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    Clinical Trial Results:
    A Study to Evaluate the Safety and Efficacy of Nivolumab Monotherapy and Nivolumab in Combination With Ipilimumab in Pediatric Participants With High Grade Primary Central Nervous System (CNS) Malignancies (CheckMate 908)

    Summary
    EudraCT number
    2016-004441-82
    Trial protocol
    ES   GB   DE   SE   NO   NL   PL   Outside EU/EEA  
    Global end of trial date
    17 Jan 2022

    Results information
    Results version number
    v1(current)
    This version publication date
    30 Jul 2022
    First version publication date
    30 Jul 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CA209-908
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03130959
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Bristol-Myers Squibb
    Sponsor organisation address
    Chaussée de la Hulpe 185, Brussels, Belgium, 1170
    Public contact
    EU Study Start-Up Unit, Bristol-Myers Squibb International Corporation, Clinical.Trials@bms.com
    Scientific contact
    Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, Clinical.Trials@bms.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-001407-PIP02-15
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    10 Mar 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Jan 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To estimate the safety and tolerability of study treatment in pediatric participants with primary high-grade CNS tumors.
    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 subjects were followed.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    12 Jun 2017
    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: 12
    Country: Number of subjects enrolled
    Brazil: 20
    Country: Number of subjects enrolled
    Canada: 10
    Country: Number of subjects enrolled
    France: 27
    Country: Number of subjects enrolled
    Germany: 11
    Country: Number of subjects enrolled
    Hong Kong: 2
    Country: Number of subjects enrolled
    Israel: 2
    Country: Number of subjects enrolled
    Netherlands: 2
    Country: Number of subjects enrolled
    Norway: 3
    Country: Number of subjects enrolled
    Poland: 1
    Country: Number of subjects enrolled
    Russian Federation: 5
    Country: Number of subjects enrolled
    Spain: 19
    Country: Number of subjects enrolled
    Sweden: 2
    Country: Number of subjects enrolled
    United Kingdom: 13
    Country: Number of subjects enrolled
    United States: 37
    Worldwide total number of subjects
    166
    EEA total number of subjects
    65
    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)
    3
    Children (2-11 years)
    87
    Adolescents (12-17 years)
    61
    Adults (18-64 years)
    15
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    166 participants were treated

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Arm A1
    Arm description
    Module A: nivolumab 3 mg/kg every 2 weeks. Cohort 1: participants with newly-diagnosed DIPG, including midline glioma with H3K27M mutation.
    Arm type
    Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    3 mg/kg was administered as an IV infusion every 2 weeks

    Arm title
    Arm B1
    Arm description
    Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter. Cohort 1: participants with newly-diagnosed DIPG, including midline glioma with H3K27M mutation.
    Arm type
    Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    3 mg/kg was administered as an IV infusion every 3 weeks for 4 doses, then 3 mg/kg as an IV infusion every 2 weeks thereafter

    Investigational medicinal product name
    Ipilimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    1 mg/kg was administered as an IV infusion every 3 weeks for 4 doses

    Arm title
    Arm A2
    Arm description
    Module A: nivolumab 3 mg/kg every 2 weeks. Cohort 2: participants with recurrent or progressive non-brainstem HGG, regardless of mutation status, including glioblastoma.
    Arm type
    Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    3 mg/kg was administered as an IV infusion every 2 weeks

    Arm title
    Arm B2
    Arm description
    Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter. Cohort 2: participants with recurrent or progressive non-brainstem HGG, regardless of mutation status, including glioblastoma.
    Arm type
    Experimental

    Investigational medicinal product name
    Ipilimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    1 mg/kg was administered as an IV infusion every 3 weeks for 4 doses

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    3 mg/kg was administered as an IV infusion every 3 weeks for 4 doses, then 3 mg/kg as an IV infusion every 2 weeks thereafter

    Arm title
    Arm A3
    Arm description
    Module A: nivolumab 3 mg/kg every 2 weeks. Cohort 3: participants with relapsed or resistant medulloblastoma.
    Arm type
    Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    3 mg/kg was administered as an IV infusion every 2 weeks

    Arm title
    Arm B3
    Arm description
    Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter. Cohort 3: participants with relapsed or resistant medulloblastoma.
    Arm type
    Experimental

    Investigational medicinal product name
    Ipilimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    1 mg/kg was administered as an IV infusion every 3 weeks for 4 doses

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    3 mg/kg was administered as an IV infusion every 3 weeks for 4 doses, then 3 mg/kg as an IV infusion every 2 weeks thereafter

    Arm title
    Arm A4
    Arm description
    Module A: nivolumab 3 mg/kg every 2 weeks. Cohort 4: participants with relapsed or resistant ependymoma.
    Arm type
    Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    3 mg/kg was administered as an IV infusion every 2 weeks

    Arm title
    Arm B4
    Arm description
    Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter. Cohort 4: participants with relapsed or resistant ependymoma.
    Arm type
    Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    3 mg/kg was administered as an IV infusion every 3 weeks for 4 doses, then 3 mg/kg as an IV infusion every 2 weeks thereafter

    Investigational medicinal product name
    Ipilimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    1 mg/kg was administered as an IV infusion every 3 weeks for 4 doses

    Arm title
    Arm A5
    Arm description
    Module A: nivolumab 3 mg/kg every 2 weeks. Cohort 5: participants with other recurrent subtypes of high-grade CNS malignancy (eg, pineoblastoma, AT/RT, germ cell tumor, and others).
    Arm type
    Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    3 mg/kg was administered as an IV infusion every 2 weeks

    Arm title
    Arm B5
    Arm description
    Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter. Cohort 5: participants with other recurrent subtypes of high-grade CNS malignancy (eg, pineoblastoma, AT/RT, germ cell tumor, and others).
    Arm type
    Experimental

    Investigational medicinal product name
    Ipilimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    1 mg/kg was administered as an IV infusion every 3 weeks for 4 doses

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    3 mg/kg was administered as an IV infusion every 3 weeks for 4 doses, then 3 mg/kg as an IV infusion every 2 weeks thereafter

    Number of subjects in period 1
    Arm A1 Arm B1 Arm A2 Arm B2 Arm A3 Arm B3 Arm A4 Arm B4 Arm A5 Arm B5
    Started
    23
    22
    16
    15
    15
    15
    12
    10
    19
    19
    Completed
    0
    12
    0
    1
    0
    9
    0
    6
    0
    4
    Not completed
    23
    10
    16
    14
    15
    6
    12
    4
    19
    15
         Participant withdrew consent
    -
    1
    -
    2
    1
    -
    -
    -
    -
    2
         Not reported
    -
    -
    -
    1
    -
    1
    -
    -
    -
    1
         Adverse Event unrelated to drug
    -
    -
    1
    1
    1
    -
    1
    -
    1
    1
         Study drug toxicity
    2
    2
    1
    2
    1
    1
    3
    -
    3
    3
         Other reasons
    -
    -
    -
    -
    -
    1
    1
    -
    -
    -
         Administrative reason by sponsor
    1
    -
    1
    -
    -
    -
    -
    -
    -
    -
         Disease progression
    19
    7
    12
    7
    12
    3
    6
    3
    15
    8
         Subject request to discontinue therapy
    -
    -
    1
    1
    -
    -
    1
    1
    -
    -
         Lost to follow-up
    1
    -
    -
    -
    -
    -
    -
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A1
    Reporting group description
    Module A: nivolumab 3 mg/kg every 2 weeks. Cohort 1: participants with newly-diagnosed DIPG, including midline glioma with H3K27M mutation.

