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    Clinical Trial Results:
    A Phase I/II, Multicenter, Open-Label, Dose-Escalation Study of the Safety and Pharmacokinetics of Cobimetinib In Pediatric and Young Adult Patients with Previously Treated Solid Tumors

    Summary
    EudraCT number
    		 2014-004685-25
    Trial protocol
    		 NL   IE   DK   GB   DE   ES   IT   FR  
    Global end of trial date
    21 Jul 2021

    Results information
    Results version number
    		 v1
    This version publication date
    05 Feb 2022
    First version publication date
    05 Feb 2022
    Other versions
    		 v2

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    GO29665
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02639546
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH4070
    Public contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001425-PIP01-13
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    21 Jul 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Jul 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the Safety and Pharmacokinetics of Cobimetinib
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    20 May 2016
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy
    Long term follow-up duration
    		 5 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 15
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    Israel: 7
    Country: Number of subjects enrolled
    Italy: 1
    Country: Number of subjects enrolled
    Spain: 6
    Country: Number of subjects enrolled
    United Kingdom: 10
    Country: Number of subjects enrolled
    United States: 14
    Worldwide total number of subjects
    56
    EEA total number of subjects
    25
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    41
    Adolescents (12-17 years)
    14
    Adults (18-64 years)
    1
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 17 centers in 7 countries.

    Pre-assignment
    Screening details
    		 A total of 63 participants were screened, of which a total of 56 participants were enrolled.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Phase I (Tablet) Cobimetinib (0.6 mg/kg)
    Arm description
    		 Dose-Escalation: Participants received 0.6 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cobimetinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Cobimetinib was administered orally once daily at a dose of 0.6 mg/kg.

    Arm title
    		 Phase I (Tablet) Cobimetinib (0.8 mg/kg)
    Arm description
    		 Dose-Escalation: Participants received 0.8 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cobimetinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Cobimetinib was administered orally once daily at a dose of 0.8 mg/kg.

    Arm title
    		 Phase I (Tablet) Cobimetinib (1 mg/kg)
    Arm description
    		 Dose-Escalation: Participants received 1 milligram per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cobimetinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Cobimetinib was administered orally once daily at a dose of 1 mg/kg.

    Arm title
    		 Phase I (Suspension) Cobimetinib (0.6 mg/kg)
    Arm description
    		 Dose-Escalation: Participants received 0.6 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cobimetinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Cobimetinib was administered orally once daily at a dose of 0.6 mg/kg.

    Arm title
    		 Phase I (Suspension) Cobimetinib (0.8 mg/kg)
    Arm description
    		 Dose-Escalation: Participants received 0.8 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cobimetinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Cobimetinib was administered orally once daily at a dose of 0.8 mg/kg.

    Arm title
    		 Phase I (Suspension) Cobimetinib (1 mg/kg)
    Arm description
    		 Dose-Escalation: Participants received 1 milligram per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cobimetinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Cobimetinib was administered orally once daily at a dose of 1 mg/kg.

    Arm title
    		 Phase I (Suspension) Cobimetinib (1.33 mg/kg)
    Arm description
    		 Dose-Escalation: Participants received 1.33 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cobimetinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Cobimetinib was administered orally once daily at a dose of 1.33 mg/kg.

    Arm title
    		 Phase II (Suspension) Cobimetinib (1 mg/kg)
    Arm description
    		 Dose-Expansion: Participants received 1 milligram per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cobimetinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Cobimetinib was administered orally once daily at a dose of 1 mg/kg.

    Number of subjects in period 1
    		Phase I (Tablet) Cobimetinib (0.6 mg/kg) Phase I (Tablet) Cobimetinib (0.8 mg/kg) Phase I (Tablet) Cobimetinib (1 mg/kg) Phase I (Suspension) Cobimetinib (0.6 mg/kg) Phase I (Suspension) Cobimetinib (0.8 mg/kg) Phase I (Suspension) Cobimetinib (1 mg/kg) Phase I (Suspension) Cobimetinib (1.33 mg/kg) Phase II (Suspension) Cobimetinib (1 mg/kg)
    Started
    6
    6
    6
    6
    7
    8
    5
    12
    Completed
    0
    0
    0
    0
    0
    0
    0
    0
    Not completed
    6
    6
    6
    6
    7
    8
    5
    12
         Withdrawal By Subject
    2
    2
    1
    -
    -
    1
    2
    1
         Study Terminated By Sponsor
    -
    2
    3
    4
    4
    3
    3
    9
         Death
    2
    2
    1
    2
    2
    2
    -
    -
         Lost to follow-up
    -
    -
    1
    -
    1
    1
    -
    1
         PI, physician decision; no response to trt.
    2
    -
    -
    -
    -
    1
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Phase I (Tablet) Cobimetinib (0.6 mg/kg)
    Reporting group description
    		 Dose-Escalation: Participants received 0.6 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

