 182 (2.75%)
    0 / 28 (0.00%)
    6 / 31 (19.35%)
    3 / 30 (10.00%)
         occurrences all number
    1
    0
    0
    5
    1
    5
    0
    6
    3
    Optic nerve disorder
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    2
    1
    0
    0
    0
    0
    0
    0
    0
    Night blindness
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Eyelid ptosis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    0 / 165 (0.00%)
    2 / 28 (7.14%)
    2 / 182 (1.10%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    1
    0
    2
    2
    0
    0
    0
    Dry eye
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    0 / 165 (0.00%)
    1 / 28 (3.57%)
    2 / 182 (1.10%)
    2 / 28 (7.14%)
    2 / 31 (6.45%)
    1 / 30 (3.33%)
         occurrences all number
    1
    0
    1
    0
    1
    2
    2
    2
    1
    Diplopia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    1 / 165 (0.61%)
    2 / 28 (7.14%)
    1 / 182 (0.55%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    0
    1
    2
    1
    0
    0
    0
    Blepharitis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    1 / 28 (3.57%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    0
    0
    Visual impairment
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    1 / 20 (5.00%)
    0 / 165 (0.00%)
    2 / 28 (7.14%)
    4 / 182 (2.20%)
    1 / 28 (3.57%)
    1 / 31 (3.23%)
    0 / 30 (0.00%)
         occurrences all number
    0
    1
    1
    0
    2
    4
    1
    2
    0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    2 / 28 (7.14%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    0
    0
    2
    0
    0
    0
    0
    Anal incontinence
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    2 / 20 (10.00%)
    1 / 165 (0.61%)
    2 / 28 (7.14%)
    4 / 182 (2.20%)
    1 / 28 (3.57%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    2
    1
    2
    4
    1
    0
    0
    Abdominal pain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    3 / 20 (15.00%)
    5 / 165 (3.03%)
    2 / 28 (7.14%)
    17 / 182 (9.34%)
    3 / 28 (10.71%)
    4 / 31 (12.90%)
    3 / 30 (10.00%)
         occurrences all number
    1
    0
    3
    7
    2
    19
    3
    9
    3
    Vomiting
         subjects affected / exposed
    2 / 10 (20.00%)
    4 / 10 (40.00%)
    4 / 20 (20.00%)
    11 / 165 (6.67%)
    7 / 28 (25.00%)
    15 / 182 (8.24%)
    3 / 28 (10.71%)
    6 / 31 (19.35%)
    3 / 30 (10.00%)
         occurrences all number
    2
    9
    4
    12
    8
    19
    5
    15
    3
    Toothache
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    4 / 165 (2.42%)
    0 / 28 (0.00%)
    4 / 182 (2.20%)
    1 / 28 (3.57%)
    3 / 31 (9.68%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    0
    4
    0
    4
    1
    4
    0
    Stomatitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    6 / 165 (3.64%)
    1 / 28 (3.57%)
    2 / 182 (1.10%)
    2 / 28 (7.14%)
    0 / 31 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    7
    2
    2
    2
    0
    1
    Constipation
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 10 (0.00%)
    4 / 20 (20.00%)
    15 / 165 (9.09%)
    12 / 28 (42.86%)
    26 / 182 (14.29%)
    1 / 28 (3.57%)
    10 / 31 (32.26%)
    4 / 30 (13.33%)
         occurrences all number
    3
    0
    4
    17
    14
    29
    2
    11
    4
    Dysphagia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    4 / 165 (2.42%)
    1 / 28 (3.57%)
    5 / 182 (2.75%)
    2 / 28 (7.14%)
    1 / 31 (3.23%)
    2 / 30 (6.67%)
         occurrences all number
    1
    0
    1
    4
    1
    6
    2
    1
    2
    Dyspepsia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    5 / 165 (3.03%)
    0 / 28 (0.00%)
    9 / 182 (4.95%)
    0 / 28 (0.00%)
    2 / 31 (6.45%)
    2 / 30 (6.67%)
         occurrences all number
    2
    0
    1
    5
    0
    10
    0
    2
    2
    Diarrhoea
         subjects affected / exposed
    2 / 10 (20.00%)
    7 / 10 (70.00%)
    7 / 20 (35.00%)
    16 / 165 (9.70%)
    3 / 28 (10.71%)
    28 / 182 (15.38%)
    8 / 28 (28.57%)
    8 / 31 (25.81%)
    4 / 30 (13.33%)
         occurrences all number
    2
    13
    12
    24
    4
    39
    11
    20
    5
    Cheilitis
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    2