    Reporting group title
    Arm B1
    Reporting group description
    Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter. Cohort 1: participants with newly-diagnosed DIPG, including midline glioma with H3K27M mutation.

    Reporting group title
    Arm A2
    Reporting group description
    Module A: nivolumab 3 mg/kg every 2 weeks. Cohort 2: participants with recurrent or progressive non-brainstem HGG, regardless of mutation status, including glioblastoma.

    Reporting group title
    Arm B2
    Reporting group description
    Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter. Cohort 2: participants with recurrent or progressive non-brainstem HGG, regardless of mutation status, including glioblastoma.

    Reporting group title
    Arm A3
    Reporting group description
    Module A: nivolumab 3 mg/kg every 2 weeks. Cohort 3: participants with relapsed or resistant medulloblastoma.

    Reporting group title
    Arm B3
    Reporting group description
    Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter. Cohort 3: participants with relapsed or resistant medulloblastoma.

    Reporting group title
    Arm A4
    Reporting group description
    Module A: nivolumab 3 mg/kg every 2 weeks. Cohort 4: participants with relapsed or resistant ependymoma.

    Reporting group title
    Arm B4
    Reporting group description
    Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter. Cohort 4: participants with relapsed or resistant ependymoma.

    Reporting group title
    Arm A5
    Reporting group description
    Module A: nivolumab 3 mg/kg every 2 weeks. Cohort 5: participants with other recurrent subtypes of high-grade CNS malignancy (eg, pineoblastoma, AT/RT, germ cell tumor, and others).

    Reporting group title
    Arm B5
    Reporting group description
    Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter. Cohort 5: participants with other recurrent subtypes of high-grade CNS malignancy (eg, pineoblastoma, AT/RT, germ cell tumor, and others).

    Reporting group values
    Arm A1 Arm B1 Arm A2 Arm B2 Arm A3 Arm B3 Arm A4 Arm B4 Arm A5 Arm B5 Total
    Number of subjects
    23 22 16 15 15 15 12 10 19 19 166
    Age Categorical
    Units: Participants
        < 2 years old
    0 0 0 0 0 0 0 1 1 1 3
        >= 2 and < 12 years old
    15 16 6 5 4 4 8 4 13 12 87
        >= 12 and < 18 years old
    6 5 6 8 11 9 3 3 4 6 61
        >= 18 years old
    2 1 4 2 0 2 1 2 1 0 15
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    9.1 ± 5.1 9.4 ± 4.3 12.1 ± 5.8 12.6 ± 5.2 12.7 ± 3.5 12.7 ± 4.7 9.7 ± 5.1 11.2 ± 6.6 7.7 ± 6.2 8.3 ± 5.0 -
    Sex: Female, Male
    Units: Participants
        Female
    12 16 6 3 5 5 6 3 4 10 70
        Male
    11 6 10 12 10 10 6 7 15 9 96
    Race/Ethnicity, Customized
    Units: Subjects
        White
    19 11 13 14 14 14 7 9 18 13 132
        Black or African American
    2 4 0 0 0 1 1 0 1 0 9
        Asian
    0 2 1 1 0 0 3 1 0 2 10
        American Indian or Alaska Native
    0 1 0 0 0 0 0 0 0 0 1
        Native Hawaiian or Other Pacific Islander
    0 0 0 0 0 0 0 0 0 0 0
        Other
    2 4 2 0 1 0 1 0 0 4 14
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    2 3 2 2 0 1 1 1 2 0 14
        Not Hispanic or Latino
    7 10 4 5 6 4 5 5 8 6 60
        Unknown or Not Reported
    14 9 10 8 9 10 6 4 9 13 92

    End points

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    End points reporting groups
    Reporting group title
    Arm A1
    Reporting group description
    Module A: nivolumab 3 mg/kg every 2 weeks. Cohort 1: participants with newly-diagnosed DIPG, including midline glioma with H3K27M mutation.

    Reporting group title
    Arm B1
    Reporting group description
    Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter. Cohort 1: participants with newly-diagnosed DIPG, including midline glioma with H3K27M mutation.

    Reporting group title
    Arm A2
    Reporting group description
    Module A: nivolumab 3 mg/kg every 2 weeks. Cohort 2: participants with recurrent or progressive non-brainstem HGG, regardless of mutation status, including glioblastoma.

    Reporting group title
    Arm B2
    Reporting group description
    Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter. Cohort 2: participants with recurrent or progressive non-brainstem HGG, regardless of mutation status, including glioblastoma.

    Reporting group title
    Arm A3
    Reporting group description
    Module A: nivolumab 3 mg/kg every 2 weeks. Cohort 3: participants with relapsed or resistant medulloblastoma.

    Reporting group title
    Arm B3
    Reporting group description
    Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter. Cohort 3: participants with relapsed or resistant medulloblastoma.

    Reporting group title
    Arm A4
    Reporting group description
    Module A: nivolumab 3 mg/kg every 2 weeks. Cohort 4: participants with relapsed or resistant ependymoma.

    Reporting group title
    Arm B4
    Reporting group description
    Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter. Cohort 4: participants with relapsed or resistant ependymoma.

    Reporting group title
    Arm A5
    Reporting group description
    Module A: nivolumab 3 mg/kg every 2 weeks. Cohort 5: participants with other recurrent subtypes of high-grade CNS malignancy (eg, pineoblastoma, AT/RT, germ cell tumor, and others).

    Reporting group title
    Arm B5
    Reporting group description
    Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter. Cohort 5: participants with other recurrent subtypes of high-grade CNS malignancy (eg, pineoblastoma, AT/RT, germ cell tumor, and others).