    Reporting group title
    Phase I (Tablet) Cobimetinib (0.8 mg/kg)
    Reporting group description
    		 Dose-Escalation: Participants received 0.8 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

    Reporting group title
    Phase I (Tablet) Cobimetinib (1 mg/kg)
    Reporting group description
    		 Dose-Escalation: Participants received 1 milligram per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

    Reporting group title
    Phase I (Suspension) Cobimetinib (0.6 mg/kg)
    Reporting group description
    		 Dose-Escalation: Participants received 0.6 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

    Reporting group title
    Phase I (Suspension) Cobimetinib (0.8 mg/kg)
    Reporting group description
    		 Dose-Escalation: Participants received 0.8 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

    Reporting group title
    Phase I (Suspension) Cobimetinib (1 mg/kg)
    Reporting group description
    		 Dose-Escalation: Participants received 1 milligram per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

    Reporting group title
    Phase I (Suspension) Cobimetinib (1.33 mg/kg)
    Reporting group description
    		 Dose-Escalation: Participants received 1.33 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

    Reporting group title
    Phase II (Suspension) Cobimetinib (1 mg/kg)
    Reporting group description
    		 Dose-Expansion: Participants received 1 milligram per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

    Reporting group values
    		 Phase I (Tablet) Cobimetinib (0.6 mg/kg) Phase I (Tablet) Cobimetinib (0.8 mg/kg) Phase I (Tablet) Cobimetinib (1 mg/kg) Phase I (Suspension) Cobimetinib (0.6 mg/kg) Phase I (Suspension) Cobimetinib (0.8 mg/kg) Phase I (Suspension) Cobimetinib (1 mg/kg) Phase I (Suspension) Cobimetinib (1.33 mg/kg) Phase II (Suspension) Cobimetinib (1 mg/kg) Total
    Number of subjects
    		 6 6 6 6 7 8 5 12 56
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0 0 0 0 0
        Children (2-11 years)
    		 3 4 5 6 5 6 3 9 41
        Adolescents (12-17 years)
    		 3 2 1 0 2 2 2 2 14
        Adults (18-64 years)
    		 0 0 0 0 0 0 0 1 1
        From 65-84 years
    		 0 0 0 0 0 0 0 0 0
        85 years and over
    		 0 0 0 0 0 0 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 11.8 ( 3.5 ) 9.5 ( 3.3 ) 9.5 ( 3.4 ) 8.5 ( 1.4 ) 9.7 ( 5.3 ) 8.9 ( 3.1 ) 10.2 ( 3.3 ) 8.7 ( 7.5 ) -
    Sex: Female, Male
    Units:
        Female
    		 1 2 4 2 0 2 5 7 23
        Male
    		 5 4 2 4 7 6 0 5 33
    Race/Ethnicity, Customized
    Units: Subjects
        Hispanic or Latino
    		 1 1 0 1 2 1 1 4 11
        Not Hispanic or Latino
    		 5 3 4 1 2 4 3 7 29
        Not Stated
    		 0 2 2 4 3 3 1 1 16
    Race/Ethnicity, Customized
    Units: Subjects
        Asian
    		 0 0 0 0 1 0 0 0 1
        Black or African American
    		 0 1 1 1 0 0 0 0 3
        Unknown
    		 1 1 2 5 4 3 1 1 18
        White
    		 5 4 3 0 2 5 4 11 34

    End points

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    End points reporting groups
    Reporting group title
    Phase I (Tablet) Cobimetinib (0.6 mg/kg)
    Reporting group description
    		 Dose-Escalation: Participants received 0.6 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

    Reporting group title
    Phase I (Tablet) Cobimetinib (0.8 mg/kg)
    Reporting group description
    		 Dose-Escalation: Participants received 0.8 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

    Reporting group title
    Phase I (Tablet) Cobimetinib (1 mg/kg)
    Reporting group description
    		 Dose-Escalation: Participants received 1 milligram per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