    1
    0
    0
    0
    0
    0
    0
    0
    Nausea
         subjects affected / exposed
    3 / 10 (30.00%)
    3 / 10 (30.00%)
    6 / 20 (30.00%)
    22 / 165 (13.33%)
    15 / 28 (53.57%)
    27 / 182 (14.84%)
    7 / 28 (25.00%)
    13 / 31 (41.94%)
    8 / 30 (26.67%)
         occurrences all number
    4
    6
    8
    28
    20
    40
    7
    24
    10
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 10 (0.00%)
    6 / 20 (30.00%)
    7 / 165 (4.24%)
    2 / 28 (7.14%)
    20 / 182 (10.99%)
    4 / 28 (14.29%)
    7 / 31 (22.58%)
    3 / 30 (10.00%)
         occurrences all number
    2
    0
    7
    9
    3
    27
    4
    9
    3
    Erythema
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    4 / 165 (2.42%)
    0 / 28 (0.00%)
    4 / 182 (2.20%)
    1 / 28 (3.57%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    0
    1
    0
    4
    0
    4
    1
    0
    0
    Dry skin
         subjects affected / exposed
    0 / 10 (0.00%)
    3 / 10 (30.00%)
    1 / 20 (5.00%)
    2 / 165 (1.21%)
    0 / 28 (0.00%)
    13 / 182 (7.14%)
    3 / 28 (10.71%)
    8 / 31 (25.81%)
    1 / 30 (3.33%)
         occurrences all number
    0
    3
    1
    2
    0
    14
    3
    8
    1
    Drug eruption
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    2 / 28 (7.14%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    0
    0
    3
    0
    0
    0
    0
    Dermatitis contact
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    0
    0
    Alopecia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    1 / 165 (0.61%)
    4 / 28 (14.29%)
    1 / 182 (0.55%)
    5 / 28 (17.86%)
    6 / 31 (19.35%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    0
    1
    4
    1
    5
    7
    2
    Dermatitis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    1 / 165 (0.61%)
    0 / 28 (0.00%)
    2 / 182 (1.10%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    2
    0
    0
    0
    Dermatitis acneiform
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    1 / 20 (5.00%)
    1 / 165 (0.61%)
    1 / 28 (3.57%)
    3 / 182 (1.65%)
    0 / 28 (0.00%)
    2 / 31 (6.45%)
    1 / 30 (3.33%)
         occurrences all number
    0
    2
    1
    1
    1
    5
    0
    2
    1
    Rash maculo-papular
         subjects affected / exposed
    0 / 10 (0.00%)
    4 / 10 (40.00%)
    2 / 20 (10.00%)
    3 / 165 (1.82%)
    1 / 28 (3.57%)
    7 / 182 (3.85%)
    1 / 28 (3.57%)
    5 / 31 (16.13%)
    4 / 30 (13.33%)
         occurrences all number
    0
    5
    2
    3
    1
    10
    1
    5
    4
    Rash
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 10 (10.00%)
    5 / 20 (25.00%)
    8 / 165 (4.85%)
    2 / 28 (7.14%)
    18 / 182 (9.89%)
    9 / 28 (32.14%)
    8 / 31 (25.81%)
    2 / 30 (6.67%)
         occurrences all number
    2
    1
    6
    9
    2
    27
    9
    12
    3
    Renal and urinary disorders
    Urinary hesitation
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    1 / 182 (0.55%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    0
    0
    Proteinuria
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    12 / 165 (7.27%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    1
    18
    0
    0
    0
    0
    0
    Pollakiuria
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    3 / 165 (1.82%)
    1 / 28 (3.57%)
    2 / 182 (1.10%)
    2 / 28 (7.14%)
    1 / 31 (3.23%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    1
    3
    1
    3
    3
    1
    0
    Micturition urgency
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    1 / 165 (0.61%)
    1 / 28 (3.57%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    2 / 31 (6.45%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    1
    1
    1
    0
    0
    2
    0
    Urinary incontinence
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    4 / 20 (20.00%)
    2 / 165 (1.21%)
    1 / 28 (3.57%)
    8 / 182 (4.40%)
    1 / 28 (3.57%)
    1 / 31 (3.23%)
    3 / 30 (10.00%)
         occurrences all number
    0
    1
    4
    2
    1
    8
    1
    1
    3
    Acute kidney injury
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    1 / 182 (0.55%)
    1 / 28 (3.57%)
    0 / 31 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    1
    0
    2
    Urinary retention