    Subject analysis set title
    Arm A1, Safety Lead-in
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Module A, Cohort 1

    Subject analysis set title
    Arms A2-A5, Safety Lead-in
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Module A, Cohorts 2 through 5

    Subject analysis set title
    Arms B2-B5, Safety Lead-in
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Module B, Cohorts 2 through 5

    Primary: Number of Safety Lead-In Participants with Dose Limiting Toxicities (DLTs)

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    End point title
    Number of Safety Lead-In Participants with Dose Limiting Toxicities (DLTs) [1]
    End point description
    A dose-limiting toxicity (DLT) is defined as a drug-related AE occurring in the first 6 weeks of study treatment. A participant was considered evaluable for a DLT if study treatment was delayed > 2 weeks or was discontinued due to a related Adverse Event (AE), or if planned study treatment (3 doses of nivolumab in Module A, 2 doses of nivolumab plus ipilimumab in Module B) was administered and safety evaluation after 6 weeks on study is available to the study steering committee (SSC).
    End point type
    Primary
    End point timeframe
    up to 6 weeks post-dosing
    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: Only summary statistics planned for this endpoint.
    End point values
    Arm A1, Safety Lead-in Arms A2-A5, Safety Lead-in Arms B2-B5, Safety Lead-in
    Number of subjects analysed
    15
    10
    16
    Units: Number of participants
    0
    0
    0
    No statistical analyses for this end point

    Primary: Number of Safety Lead-In Participants with Serious Adverse Events (SAEs)

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    End point title
    Number of Safety Lead-In Participants with Serious Adverse Events (SAEs) [2]
    End point description
    The number of Safety Lead-In Participants who experienced a Serious Adverse Event (SAE) during the course of the study.
    End point type
    Primary
    End point timeframe
    up to 6 weeks post-dosing
    Notes
    [2] - 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: Only summary statistics planned for this endpoint.
    End point values
    Arm A1, Safety Lead-in Arms A2-A5, Safety Lead-in Arms B2-B5, Safety Lead-in
    Number of subjects analysed
    15
    10
    16
    Units: Number of participants
    7
    6
    8
    No statistical analyses for this end point

    Primary: Number of Safety Lead-In Participants with Adverse Events (AEs) Leading to Discontinuation

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    End point title
    Number of Safety Lead-In Participants with Adverse Events (AEs) Leading to Discontinuation [3]
    End point description
    The number of Safety Lead-In Participants who experienced an Adverse Event (AE) during the course of the study that lead to discontinuation of study therapy.
    End point type
    Primary
    End point timeframe
    up to 6 weeks post-dosing
    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: Only summary statistics planned for this endpoint.
    End point values
    Arm A1, Safety Lead-in Arms A2-A5, Safety Lead-in Arms B2-B5, Safety Lead-in
    Number of subjects analysed
    15
    10
    16
    Units: Number of participants
    3
    4
    2
    No statistical analyses for this end point

    Primary: Overall Survival (OS), Cohort 1 only

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    End point title
    Overall Survival (OS), Cohort 1 only [4] [5]
    End point description
    Overall survival (OS) is defined as the time between the date of diagnosis and the date of death in Cohort 1.
    End point type
    Primary
    End point timeframe
    up to approximately 42 months
    Notes
    [4] - 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: Only summary statistics planned for this endpoint.
    [5] - 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: Endpoints are cohort and/or safety lead-in specific and do not report for all arms.
    End point values
    Arm A1 Arm B1
    Number of subjects analysed
    23
    22
    Units: months
        median (confidence interval 80%)
    11.66 (10.32 to 16.46)
    10.78 (9.13 to 15.77)
    No statistical analyses for this end point

    Primary: Progression-Free Survival (PFS), Cohorts 2-4

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    End point title
    Progression-Free Survival (PFS), Cohorts 2-4 [6] [7]
    End point description
    Progression-free survival (PFS) is defined as the time from first dose to the date of the first documented tumor progression or death due to any cause.
    End point type
    Primary
    End point timeframe
    up to approximately 42 months
    Notes
    [6] - 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: Only summary statistics planned for this endpoint.
    [7] - 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: Endpoints are cohort and/or safety lead-in specific and do not report for all arms.
    End point values
    Arm A2 Arm B2 Arm A3 Arm B3 Arm A4 Arm B4
    Number of subjects analysed
    16
    15
    15
    15
    12
    10
    Units: months
        median (confidence interval 80%)
    1.74 (1.35 to 2.73)
    1.31 (1.18 to 1.45)
    1.38 (1.22 to 1.38)
    2.76 (1.48 to 4.53)
    1.41 (1.41 to 2.60)
    4.60 (1.41 to 5.39)
    No statistical analyses for this end point

    Primary: Progression-Free Survival (PFS), Cohort 5 only

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    End point title
    Progression-Free Survival (PFS), Cohort 5 only [8] [9]
    End point description
    Progression-free survival (PFS) is defined as the time from first dose to the date of the first documented tumor progression or death due to any cause.
    End point type
    Primary
    End point timeframe
    up to approximately 42 months
    Notes
    [8] - 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: Only summary statistics planned for this endpoint.
    [9] - 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: Endpoints are cohort and/or safety lead-in specific and do not report for all arms.
    End point values
    Arm A5 Arm B5
    Number of subjects analysed
    19
    19
    Units: months
        median (confidence interval 95%)
    1.22 (1.08 to 1.31)
    1.61 (1.31 to 3.45)
    No statistical analyses for this end point

    Secondary: Progression-Free Survival (PFS), Cohort 1 only

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    End point title
    Progression-Free Survival (PFS), Cohort 1 only [10]
    End point description
    Progression-free survival (PFS) is defined as the time from first dose to the date of the first documented tumor progression or death due to any cause. Progression is defined as: - ≥ 25% increase in sum of the products of perpendicular diameters of enhancing lesions compared with the smallest tumor measurement - Significant increase in T2 or fast fluid-attenuated inversion recovery (FLAIR) non-enhancing lesions on stable or increasing doses of corticosteroids - Any new lesion - Clear clinical deterioration not attributable to other causes apart from the tumor - Failure to return for evaluation as a result of death or deteriorating condition - Clear progression of non-measurable disease
    End point type
    Secondary
    End point timeframe
    From first dose to the date of the first documented tumor progression or death due to any cause (up to approximately 55 months)
    Notes
    [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: Endpoints are cohort and/or safety lead-in specific and do not report for all arms.
    End point values
    Arm A1 Arm B1
    Number of subjects analysed
    23
    22
    Units: Months
        median (confidence interval 95%)
    6.21 (3.75 to 6.54)
    4.53 (2.99 to 6.44)
    No statistical analyses for this end point