    Reporting group title
    Phase I (Suspension) Cobimetinib (0.6 mg/kg)
    Reporting group description
    		 Dose-Escalation: Participants received 0.6 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

    Reporting group title
    Phase I (Suspension) Cobimetinib (0.8 mg/kg)
    Reporting group description
    		 Dose-Escalation: Participants received 0.8 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

    Reporting group title
    Phase I (Suspension) Cobimetinib (1 mg/kg)
    Reporting group description
    		 Dose-Escalation: Participants received 1 milligram per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

    Reporting group title
    Phase I (Suspension) Cobimetinib (1.33 mg/kg)
    Reporting group description
    		 Dose-Escalation: Participants received 1.33 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

    Reporting group title
    Phase II (Suspension) Cobimetinib (1 mg/kg)
    Reporting group description
    		 Dose-Expansion: Participants received 1 milligram per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

    Subject analysis set title
    Cobimetinib (Tablet) Population
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received Cobimetinib (Tablet) Formulation.

    Subject analysis set title
    Cobimetinib (Suspension) Population
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received Cobimetinib (Suspension) Formulation.

    Subject analysis set title
    Neuroblastoma
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants with Neuroblastoma.

    Subject analysis set title
    High Grade Glioma
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants with High Grade Glioma.

    Subject analysis set title
    Low Grade Glioma (Phase I and II)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants with Low Grade Glioma.

    Subject analysis set title
    Dnet In Noonan's Syn Tumr (RAS/RAF/MEK/ERK Pathway Activation)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants with Dnet In Noonan's Syndrome Tumor With RAS/RAF/MEK/ERK Pathway Activation.

    Subject analysis set title
    Malignant Peripheral Nerve Sheath Tumor
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants with Malignant Peripheral Nerve Sheath Tumor.

    Subject analysis set title
    Metstic Mdstnl Ylksc Tumr (RAS/RAF/MEK/ERK Pathway Activation)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants with Metastatic Mediastinal Yolksac Tumor With RAS/RAF/MEK/ERK Pathway Activation.

    Subject analysis set title
    Non-Rhabdomyosarcoma Soft Tissue Sarcoma
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants with Non-Rhabdomyosarcoma Soft Tissue Sarcoma.

    Subject analysis set title
    Plexiform Neurofibroma
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants with Plexiform Neurofibroma.

    Subject analysis set title
    Rhabdoid Tumor/ATRT
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants with Rhabdoid Tumor/ATRT.

    Subject analysis set title
    Low Grade Glioma (Phase II)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants with Low Grade Glioma.

    Subject analysis set title
    Phase I (Tablet) Cobimetinib (0.6 mg/kg) (PK Population)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Dose-Escalation: Participants received 0.6 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

    Subject analysis set title
    Phase I (Tablet) Cobimetinib (0.8 mg/kg) (PK Population)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Dose-Escalation: Participants received 0.8 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

    Subject analysis set title
    Phase I (Tablet) Cobimetinib (1 mg/kg) (PK Population)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Dose-Escalation: Participants received 1 milligram per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

    Subject analysis set title
    Phase I (Suspension) Cobimetinib (0.6 mg/kg) (PK Population)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Dose-Escalation: Participants received 0.6 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

    Subject analysis set title
    Phase I (Suspension) Cobimetinib (0.8 mg/kg) (PK Population)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Dose-Escalation: Participants received 0.8 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

    Subject analysis set title
    Phase I (Suspension) Cobimetinib (1 mg/kg) (PK Population)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Dose-Escalation: Participants received 1 milligram per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

    Subject analysis set title
    Phase I (Suspension) Cobimetinib (1.33 mg/kg) (PK Population)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Dose-Escalation: Participants received 1.33 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

    Subject analysis set title
    Phase II (Suspension) Cobimetinib (1 mg/kg) (PK Population)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Dose-Expansion: Participants received 1 milligram per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

    Primary: Percentage of Participants with Dose-Limiting Toxicities (DLTs)