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    1 / 165 (0.61%)
    0 / 28 (0.00%)
    2 / 182 (1.10%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    2
    0
    0
    0
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 10 (20.00%)
    1 / 20 (5.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    5 / 182 (2.75%)
    0 / 28 (0.00%)
    2 / 31 (6.45%)
    3 / 30 (10.00%)
         occurrences all number
    1
    2
    1
    0
    0
    5
    0
    2
    3
    Endocrine disorder
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    2
    Cushingoid
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    1 / 20 (5.00%)
    2 / 165 (1.21%)
    0 / 28 (0.00%)
    2 / 182 (1.10%)
    0 / 28 (0.00%)
    1 / 31 (3.23%)
    0 / 30 (0.00%)
         occurrences all number
    0
    1
    1
    2
    0
    2
    0
    1
    0
    Hypothyroidism
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 10 (10.00%)
    1 / 20 (5.00%)
    2 / 165 (1.21%)
    2 / 28 (7.14%)
    9 / 182 (4.95%)
    3 / 28 (10.71%)
    3 / 31 (9.68%)
    3 / 30 (10.00%)
         occurrences all number
    2
    1
    1
    2
    2
    9
    3
    4
    3
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 10 (20.00%)
    1 / 20 (5.00%)
    11 / 165 (6.67%)
    1 / 28 (3.57%)
    13 / 182 (7.14%)
    5 / 28 (17.86%)
    6 / 31 (19.35%)
    2 / 30 (6.67%)
         occurrences all number
    1
    2
    1
    12
    1
    14
    5
    7
    2
    Arthralgia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    3 / 20 (15.00%)
    22 / 165 (13.33%)
    7 / 28 (25.00%)
    26 / 182 (14.29%)
    4 / 28 (14.29%)
    9 / 31 (29.03%)
    4 / 30 (13.33%)
         occurrences all number
    2
    0
    3
    24
    7
    29
    4
    10
    4
    Groin pain
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    2 / 31 (6.45%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    2
    0
    Muscular weakness
         subjects affected / exposed
    3 / 10 (30.00%)
    2 / 10 (20.00%)
    5 / 20 (25.00%)
    15 / 165 (9.09%)
    3 / 28 (10.71%)
    15 / 182 (8.24%)
    3 / 28 (10.71%)
    3 / 31 (9.68%)
    2 / 30 (6.67%)
         occurrences all number
    3
    2
    6
    15
    4
    17
    3
    3
    2
    Muscle spasms
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    5 / 165 (3.03%)
    0 / 28 (0.00%)
    10 / 182 (5.49%)
    1 / 28 (3.57%)
    1 / 31 (3.23%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    0
    5
    0
    13
    1
    1
    1
    Flank pain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Pain in extremity
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    9 / 165 (5.45%)
    0 / 28 (0.00%)
    15 / 182 (8.24%)
    0 / 28 (0.00%)
    1 / 31 (3.23%)
    3 / 30 (10.00%)
         occurrences all number
    1
    0
    0
    9
    0
    18
    0
    1
    3
    Spinal pain
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Scoliosis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Rotator cuff syndrome
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    1 / 28 (3.57%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    1 / 31 (3.23%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    1
    0
    Neck pain
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    6 / 165 (3.64%)
    1 / 28 (3.57%)
    6 / 182 (3.30%)
    1 / 28 (3.57%)
    0 / 31 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    0
    7
    1
    6
    1
    0
    2
    Myalgia
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    10 / 165 (6.06%)
    3 / 28 (10.71%)
    7 / 182 (3.85%)
    0 / 28 (0.00%)
    3 / 31 (9.68%)
    1 / 30 (3.33%)
         occurrences all number
    2
    0
    1
    11
    4
    7
    0
    4
    1
    Infections and infestations
    Mucosal infection
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 10 (20.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    1 / 28 (3.57%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    0
    2
    0
    0
    1
    0
    0
    0
    0
    Klebsiella infection
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Hordeolum
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    1 / 28 (3.57%)
    0 / 182 (0.00%)
    1 / 28 (3.57%)
    2 / 31 (6.45%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    0
    0
    3
    0
    1