    Secondary: Overall Survival at 12 Months (OS12), Cohorts 1-4

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    End point title
    Overall Survival at 12 Months (OS12), Cohorts 1-4 [11]
    End point description
    Overall survival at 12 months (OS12) is defined as the percentage of participants who are alive at 12 months, measured as the survival rate at 12 months from Kaplan-Meier product limit cumulative probability.
    End point type
    Secondary
    End point timeframe
    From first dose to up to 12 months after first dose
    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: Endpoints are cohort and/or safety lead-in specific and do not report for all arms.
    End point values
    Arm A1 Arm B1 Arm A2 Arm B2 Arm A3 Arm B3 Arm A4 Arm B4
    Number of subjects analysed
    23
    22
    16
    15
    15
    15
    12
    10
    Units: Percentage of participants
        number (confidence interval 95%)
    47.3 (25.2 to 66.5)
    42.9 (21.9 to 62.3)
    37.5 (15.4 to 59.8)
    32.8 (10.5 to 57.6)
    38.9 (14.3 to 63.2)
    86.7 (56.4 to 96.5)
    41.7 (15.2 to 66.5)
    44.4 (13.6 to 71.9)
    No statistical analyses for this end point

    Secondary: Progression-Free Survival at 6 Months (PFS6), Cohorts 2-5

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    End point title
    Progression-Free Survival at 6 Months (PFS6), Cohorts 2-5 [12]
    End point description
    Progression-free survival at 6 months (PFS6) is defined as the percentage of participants who are progression free and alive at 6 months following first dose date, measured as the survival rate at 6 months from Kaplan-Meier product limit cumulative probability of progression free. Progression is defined as: - ≥ 25% increase in sum of the products of perpendicular diameters of enhancing lesions compared with the smallest tumor measurement - Significant increase in T2 or fast fluid-attenuated inversion recovery (FLAIR) non-enhancing lesions on stable or increasing doses of corticosteroids - Any new lesion - Clear clinical deterioration not attributable to other causes apart from the tumor - Failure to return for evaluation as a result of death or deteriorating condition - Clear progression of non-measurable disease 99999 = NA
    End point type
    Secondary
    End point timeframe
    From first dose to up to 6 months after first dose
    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: Endpoints are cohort and/or safety lead-in specific and do not report for all arms.
    End point values
    Arm A2 Arm B2 Arm A3 Arm B3 Arm A4 Arm B4 Arm A5 Arm B5
    Number of subjects analysed
    16
    15
    15
    15
    12
    10
    19
    19
    Units: Percentage of participants
        number (confidence interval 95%)
    9.4 (0.7 to 31.8)
    14.3 (2.3 to 36.6)
    0 (-99999 to 99999)
    20.0 (4.9 to 42.4)
    20.0 (3.1 to 47.5)
    11.4 (0.6 to 39.5)
    5.3 (0.4 to 21.4)
    14.0 (2.8 to 34.1)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS), Cohorts 2-5

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    End point title
    Overall Survival (OS), Cohorts 2-5 [13]
    End point description
    Overall survival (OS) is defined as the time between date of first dose and the date of death for Cohorts 2-5. 99999 = NA
    End point type
    Secondary
    End point timeframe
    From first dose to the date of death (up to approximately 55 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: Endpoints are cohort and/or safety lead-in specific and do not report for all arms.
    End point values
    Arm A2 Arm B2 Arm A3 Arm B3 Arm A4 Arm B4 Arm A5 Arm B5
    Number of subjects analysed
    16
    15
    15
    15
    12
    10
    19
    19
    Units: Months
        median (confidence interval 95%)
    6.67 (2.99 to 14.62)
    6.47 (2.14 to 13.17)
    7.36 (2.46 to 30.23)
    22.21 (13.77 to 9999)
    5.70 (1.81 to 99999)
    9.82 (2.50 to 99999)
    5.91 (1.97 to 7.98)
    8.48 (3.45 to 17.28)
    No statistical analyses for this end point

    Secondary: Number of Treated Participants with Adverse Events (AEs)

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    End point title
    Number of Treated Participants with Adverse Events (AEs)
    End point description
    The number of treated participants who experienced an Adverse Event (AE) during the course of the study. An AE is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation participant administered study drug and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug.
    End point type
    Secondary
    End point timeframe
    From first dose to 30 days post-last dose (up to approximately an average of 3 months and a maximum of 51 months)
    End point values
    Arm A1 Arm B1 Arm A2 Arm B2 Arm A3 Arm B3 Arm A4 Arm B4 Arm A5 Arm B5
    Number of subjects analysed
    23
    22
    16
    15
    15
    15
    12
    10
    19
    19
    Units: Participants
    23
    21
    15
    14
    14
    15
    12
    10
    18
    18
    No statistical analyses for this end point

    Secondary: Number of Treated Participants with Serious Adverse Events (SAEs)

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    End point title
    Number of Treated Participants with Serious Adverse Events (SAEs)
    End point description
    The number of treated participants who experienced a Serious Adverse Event (SAE) during the course of the study. SAE is defined as any untoward medical occurrence that, at any dose: - Results in death - Is life-threatening - Requires inpatient hospitalization or causes prolongation of existing hospitalization - Results in persistent or significant disability/incapacity - Is a congenital anomaly/birth defect - Is an important medical event Note: The reporting timeframe of the SAEs for this Outcome Measure (first dose to 30 days post last dose) differs than that of the reporting timeframe of the SAEs reported under the AE section of the results form (first dose to 100 days post last dose) and thus, the data in each table of SAEs reflects the specific timeframe applied.
    End point type
    Secondary
    End point timeframe
    From first dose to 30 days post-last dose (up to approximately an average of 3 months and a maximum of 51 months)
    End point values
    Arm A1 Arm B1 Arm A2 Arm B2 Arm A3 Arm B3 Arm A4 Arm B4 Arm A5 Arm B5
    Number of subjects analysed
    23
    22
    16
    15
    15
    15
    12
    10
    19
    19
    Units: Participants
    10
    14
    10
    9
    6
    7
    7
    5
    13
    14
    No statistical analyses for this end point

    Secondary: Number of Treated Participants with Drug-Related Adverse Events

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    End point title
    Number of Treated Participants with Drug-Related Adverse Events
    End point description
    The number of treated participants who experienced a Drug-Related Adverse Event during the course of the study. An AE is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation participant administered study drug and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug.
    End point type
    Secondary
    End point timeframe
    From first dose to 30 days post-last dose (up to approximately an average of 3 months and a maximum of 51 months)
    End point values
    Arm A1 Arm B1 Arm A2 Arm B2 Arm A3 Arm B3 Arm A4 Arm B4 Arm A5 Arm B5
    Number of subjects analysed
    23
    22
    16
    15
    15
    15
    12
    10
    19
    19
    Units: Participants
    14
    16
    12
    8
    6
    11
    6
    6
    11
    10
    No statistical analyses for this end point

    Secondary: Number of Treated Participants with Adverse Events Leading to Discontinuation