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    End point title
    		 Percentage of Participants with Dose-Limiting Toxicities (DLTs) [1]
    End point description
    Dose-Limiting Toxicities (DLTs) were defined as cobimetinib-related adverse events occurring within the first 28 days of each administration of cobimetinib.
    End point type
    Primary
    End point timeframe
    Baseline up until 30 days after the last dose of study drug (up to 5 years, 2 months)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No Statistical Analyses provided as no formal hypothesis testing was planned for this study.
    End point values
    		 Phase I (Tablet) Cobimetinib (0.6 mg/kg) Phase I (Tablet) Cobimetinib (0.8 mg/kg) Phase I (Tablet) Cobimetinib (1 mg/kg) Phase I (Suspension) Cobimetinib (0.6 mg/kg) Phase I (Suspension) Cobimetinib (0.8 mg/kg) Phase I (Suspension) Cobimetinib (1 mg/kg) Phase I (Suspension) Cobimetinib (1.33 mg/kg) Phase II (Suspension) Cobimetinib (1 mg/kg)
    Number of subjects analysed
    6
    6
    6
    6
    7
    8
    5
    12
    Units: Percentage of Participants
        number (not applicable)
    0
    0
    33.3
    16.7
    0
    0
    60.0
    0
    No statistical analyses for this end point

    Primary: Percentage of Participants with Adverse Events (AEs), including Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs)

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    End point title
    		 Percentage of Participants with Adverse Events (AEs), including Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs) [2]
    End point description
    An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign (including abnormal laboratory values or abnormal clinical test results), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as AEs.
    End point type
    Primary
    End point timeframe
    Baseline up until 30 days after the last dose of study drug (up to 5 years, 2 months)
    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: No Statistical Analyses provided as no formal hypothesis testing was planned for this study.
    End point values
    		 Phase I (Tablet) Cobimetinib (0.6 mg/kg) Phase I (Tablet) Cobimetinib (0.8 mg/kg) Phase I (Tablet) Cobimetinib (1 mg/kg) Phase I (Suspension) Cobimetinib (0.6 mg/kg) Phase I (Suspension) Cobimetinib (0.8 mg/kg) Phase I (Suspension) Cobimetinib (1 mg/kg) Phase I (Suspension) Cobimetinib (1.33 mg/kg) Phase II (Suspension) Cobimetinib (1 mg/kg)
    Number of subjects analysed
    6
    6
    6
    6
    7
    8
    5
    12
    Units: Percentage of Participants
    number (not applicable)
        AEs
    100.0
    100.0
    100.0
    100.0
    100.0
    100.0
    100.0
    100.0
        SAEs
    33.3
    33.3
    33.3
    33.3
    14.3
    25.0
    40.0
    41.7
        AESIs
    33.3
    33.3
    33.3
    50.0
    42.9
    25.0
    100.0
    58.3
    No statistical analyses for this end point

    Primary: Maximum Tolerated Dose (MTD) or Maximum Administered Dose (MAD) of Cobimetinib

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    End point title
    		 Maximum Tolerated Dose (MTD) or Maximum Administered Dose (MAD) of Cobimetinib [3]
    End point description
    A prior dose level was defined as an MTD/MAD if at a certain dose level, there were greater than or equal to (>=) 2 out of 6 participants who had Dose Limiting Toxicities (DLTs).
    End point type
    Primary
    End point timeframe
    Cycle 1 Day 1 up to Cycle 1 Day 28 (cycle length=28 days)
    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: No Statistical Analyses provided as no formal hypothesis testing was planned for this study.
    End point values
    		 Cobimetinib (Tablet) Population Cobimetinib (Suspension) Population
    Number of subjects analysed
    18
    38
    Units: mg/kg
        number (not applicable)
    0.8
    1
    No statistical analyses for this end point

    Primary: Percentage of Participants with Objective Response (Complete Response (CR) or Partial Response (PR)) as Determined by the Investigator using modified International Neuroblastoma Response Criteria (mINRC) for Participants with Neuroblastoma (Phase I)

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    End point title
    		 Percentage of Participants with Objective Response (Complete Response (CR) or Partial Response (PR)) as Determined by the Investigator using modified International Neuroblastoma Response Criteria (mINRC) for Participants with Neuroblastoma (Phase I) [4]
    End point description
    Tumor assessment will be performed using mINRC for Participants with Neuroblastoma. Efficacy analyses were based on tumour type for this study. Following MTD/MAD determination for each formulation, participants were enrolled in tumour type cohorts to obtain preliminary evidence of anti-cancer activity. In addition, each Dose-Escalation cohort consisted of a combination of tumour types.
    End point type
    Primary
    End point timeframe
    Baseline up to disease progression or death due to any cause, whichever occurs first (up to 5 years, 2 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: No Statistical Analyses provided as no formal hypothesis testing was planned for this study.
    End point values
    		 Neuroblastoma
    Number of subjects analysed
    1
    Units: Percentage of Participants
    0
    No statistical analyses for this end point