    4
    0
    Enterocolitis infectious
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    1 / 20 (5.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    0
    0
    0
    Conjunctivitis
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    1 / 165 (0.61%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    1
    1
    0
    1
    0
    0
    0
    0
    0
    Candida infection
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 10 (20.00%)
    2 / 20 (10.00%)
    4 / 165 (2.42%)
    2 / 28 (7.14%)
    1 / 182 (0.55%)
    3 / 28 (10.71%)
    1 / 31 (3.23%)
    3 / 30 (10.00%)
         occurrences all number
    0
    2
    3
    4
    2
    1
    3
    1
    4
    Herpes zoster
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    0 / 165 (0.00%)
    1 / 28 (3.57%)
    1 / 182 (0.55%)
    0 / 28 (0.00%)
    2 / 31 (6.45%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    0
    1
    1
    0
    4
    1
    Nasopharyngitis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    6 / 165 (3.64%)
    1 / 28 (3.57%)
    7 / 182 (3.85%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    4
    0
    0
    7
    1
    8
    0
    0
    0
    Oral candidiasis
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 10 (10.00%)
    1 / 20 (5.00%)
    2 / 165 (1.21%)
    1 / 28 (3.57%)
    3 / 182 (1.65%)
    3 / 28 (10.71%)
    1 / 31 (3.23%)
    1 / 30 (3.33%)
         occurrences all number
    1
    1
    2
    2
    1
    3
    3
    1
    1
    Pneumonia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    1 / 20 (5.00%)
    2 / 165 (1.21%)
    0 / 28 (0.00%)
    5 / 182 (2.75%)
    1 / 28 (3.57%)
    1 / 31 (3.23%)
    0 / 30 (0.00%)
         occurrences all number
    0
    1
    1
    2
    0
    5
    1
    1
    0
    Rash pustular
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    1 / 182 (0.55%)
    1 / 28 (3.57%)
    1 / 31 (3.23%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    1
    1
    0
    Sinusitis
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    2 / 165 (1.21%)
    1 / 28 (3.57%)
    3 / 182 (1.65%)
    0 / 28 (0.00%)
    1 / 31 (3.23%)
    1 / 30 (3.33%)
         occurrences all number
    1
    1
    0
    3
    1
    4
    0
    1
    1
    Staphylococcal infection
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    1 / 182 (0.55%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    0
    Tooth infection
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    2 / 20 (10.00%)
    2 / 165 (1.21%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    1 / 31 (3.23%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    2
    3
    0
    0
    0
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    2 / 20 (10.00%)
    6 / 165 (3.64%)
    1 / 28 (3.57%)
    6 / 182 (3.30%)
    1 / 28 (3.57%)
    4 / 31 (12.90%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    2
    6
    1
    8
    1
    5
    1
    Urinary tract infection
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    5 / 20 (25.00%)
    7 / 165 (4.24%)
    1 / 28 (3.57%)
    11 / 182 (6.04%)
    2 / 28 (7.14%)
    1 / 31 (3.23%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    5
    7
    1
    18
    2
    2
    2
    Viral infection
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    3 / 165 (1.82%)
    0 / 28 (0.00%)
    1 / 182 (0.55%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    0
    4
    0
    1
    0
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 10 (20.00%)
    3 / 20 (15.00%)
    9 / 165 (5.45%)
    7 / 28 (25.00%)
    11 / 182 (6.04%)
    9 / 28 (32.14%)
    5 / 31 (16.13%)
    3 / 30 (10.00%)
         occurrences all number
    0
    4
    3
    9
    7
    12
    10
    7
    3
    Dehydration
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 10 (10.00%)
    2 / 20 (10.00%)
    1 / 165 (0.61%)
    0 / 28 (0.00%)
    3 / 182 (1.65%)
    4 / 28 (14.29%)
    3 / 31 (9.68%)
    1 / 30 (3.33%)
         occurrences all number
    1
    1
    3
    2
    0
    8
    5
    3
    1
    Hyperglycaemia
         subjects affected / exposed
    3 / 10 (30.00%)
    0 / 10 (0.00%)
    5 / 20 (25.00%)
    4 / 165 (2.42%)
    6 / 28 (21.43%)
    10 / 182 (5.49%)
    2 / 28 (7.14%)
    7 / 31 (22.58%)
    7 / 30 (23.33%)
         occurrences all number
    3
    0