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    End point title
    Number of Treated Participants with Adverse Events Leading to Discontinuation
    End point description
    The number of treated participants who experienced an Adverse Event leading to discontinuation during the course of the study. An AE is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation participant administered study drug and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug.
    End point type
    Secondary
    End point timeframe
    From first dose to 30 days post-last dose (up to approximately an average of 3 months and a maximum of 51 months)
    End point values
    Arm A1 Arm B1 Arm A2 Arm B2 Arm A3 Arm B3 Arm A4 Arm B4 Arm A5 Arm B5
    Number of subjects analysed
    23
    22
    16
    15
    15
    15
    12
    10
    19
    19
    Units: Participants
    4
    7
    3
    5
    2
    3
    6
    1
    6
    8
    No statistical analyses for this end point

    Secondary: Number of Treated Participant Deaths

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    End point title
    Number of Treated Participant Deaths
    End point description
    The number of treated participants who died during the course of the study.
    End point type
    Secondary
    End point timeframe
    From first dose to the date of death (up to approximately 55 months)
    End point values
    Arm A1 Arm B1 Arm A2 Arm B2 Arm A3 Arm B3 Arm A4 Arm B4 Arm A5 Arm B5
    Number of subjects analysed
    23
    22
    16
    15
    15
    15
    12
    10
    19
    19
    Units: Participants
    18
    18
    12
    13
    12
    11
    9
    7
    18
    15
    No statistical analyses for this end point

    Secondary: Number of Treated Participant with Laboratory Abnormalities - Liver

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    End point title
    Number of Treated Participant with Laboratory Abnormalities - Liver
    End point description
    The number of treated participants who experienced a laboratory abnormality of the liver during the course of the study. Aspartate aminotransferase (AST) Alanine aminotransferase (ALT) Upper Limit of Normal (ULN) Units per Liter (U/L) Results reported in International System of Units (SI)
    End point type
    Secondary
    End point timeframe
    From first dose to 30 days post-last dose (up to approximately an average of 3 months and a maximum of 51 months)
    End point values
    Arm A1 Arm B1 Arm A2 Arm B2 Arm A3 Arm B3 Arm A4 Arm B4 Arm A5 Arm B5
    Number of subjects analysed
    23
    21
    16
    12
    13
    14
    11
    10
    19
    18
    Units: Participants
        ALT OR AST > 3XULN
    3
    7
    2
    0
    0
    3
    1
    1
    3
    2
        ALT OR AST > 5XULN
    2
    4
    1
    0
    0
    1
    0
    1
    2
    2
        ALT OR AST > 10XULN
    2
    1
    1
    0
    0
    1
    0
    1
    2
    2
        ALT OR AST > 20XULN
    0
    1
    1
    0
    0
    0
    0
    0
    0
    2
        TOTAL BILIRUBIN > 2XULN
    0
    2
    0
    0
    0
    0
    0
    0
    1
    1
        ALP > 1.5XULN
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
        ALT or AST>3xULN w/ Tbili>1.5*ULN within 1 day
    0
    1
    1
    0
    0
    0
    0
    0
    0
    1
        ALT or AST>3xULN w/ Tbili>1.5*ULN within 30 days
    0
    2
    1
    0
    0
    0
    0
    0
    0
    1
        ALT or AST>3xULN w/ Tbili>2*ULN within 1 day
    0
    1
    0
    0
    0
    0
    0
    0
    0
    1
        ALT or AST>3xULN w/ Tbili>2*ULN within 30 days
    0
    2
    0
    0
    0
    0
    0
    0
    0
    1
    No statistical analyses for this end point

    Secondary: Number of Treated Participant with Laboratory Abnormalities - Thyroid

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    End point title
    Number of Treated Participant with Laboratory Abnormalities - Thyroid
    End point description
    The number of treated participants who experienced a laboratory abnormality of the thyroid during the course of the study. Free T3 (FT3) Free T4 (FT4) Thyroid stimulating hormone (TSH) Lower Limit of Normal (LLN) Upper limit of normal (ULN) Milliunits per Liter (mlU/L) Results reported in International System of Units (SI)
    End point type
    Secondary
    End point timeframe
    From first dose to 30 days post-last dose (up to approximately an average of 3 months and a maximum of 51 months)
    End point values
    Arm A1 Arm B1 Arm A2 Arm B2 Arm A3 Arm B3 Arm A4 Arm B4 Arm A5 Arm B5
    Number of subjects analysed
    20
    20
    10
    8
    8
    13
    9
    8
    11
    14
    Units: Participants
        TSH > ULN
    2
    1
    3
    1
    3
    7
    2
    3
    1
    5
        TSH > ULN, WITH TSH <= ULN AT BASELINE
    2
    1
    2
    1
    0
    7
    1
    3
    1
    2
        TSH > ULN, WITH AT LEAST ONE FT3/FT4 TEST < LLN
    1
    1
    1
    1
    1
    6
    2
    2
    0
    2
        TSH > ULN, WITH ALL OTHER FT3/FT4 TEST >= LLN
    0
    0
    1
    0
    0
    0
    0
    0
    1
    3
        TSH > ULN, WITH FT3/FT4 TEST MISSING
    1
    0
    1
    0
    2
    1
    0
    1
    0
    0
        TSH < LLN
    3
    7
    2
    2
    0
    3
    0
    0
    0
    1
        TSH < LLN, WITH TSH >= LLN AT BASELINE
    3
    6
    1
    2
    0
    1
    0
    0
    0
    1
        TSH<LLN, LLN WITH AT LEAST ONE FT3/FT4 TEST>ULN
    0
    1
    0
    0
    0
    2
    0
    0
    0
    0
        TSH < LLN, WITH ALL OTHER FT3/FT4 TEST <= ULN
    1
    2
    1
    2
    0
    1
    0
    0
    0
    1
        TSH < LLN, WITH FT3/FT4 TEST MISSING
    2
    4
    1
    0
    0
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Post-hoc: Overall Survival (OS), Cohort 1 only - Extended Collection

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    End point title
    Overall Survival (OS), Cohort 1 only - Extended Collection [14]
    End point description
    Overall survival (OS) is defined as the time between the date of diagnosis and the date of death in Cohort 1. Note: This outcome measure represents an updated version of the primary endpoint to include additional data collection that has occurred after the primary completion date. (Assessments were made until 17-Jan-2022).
    End point type
    Post-hoc
    End point timeframe
    From first dose to the date of death (up to approximately 55 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: Endpoints are cohort and/or safety lead-in specific and do not report for all arms.
    End point values
    Arm A1 Arm B1
    Number of subjects analysed
    23
    22
    Units: Months
        median (confidence interval 80%)
    11.66 (10.32 to 23.49)
    10.78 (9.13 to 15.77)
    No statistical analyses for this end point