    Primary: Percentage of Participants with Objective Response (CR or PR) as Determined by the Investigator using RANO criteria for Participants with High-Grade Glioma (HGG) (Phase I) and RECIST v1.1 for Participants with Low-Grade Glioma (LGG) (Phase I and II)

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    End point title
    		 Percentage of Participants with Objective Response (CR or PR) as Determined by the Investigator using RANO criteria for Participants with High-Grade Glioma (HGG) (Phase I) and RECIST v1.1 for Participants with Low-Grade Glioma (LGG) (Phase I and II) [5]
    End point description
    Tumor assessment will be performed using Response Assessment in Neuro-Oncology (RANO) criteria for participants with HGG and Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) for participants with LGG. Efficacy analyses were based on tumour type for this study. Following MTD/MAD determination for each formulation, participants were enrolled in tumour type cohorts to obtain preliminary evidence of anti-cancer activity. In addition, each Dose-Escalation cohort consisted of a combination of tumour types.
    End point type
    Primary
    End point timeframe
    Baseline up to disease progression or death due to any cause, whichever occurs first (up to 5 years, 2 months)
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No Statistical Analyses provided as no formal hypothesis testing was planned for this study.
    End point values
    		 High Grade Glioma Low Grade Glioma (Phase I and II)
    Number of subjects analysed
    5
    32
    Units: Percentage of Participants
        number (not applicable)
    0
    9.4
    No statistical analyses for this end point

    Primary: Percentage of Participants with Objective Response (CR or PR) as Determined by the Investigator using RECIST v1.1 criteria for Participants with All Other Tumours (Phase I)

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    End point title
    		 Percentage of Participants with Objective Response (CR or PR) as Determined by the Investigator using RECIST v1.1 criteria for Participants with All Other Tumours (Phase I) [6]
    End point description
    Tumor assessment will be performed using RECIST v1.1 for Participants with All Other Tumours. Efficacy analyses were based on tumour type for this study. Following MTD/MAD determination for each formulation, participants were enrolled in tumour type cohorts to obtain preliminary evidence of anti-cancer activity. In addition, each Dose-Escalation cohort consisted of a combination of tumour types.
    End point type
    Primary
    End point timeframe
    Baseline up to disease progression or death due to any cause, whichever occurs first (up to 5 years, 2 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: No Statistical Analyses provided as no formal hypothesis testing was planned for this study.
    End point values
    		 Dnet In Noonan's Syn Tumr (RAS/RAF/MEK/ERK Pathway Activation) Malignant Peripheral Nerve Sheath Tumor Metstic Mdstnl Ylksc Tumr (RAS/RAF/MEK/ERK Pathway Activation) Non-Rhabdomyosarcoma Soft Tissue Sarcoma Plexiform Neurofibroma Rhabdoid Tumor/ATRT
    Number of subjects analysed
    1
    2
    1
    1
    12
    1
    Units: Percentage of Participants
    0
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Percentage of Participants with Objective Response (CR or PR) as Determined by the Investigator using RANO criteria for Participants with LGG (Phase II)

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    End point title
    		 Percentage of Participants with Objective Response (CR or PR) as Determined by the Investigator using RANO criteria for Participants with LGG (Phase II) [7]
    End point description
    Tumor assessment will be performed using RANO criteria for LGG. Efficacy analyses were based on tumour type for this study. Following MTD/MAD determination for each formulation, participants were enrolled in tumour type cohorts to obtain preliminary evidence of anti-cancer activity. In addition, each Dose-Escalation cohort consisted of a combination of tumour types.
    End point type
    Primary
    End point timeframe
    Baseline up to disease progression or death due to any cause, whichever occurs first (up to 5 years, 2 months)
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No Statistical Analyses provided as no formal hypothesis testing was planned for this study.
    End point values
    		 Low Grade Glioma (Phase II)
    Number of subjects analysed
    12
    Units: Percentage of Participants
        number (not applicable)
    8.3
    No statistical analyses for this end point

    Primary: Progression-Free Survival (PFS) as Determined by the Investigator using mINRC for Participants with Neuroblastoma (Phase I)