    8
    5
    10
    14
    3
    28
    9
    Hyperkalaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    2 / 165 (1.21%)
    0 / 28 (0.00%)
    2 / 182 (1.10%)
    1 / 28 (3.57%)
    2 / 31 (6.45%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    0
    5
    0
    2
    1
    2
    0
    Hyperlipasaemia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 165 (0.00%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    0
    0
    Hypernatraemia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    1 / 165 (0.61%)
    0 / 28 (0.00%)
    0 / 182 (0.00%)
    0 / 28 (0.00%)
    2 / 31 (6.45%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    2
    0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    2 / 20 (10.00%)
    0 / 165 (0.00%)
    1 / 28 (3.57%)
    2 / 182 (1.10%)
    0 / 28 (0.00%)
    2 / 31 (6.45%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    3
    0
    1
    2
    0
    2
    0
    Hyponatraemia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    2 / 20 (10.00%)
    1 / 165 (0.61%)
    2 / 28 (7.14%)
    4 / 182 (2.20%)
    2 / 28 (7.14%)
    5 / 31 (16.13%)
    5 / 30 (16.67%)
         occurrences all number
    0
    0
    4
    1
    3
    4
    3
    7
    5
    Hypomagnesaemia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    1 / 165 (0.61%)
    0 / 28 (0.00%)
    2 / 182 (1.10%)
    1 / 28 (3.57%)
    2 / 31 (6.45%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    2
    1
    2
    0
    Hypocalcaemia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
    1 / 165 (0.61%)
    1 / 28 (3.57%)
    1 / 182 (0.55%)
    1 / 28 (3.57%)
    3 / 31 (9.68%)
    1 / 30 (3.33%)
         occurrences all number
    1
    0
    2
    1
    2
    6
    1
    3
    1
    Hypokalaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    2 / 20 (10.00%)
    6 / 165 (3.64%)
    2 / 28 (7.14%)
    5 / 182 (2.75%)
    2 / 28 (7.14%)
    4 / 31 (12.90%)
    2 / 30 (6.67%)
         occurrences all number
    0
    1
    3
    10
    3
    42
    2
    7
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Dec 2013
    Adds 12-lead ECG at screening and as clinically indicated while on treatment; Clarifies guidance regarding corticosteroid use during the study; Includes guidance on the use of PPI or H2 blockers for patients on chronic steroids; Excludes patients with a history of gastrointestinal diverticulitis. Corrects inconsistencies in the statistical considerations section
    15 Jul 2014
    Updated title of protocol Added selection of dose and study design for Cohort 2:Since evaluation of a second dosing regimen for the combination therapy is on-going, the randomized portion of this study (Cohort 2) will be limited to nivolumab monotherapy versus bevacizumab randomized in a 1:1 ratio. Study design, rationale for dose selection, study hypothesis, study objectives, and statistical considerations updated accordingly. Added details for Cohort 1b (US sites only) Clarified inclusion that required a measurable lesion at baseline is limited to Cohort 1 and 1b; Clarified the interval of time after surgical resection to be 28days for inclusion; Clarified interval of time for baseline MRI to be 21 days instead of 28 days Clarified exclusion of active, known or suspected autoimmune disease
    27 Feb 2015
    Increase sample size of Cohort by 120 subjects to 340 Change from 2plannedinterim analyses to a single interim analysis at 80% of the total number of events Added clarification to allow collection of OS data outside the protocol specified windows
    15 Aug 2015
    Added Cogstate assessment to Cohort 2 Added clarification for allowing resection for assessment of progression/pseudoprogression. Added central neruopathic review of tumor samples obtained after biopsy or resection in subjects for whom determination of progression versus pseudoprogression cannot be determined Changed confirmation of progression to be 12 weeks rather than 8 weeks after initial radiologic progression for subjects who meet criteria for continuation of study treatment. Added table to summarize assessment of best overall response (BOR). Combined site specific amendment for Cohort1b into global protocol.

    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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