    Post-hoc: Progression-Free Survival (PFS), Cohorts 2-4 - Extended Collection

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    End point title
    Progression-Free Survival (PFS), Cohorts 2-4 - Extended Collection [15]
    End point description
    Progression-free survival (PFS) is defined as the time from first dose to the date of the first documented tumor progression or death due to any cause. Note: This outcome measure represents an updated version of the primary endpoint to include additional data collection that has occurred after the primary completion date. (Assessments were made until 17-Jan-2022). Progression is defined as: - ≥ 25% increase in sum of the products of perpendicular diameters of enhancing lesions compared with the smallest tumor measurement - Significant increase in T2 or fast fluid-attenuated inversion recovery (FLAIR) non-enhancing lesions on stable or increasing doses of corticosteroids - Any new lesion - Clear clinical deterioration not attributable to other causes apart from the tumor - Failure to return for evaluation as a result of death or deteriorating condition - Clear progression of non-measurable disease
    End point type
    Post-hoc
    End point timeframe
    From first dose to the date of the first documented tumor progression or death due to any cause (up to approximately 55 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: Endpoints are cohort and/or safety lead-in specific and do not report for all arms.
    End point values
    Arm A2 Arm B2 Arm A3 Arm B3 Arm A4 Arm B4
    Number of subjects analysed
    16
    15
    15
    15
    12
    10
    Units: Months
        median (confidence interval 80%)
    1.74 (1.35 to 2.73)
    1.38 (1.22 to 1.48)
    1.38 (1.22 to 1.38)
    2.69 (1.48 to 4.53)
    1.41 (1.38 to 2.60)
    4.60 (1.41 to 5.39)
    No statistical analyses for this end point

    Post-hoc: Progression-Free Survival (PFS), Cohort 5 only - Extended Collection

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    End point title
    Progression-Free Survival (PFS), Cohort 5 only - Extended Collection [16]
    End point description
    Progression-free survival (PFS) is defined as the time from first dose to the date of the first documented tumor progression or death due to any cause. Note: This outcome measure represents an updated version of the primary endpoint to include additional data collection that has occurred after the primary completion date. (Assessments were made until 17-Jan-2022). Progression is defined as: - ≥ 25% increase in sum of the products of perpendicular diameters of enhancing lesions compared with the smallest tumor measurement - Significant increase in T2 or fast fluid-attenuated inversion recovery (FLAIR) non-enhancing lesions on stable or increasing doses of corticosteroids - Any new lesion - Clear clinical deterioration not attributable to other causes apart from the tumor - Failure to return for evaluation as a result of death or deteriorating condition - Clear progression of non-measurable disease
    End point type
    Post-hoc
    End point timeframe
    From first dose to the date of the first documented tumor progression or death due to any cause (up to approximately 55 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: Endpoints are cohort and/or safety lead-in specific and do not report for all arms.
    End point values
    Arm A5 Arm B5
    Number of subjects analysed
    19
    19
    Units: Months
        median (confidence interval 95%)
    1.22 (1.08 to 1.31)
    1.61 (1.31 to 3.45)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All-cause mortality was assessed from first dose to study completion (up to approximately 55 months). SAEs and Other AEs were monitored from first dose to 100 days after last dose (up to an average of 5 months and to a maximum of 53 months).
    Adverse event reporting additional description
    Note: The reporting timeframe of the below SAEs (first dose to 100 days post last dose) differs than that of the reporting timeframe of the SAEs reported under the Outcome Measures section of the results form (first dose to 30 days post last dose) and thus, the data in each table of SAEs reflects the specific timeframe applied.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    24.1
    Reporting groups
    Reporting group title
    Arm A1
    Reporting group description
    Module A: nivolumab 3 mg/kg every 2 weeks. Cohort 1: participants with newly-diagnosed DIPG, including midline glioma with H3K27M mutation.

    Reporting group title
    Arm B1
    Reporting group description
    Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter. Cohort 1: participants with newly-diagnosed DIPG, including midline glioma with H3K27M mutation.

    Reporting group title
    Arm A2
    Reporting group description
    Module A: nivolumab 3 mg/kg every 2 weeks. Cohort 2: participants with recurrent or progressive non-brainstem HGG, regardless of mutation status, including glioblastoma.

    Reporting group title
    Arm B2
    Reporting group description
    Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter. Cohort 2: participants with recurrent or progressive non-brainstem HGG, regardless of mutation status, including glioblastoma.

    Reporting group title
    Arm A3
    Reporting group description
    Module A: nivolumab 3 mg/kg every 2 weeks. Cohort 3: participants with relapsed or resistant medulloblastoma.

    Reporting group title
    Arm B3
    Reporting group description
    Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter. Cohort 3: participants with relapsed or resistant medulloblastoma.

    Reporting group title
    Arm A4
    Reporting group description
    Module A: nivolumab 3 mg/kg every 2 weeks. Cohort 4: participants with relapsed or resistant ependymoma.

    Reporting group title
    Arm B4
    Reporting group description
    Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter. Cohort 4: participants with relapsed or resistant ependymoma.

    Reporting group title
    Arm A5
    Reporting group description
    Module A: nivolumab 3 mg/kg every 2 weeks. Cohort 5: participants with other recurrent subtypes of high-grade CNS malignancy (eg, pineoblastoma, AT/RT, germ cell tumor, and others).

    Reporting group title
    Arm B5
    Reporting group description
    Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter. Cohort 5: participants with other recurrent subtypes of high-grade CNS malignancy (eg, pineoblastoma, AT/RT, germ cell tumor, and others).