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    End point title
    		 Progression-Free Survival (PFS) as Determined by the Investigator using mINRC for Participants with Neuroblastoma (Phase I) [8]
    End point description
    Tumor assessment will be performed using mINRC for Participants with Neuroblastoma. Efficacy analyses were based on tumour type for this study. Following MTD/MAD determination for each formulation, participants were enrolled in tumour type cohorts to obtain preliminary evidence of anti-cancer activity. In addition, each Dose-Escalation cohort consisted of a combination of tumour types. 0.0 to 9999999 = The confidence interval could not be calculated from the data of one participant.
    End point type
    Primary
    End point timeframe
    From the time of cobimetinib study drug initiation to the first documented disease progression, or death due to any cause, whichever occurs first (up to 5 years, 2 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: No Statistical Analyses provided as no formal hypothesis testing was planned for this study.
    End point values
    		 Neuroblastoma
    Number of subjects analysed
    1
    Units: Months
        median (confidence interval 95%)
    1.3 (0.0 to 9999999)
    No statistical analyses for this end point

    Primary: PFS as Determined by the Investigator using RANO criteria for participants with HGG (Phase I) and RECIST v1.1 for partcipants with LGG (Phase I and II)

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    End point title
    		 PFS as Determined by the Investigator using RANO criteria for participants with HGG (Phase I) and RECIST v1.1 for partcipants with LGG (Phase I and II) [9]
    End point description
    Tumor assessment will be performed using RANO for participants with HGG and RECIST v1.1 for participants with LGG. Efficacy analyses were based on tumour type for this study. Following MTD/MAD determination for each formulation, participants were enrolled in tumour type cohorts to obtain preliminary evidence of anti-cancer activity. In addition, each Dose-Escalation cohort consisted of a combination of tumour types. 9999999 = The upper limit cannot be calculated from the data.
    End point type
    Primary
    End point timeframe
    From the time of cobimetinib study drug initiation to the first documented disease progression, or death due to any cause, whichever occurs first (up to approximately 6.75 years)
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No Statistical Analyses provided as no formal hypothesis testing was planned for this study.
    End point values
    		 High Grade Glioma Low Grade Glioma (Phase I and II)
    Number of subjects analysed
    5
    32
    Units: Months
        median (confidence interval 95%)
    1.0 (0.6 to 9999999)
    22.0 (9.3 to 9999999)
    No statistical analyses for this end point

    Primary: PFS as Determined by the Investigator using RECIST v1.1 criteria for Participants with All Other Tumours (Phase I)

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    End point title
    		 PFS as Determined by the Investigator using RECIST v1.1 criteria for Participants with All Other Tumours (Phase I) [10]
    End point description
    Tumor assessment will be performed using RECIST v1.1 for Participants with All Other Tumours. Efficacy analyses were based on tumour type for this study. Following MTD/MAD determination for each formulation, participants were enrolled in tumour type cohorts to obtain preliminary evidence of anti-cancer activity. In addition, each Dose-Escalation cohort consisted of a combination of tumour types. 9999999 = The median and or upper limit could not be calculated from the data. 0.0 to 9999999 = The upper and lower limits could not be calculated from the data.
    End point type
    Primary
    End point timeframe
    From the time of cobimetinib study drug initiation to the first documented disease progression, or death due to any cause, whichever occurs first (up to 5 years, 2 months)
    Notes
    [10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No Statistical Analyses provided as no formal hypothesis testing was planned for this study.
    End point values
    		 Dnet In Noonan's Syn Tumr (RAS/RAF/MEK/ERK Pathway Activation) Malignant Peripheral Nerve Sheath Tumor Metstic Mdstnl Ylksc Tumr (RAS/RAF/MEK/ERK Pathway Activation) Non-Rhabdomyosarcoma Soft Tissue Sarcoma Plexiform Neurofibroma Rhabdoid Tumor/ATRT
    Number of subjects analysed
    1
    2
    1
    1
    12
    1
    Units: Months
        median (confidence interval 95%)
    9999999 (0.0 to 9999999)
    4.1 (0.7 to 9999999)
    1.1 (0.0 to 9999999)
    3.4 (0.0 to 9999999)
    9999999 (18.4 to 9999999)
    0.5 (0.0 to 9999999)
    No statistical analyses for this end point

    Primary: PFS as Determined by the Investigator using RANO criteria for Participants with LGG (Phase II)