    Serious adverse events
    Arm A1 Arm B1 Arm A2 Arm B2 Arm A3 Arm B3 Arm A4 Arm B4 Arm A5 Arm B5
    Total subjects affected by serious adverse events
         subjects affected / exposed
    17 / 23 (73.91%)
    16 / 22 (72.73%)
    13 / 16 (81.25%)
    12 / 15 (80.00%)
    7 / 15 (46.67%)
    10 / 15 (66.67%)
    11 / 12 (91.67%)
    6 / 10 (60.00%)
    14 / 19 (73.68%)
    15 / 19 (78.95%)
         number of deaths (all causes)
    18
    18
    12
    13
    12
    11
    9
    7
    18
    15
         number of deaths resulting from adverse events
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (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
    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
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (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
    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
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant neoplasm progression
         subjects affected / exposed
    9 / 23 (39.13%)
    7 / 22 (31.82%)
    6 / 16 (37.50%)
    5 / 15 (33.33%)
    6 / 15 (40.00%)
    2 / 15 (13.33%)
    7 / 12 (58.33%)
    5 / 10 (50.00%)
    7 / 19 (36.84%)
    7 / 19 (36.84%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 7
    0 / 6
    0 / 8
    0 / 7
    0 / 3
    0 / 8
    0 / 5
    0 / 9
    0 / 7
         deaths causally related to treatment / all
    0 / 8
    0 / 6
    0 / 6
    0 / 3
    0 / 6
    0 / 0
    0 / 6
    0 / 5
    0 / 7
    0 / 6
    Neoplasm
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Neoplasm progression
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    1 / 10 (10.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    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 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Schwannoma
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (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
    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
    0 / 0
    Tumour flare
         subjects affected / exposed
    1 / 23 (4.35%)
    3 / 22 (13.64%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
    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
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (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
    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
    0 / 0
    Immune system disorders
    Haemophagocytic lymphohistiocytosis
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (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
    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
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Immune-mediated adverse reaction
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (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
    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
    0 / 0
    Multisystem inflammatory syndrome in children
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (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
    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
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (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
    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
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (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
    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
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    1 / 16 (6.25%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    2 / 10 (20.00%)
    1 / 19 (5.26%)
    2 / 19 (10.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    0 / 0
    0 / 0
    1 / 1
    0 / 3
    1 / 1
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (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
    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
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Injury, poisoning and procedural complications
    Brain herniation
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (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
    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
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 19 (0.00%)
    0 / 19 (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
    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
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    1 / 19 (5.26%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (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
    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
    0 / 0
    Shunt malfunction
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 19 (0.00%)
    0 / 19 (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
    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
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 22 (4.55%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 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
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 22 (4.55%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (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
    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
    0 / 0
    Chest X-ray abnormal
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 22 (4.55%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (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
    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
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    1 / 1
    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
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    1 / 19 (5.26%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Aspiration
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 22 (4.55%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (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
    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
    0 / 0
    Bronchospasm
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 22 (4.55%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (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
    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
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 2
    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
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (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
    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
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 22 (4.55%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (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
    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
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (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
    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
    0 / 0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (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
    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
    0 / 0
    Dysarthria
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 22 (4.55%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (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
    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
    0 / 0
    Dyskinesia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Facial nerve disorder
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (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
    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
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    1 / 19 (5.26%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 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
    0 / 0
    Headache
         subjects affected / exposed
    1 / 23 (4.35%)
    2 / 22 (9.09%)
    0 / 16 (0.00%)
    2 / 15 (13.33%)
    1 / 15 (6.67%)
    1 / 15 (6.67%)
    1 / 12 (8.33%)
    2 / 10 (20.00%)
    1 / 19 (5.26%)
    2 / 19 (10.53%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    1 / 3
    0 / 1
    0 / 1
    0 / 1
    0 / 3
    0 / 2
    1 / 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
    0 / 0
    Hemiparesis
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    1 / 19 (5.26%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    0 / 23 (0.00%)
    4 / 22 (18.18%)
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    3 / 12 (25.00%)
    2 / 10 (20.00%)
    1 / 19 (5.26%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 7
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 3
    0 / 2
    0 / 1
    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
    0 / 0
    Intracranial pressure increased
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    1 / 16 (6.25%)
    1 / 15 (6.67%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    2 / 19 (10.53%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lethargy
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Motor dysfunction
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (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
    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
    0 / 0
    Myoclonus
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 22 (4.55%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (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
    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
    0 / 0
    Nervous system disorder
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 19 (0.00%)
    0 / 19 (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
    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
    0 / 0
    Neurological decompensation
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (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
    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
    0 / 0
    Paraesthesia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    1 / 19 (5.26%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Partial seizures
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (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
    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
    0 / 0
    Peripheral motor neuropathy
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    1 / 19 (5.26%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    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
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 22 (4.55%)
    1 / 16 (6.25%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    1 / 19 (5.26%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    1 / 2
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    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
    0 / 0
    Somnolence
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 22 (4.55%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    Status epilepticus
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Eye disorders
    Vision blurred
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (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
    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
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (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
    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
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 22 (4.55%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    2 / 15 (13.33%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    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
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (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
    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
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 23 (0.00%)
    2 / 22 (9.09%)
    1 / 16 (6.25%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    1 / 1
    1 / 1
    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
    0 / 0
    Enterocolitis
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (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
    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
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (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
    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
    0 / 0
    Immune-mediated enterocolitis
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    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
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    2 / 12 (16.67%)
    1 / 10 (10.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 1
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 23 (0.00%)
    3 / 22 (13.64%)
    1 / 16 (6.25%)
    2 / 15 (13.33%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    2 / 12 (16.67%)
    1 / 10 (10.00%)
    1 / 19 (5.26%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 1
    1 / 3
    0 / 0
    0 / 1
    0 / 2
    0 / 1
    0 / 2
    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
    0 / 0
    Renal and urinary disorders
    Bladder dysfunction
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (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
    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
    0 / 0
    Urinary incontinence
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (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
    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
    0 / 0
    Hepatobiliary disorders
    Autoimmune hepatitis
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    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
    0 / 0
    Hepatitis
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    1 / 19 (5.26%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    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
    0 / 0
    Hepatitis acute
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (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
    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
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    1 / 19 (5.26%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    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
    0 / 0
    Toxic skin eruption
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Musculoskeletal and connective tissue disorders