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    End point title
    		 PFS as Determined by the Investigator using RANO criteria for Participants with LGG (Phase II) [11]
    End point description
    Tumor assessment will be performed using RANO criteria for Participants with LGG. Efficacy analyses were based on tumour type for this study. Following MTD/MAD determination for each formulation, participants were enrolled in tumour type cohorts to obtain preliminary evidence of anti-cancer activity. In addition, each Dose-Escalation cohort consisted of a combination of tumour types. 9999999 = The upper limit could not be calculated from the data.
    End point type
    Primary
    End point timeframe
    From the time of cobimetinib study drug initiation to the first documented disease progression, or death due to any cause, whichever occurs first (up to 5 years, 2 months)
    Notes
    [11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No Statistical Analyses provided as no formal hypothesis testing was planned for this study.No Statistical Analyses provided as no formal hypothesis testing was planned for this study.
    End point values
    		 Low Grade Glioma (Phase II)
    Number of subjects analysed
    12
    Units: Months
        median (confidence interval 95%)
    18.4 (3.6 to 9999999)
    No statistical analyses for this end point

    Secondary: Recommended Phase II Dose (RP2D) of Cobimetinib

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    End point title
    		 Recommended Phase II Dose (RP2D) of Cobimetinib
    End point description
    A prior dose level was defined as an RP2D if at a certain dose level, there were greater than or equal to (≥) 2 out of 6 participants who had Dose Limiting Toxicities (DLTs).
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 up to Cycle 1 Day 28 (cycle length=28 days)
    End point values
    		 Cobimetinib (Suspension) Population
    Number of subjects analysed
    38
    Units: mg/kg
    1
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR) as Determined by the Investigator using RECIST v1.1 for participants with LGG (Phase I and II)

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    End point title
    		 Duration of Response (DOR) as Determined by the Investigator using RECIST v1.1 for participants with LGG (Phase I and II)
    End point description
    Tumor assessment will be performed using RECIST v1.1 criteria for participants with LGG. Efficacy analyses were based on tumour type for this study. Following MTD/MAD determination for each formulation, participants were enrolled in tumour type cohorts to obtain preliminary evidence of anti-cancer activity. In addition, each Dose-Escalation cohort consisted of a combination of tumour types. 9999999, 0.0 to 9999999 = no participants experienced an event and DOR wasn't reached.
    End point type
    Secondary
    End point timeframe
    From first occurrence of objective response to disease progression or death due to any cause, whichever occurs first (up to 5 years, 2 months)
    End point values
    		 Low Grade Glioma (Phase I and II)
    Number of subjects analysed
    3
    Units: Months
        median (confidence interval 95%)
    9999999 (0.0 to 9999999)
    No statistical analyses for this end point

    Secondary: DOR as Determined by the Investigator RANO criteria for Participants with LGG (Phase II)

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    End point title
    		 DOR as Determined by the Investigator RANO criteria for Participants with LGG (Phase II)
    End point description
    Tumor assessment will be performed using RANO criteria for Participants with LGG. Efficacy analyses were based on tumour type for this study. Following MTD/MAD determination for each formulation, participants were enrolled in tumour type cohorts to obtain preliminary evidence of anti-cancer activity. In addition, each Dose-Escalation cohort consisted of a combination of tumour types. 9999999, 0.0 to 9999999 = no participants experienced an event and DOR wasn't reached.
    End point type
    Secondary
    End point timeframe
    From first occurrence of objective response to disease progression or death due to any cause, whichever occurs first (up to 5 years, 2 months)
    End point values
    		 Low Grade Glioma (Phase II)
    Number of subjects analysed
    1
    Units: Months
        median (confidence interval 95%)
    9999999 (0.0 to 9999999)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS) for Participants with Neuroblastoma (Phase I)

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    End point title
    		 Overall Survival (OS) for Participants with Neuroblastoma (Phase I)
    End point description
    OS is defined as the time from initiation of study drug to death from any cause. Efficacy analyses were based on tumour type for this study. Following MTD/MAD determination for each formulation, participants were enrolled in tumour type cohorts to obtain preliminary evidence of anti-cancer activity. In addition, each Dose-Escalation cohort consisted of a combination of tumour types. 0.0 to 9999999 = The 95% confidence interval could not be calculated from the data of one participant.
    End point type
    Secondary
    End point timeframe
    Baseline until death due to any cause (up to 5 years, 2 months)
    End point values
    		 Neuroblastoma
    Number of subjects analysed
    1
    Units: Months
        median (confidence interval 95%)
    4.6 (0.0 to 9999999)
    No statistical analyses for this end point