    Mobility decreased
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Muscular weakness
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (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
    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
    0 / 0
    Spinal deformity
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (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
    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
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 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
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (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
    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
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (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
    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
    0 / 0
    Hypophagia
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (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
    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
    0 / 0
    Steroid diabetes
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (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
    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
    0 / 0
    Infections and infestations
    Bacterial infection
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (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
    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
    0 / 0
    Coronavirus infection
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 22 (4.55%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (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
    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
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    1 / 19 (5.26%)
    2 / 19 (10.53%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Diarrhoea infectious
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 22 (4.55%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (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
    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
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (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
    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
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    1 / 19 (5.26%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Measles
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (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
    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
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (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
    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
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (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
    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
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (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
    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
    0 / 0
    Tonsillitis
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (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
    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
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    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
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (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
    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
    0 / 0
    Vascular device infection
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Wound infection staphylococcal
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Arm A1 Arm B1 Arm A2 Arm B2 Arm A3 Arm B3 Arm A4 Arm B4 Arm A5 Arm B5
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    22 / 23 (95.65%)
    21 / 22 (95.45%)
    15 / 16 (93.75%)
    14 / 15 (93.33%)
    14 / 15 (93.33%)
    14 / 15 (93.33%)
    11 / 12 (91.67%)
    10 / 10 (100.00%)
    18 / 19 (94.74%)
    18 / 19 (94.74%)
    Vascular disorders
    Bloody discharge
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Embolism
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Extremity necrosis
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    1 / 19 (5.26%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Flushing
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    0
    0
    0
    Hypertension
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 22 (4.55%)
    0 / 16 (0.00%)
    3 / 15 (20.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    2 / 19 (10.53%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    3
    0
    0
    0
    0
    2
    0
    Hypotension
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    1 / 19 (5.26%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    1
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant neoplasm progression
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 22 (4.55%)
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    1 / 19 (5.26%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1
    1
    0
    0
    0
    0
    1
    1
    1
    Melanocytic naevus
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Myelodysplastic syndrome
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 22 (4.55%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    2 / 10 (20.00%)
    0 / 19 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    2
    1
    0
    0
    0
    0
    1
    2
    0
    1
    Drug hypersensitivity
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Infusion related hypersensitivity reaction
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 22 (4.55%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    0
    0
    Seasonal allergy
         subjects affected / exposed
    0 / 23 (0.00%)
    2 / 22 (9.09%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    1
    0
    0
    0
    0
    General disorders and administration site conditions
    Application site pruritus
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Asthenia
         subjects affected / exposed
    3 / 23 (13.04%)
    0 / 22 (0.00%)
    2 / 16 (12.50%)
    3 / 15 (20.00%)
    0 / 15 (0.00%)
    3 / 15 (20.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    3
    0
    2
    3
    0
    4
    0
    0
    0
    0
    Chills
         subjects affected / exposed
    0 / 23 (0.00%)
    2 / 22 (9.09%)
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    2
    1
    0
    0
    0
    0
    0
    0
    0
    Device related thrombosis
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Facial pain
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Fatigue
         subjects affected / exposed
    8 / 23 (34.78%)
    6 / 22 (27.27%)
    4 / 16 (25.00%)
    3 / 15 (20.00%)
    2 / 15 (13.33%)
    4 / 15 (26.67%)
    2 / 12 (16.67%)
    1 / 10 (10.00%)
    5 / 19 (26.32%)
    4 / 19 (21.05%)
         occurrences all number
    10
    6
    5
    3
    2
    6
    3
    1
    6
    6
    Gait disturbance
         subjects affected / exposed
    4 / 23 (17.39%)
    1 / 22 (4.55%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    1 / 15 (6.67%)
    1 / 15 (6.67%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    2 / 19 (10.53%)
    1 / 19 (5.26%)
         occurrences all number
    4
    1
    0
    1
    1
    1
    1
    0
    2
    1
    General physical health deterioration
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    1 / 19 (5.26%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    1
    Generalised oedema
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Hypothermia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    1 / 19 (5.26%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    2
    0
    Influenza like illness
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    1 / 19 (5.26%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    1
    1
    Mucosal inflammation
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 22 (4.55%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    0
    0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 22 (4.55%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    1
    0
    0
    1
    1
    0
    1
    0
    0
    Oedema peripheral
         subjects affected / exposed
    0 / 23 (0.00%)
    2 / 22 (9.09%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    2 / 15 (13.33%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    2
    0
    0
    1
    2
    1
    0
    0
    0
    Pain
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 22 (4.55%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    4 / 19 (21.05%)
    2 / 19 (10.53%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    1
    0
    4
    2
    Pyrexia
         subjects affected / exposed
    5 / 23 (21.74%)
    6 / 22 (27.27%)
    2 / 16 (12.50%)
    4 / 15 (26.67%)
    1 / 15 (6.67%)
    2 / 15 (13.33%)
    3 / 12 (25.00%)
    2 / 10 (20.00%)
    2 / 19 (10.53%)
    5 / 19 (26.32%)
         occurrences all number
    7
    14
    3
    6
    3
    3
    5
    3
    3
    7
    Sensation of foreign body
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Xerosis
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
    2 / 16 (12.50%)
    1 / 15 (6.67%)
    2 / 15 (13.33%)
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    2
    1
    2
    0
    1
    0
    0
    1
    Behaviour disorder
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Confusional state
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
    1 / 16 (6.25%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    2 / 10 (20.00%)
    1 / 19 (5.26%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    1
    0
    0
    1
    2
    1
    1
    Depression
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    1 / 19 (5.26%)
    0 / 19 (0.00%)
         occurrences all number
    2
    0
    0
    0
    1
    0
    0
    0
    1
    0
    Dysphemia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    1 / 19 (5.26%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Insomnia
         subjects affected / exposed
    4 / 23 (17.39%)
    2 / 22 (9.09%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    1 / 19 (5.26%)
    1 / 19 (5.26%)
         occurrences all number
    4
    2
    0
    1
    0
    1
    0
    0
    1
    1
    Irritability
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    1 / 19 (5.26%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    1
    0
    1
    1
    Mood swings
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Phonophobia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    0
    0
    Restlessness
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Sleep disorder
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    1
    Suicidal ideation
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    1 / 19 (5.26%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Reproductive system and breast disorders
    Testicular pain
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Vaginal haemorrhage
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 22 (4.55%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    1 / 19 (5.26%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    1
    0
    Contusion
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Facial bones fracture
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Fall
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    3
    0
    1
    0
    0
    0
    0
    0
    0
    2
    Fracture
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Head injury
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    1 / 19 (5.26%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Infusion related reaction
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Mouth injury
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Procedural pain
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    1 / 19 (5.26%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    0
    1
    0
    Shunt malfunction
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Skin abrasion
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    0
    0
    0
    0
    Stoma site discharge
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Vascular access complication
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    3
    0
    0
    0
    2
    0
    0
    0
    0
    0
    Tongue injury
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Vascular access site discharge
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Vascular access site rash
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 22 (4.55%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    1
    Vascular access site pain
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    1 / 19 (5.26%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Wound
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 22 (4.55%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    1
    0
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 23 (8.70%)
    6 / 22 (27.27%)
    2 / 16 (12.50%)
    3 / 15 (20.00%)
    2 / 15 (13.33%)
    4 / 15 (26.67%)
    1 / 12 (8.33%)
    1 / 10 (10.00%)
    4 / 19 (21.05%)
    1 / 19 (5.26%)
         occurrences all number
    4
    7
    2
    5
    2
    5
    1
    1
    6
    1
    Amylase increased
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Anion gap increased
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    1 / 16 (6.25%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    2
    1
    0
    0
    1
    0
    0
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 23 (8.70%)
    4 / 22 (18.18%)
    2 / 16 (12.50%)
    2 / 15 (13.33%)
    1 / 15 (6.67%)
    5 / 15 (33.33%)
    1 / 12 (8.33%)
    1 / 10 (10.00%)
    4 / 19 (21.05%)
    1 / 19 (5.26%)
         occurrences all number
    5
    5
    2
    2
    1
    7
    1
    2
    7
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    1
    0
    0
    Blood bicarbonate increased
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Blood chloride decreased
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 19 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Blood creatine increased