    Secondary: OS for Participants with High-Grade Glioma (HGG) and Low-Grade Glioma (LGG) (Phase I)

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    End point title
    		 OS for Participants with High-Grade Glioma (HGG) and Low-Grade Glioma (LGG) (Phase I)
    End point description
    OS is defined as the time from initiation of study drug to death from any cause. Efficacy analyses were based on tumour type for this study. Following MTD/MAD determination for each formulation, participants were enrolled in tumour type cohorts to obtain preliminary evidence of anti-cancer activity. In addition, each Dose-Escalation cohort consisted of a combination of tumour types. Data collection is still ongoing and the results will be disclosed within 6 months from the Study Completion Date. 9999999 = The upper limit cannot be calculated due to insufficient number of events. (HGG) 9999999, 0.0 to 9999999 = No participants experienced an event and DOR was not reached (LGG)
    End point type
    Secondary
    End point timeframe
    Baseline until death due to any cause (up to 5 years, 2 months)
    End point values
    		 High Grade Glioma Low Grade Glioma (Phase I and II)
    Number of subjects analysed
    5
    32
    Units: Months
        median (confidence interval 95%)
    1.4 (0.6 to 9999999)
    9999999 (0.0 to 9999999)
    No statistical analyses for this end point

    Secondary: OS for Participants with All Other Tumours (Phase I)

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    End point title
    		 OS for Participants with All Other Tumours (Phase I)
    End point description
    OS is defined as the time from initiation of study drug to death from any cause. Efficacy analyses were based on tumour type for this study. Following MTD/MAD determination for each formulation, participants were enrolled in tumour type cohorts to obtain preliminary evidence of anti-cancer activity. In addition, each Dose-Escalation cohort consisted of a combination of tumour types. 0.0 to 9999999 = The 95% confidence interval could not be calculated. 9999999 = the median was not estimable.
    End point type
    Secondary
    End point timeframe
    Baseline until death due to any cause (up to 5 years, 2 months)
    End point values
    		 Dnet In Noonan's Syn Tumr (RAS/RAF/MEK/ERK Pathway Activation) Malignant Peripheral Nerve Sheath Tumor Metstic Mdstnl Ylksc Tumr (RAS/RAF/MEK/ERK Pathway Activation) Non-Rhabdomyosarcoma Soft Tissue Sarcoma Plexiform Neurofibroma Rhabdoid Tumor/ATRT
    Number of subjects analysed
    1
    2
    1
    1
    12
    1
    Units: Months
        median (confidence interval 95%)
    9999999 (0.0 to 9999999)
    5.5 (0.8 to 9999999)
    1.1 (0.0 to 9999999)
    6.3 (0.0 to 9999999)
    9999999 (0.0 to 9999999)
    5.1 (0.0 to 9999999)
    No statistical analyses for this end point

    Secondary: Maximum Plasma Concentration Observed (Cmax) of Cobimetinib

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    End point title
    		 Maximum Plasma Concentration Observed (Cmax) of Cobimetinib
    End point description
    Plasma samples for determination of Cobimetinib concentration will be collected prior to dosing and at 2, 4, 6 and 24 hours after dosing on Days 1 and 21 of Cycle 1. The sampling will allow determination of Cmax.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 2, 4, 6, and 24 hours post-dose on Cycle 1 Days 1 and 21 (predose=within 4 hours prior to dose; cycle length=28 days)
    End point values
    		 Phase I (Tablet) Cobimetinib (0.6 mg/kg) (PK Population) Phase I (Tablet) Cobimetinib (0.8 mg/kg) (PK Population) Phase I (Tablet) Cobimetinib (1 mg/kg) (PK Population) Phase I (Suspension) Cobimetinib (0.6 mg/kg) (PK Population) Phase I (Suspension) Cobimetinib (0.8 mg/kg) (PK Population) Phase I (Suspension) Cobimetinib (1 mg/kg) (PK Population) Phase I (Suspension) Cobimetinib (1.33 mg/kg) (PK Population) Phase II (Suspension) Cobimetinib (1 mg/kg) (PK Population)
    Number of subjects analysed
    6
    6
    6
    6
    7
    8
    5
    12
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Cycle 1 Day 1 (n= 6,5,6,6,7,8,4,9)
    62.0 ( 82.3 )
    88.3 ( 102 )
    144 ( 58.6 )
    51.5 ( 73.4 )
    67.4 ( 165 )
    136 ( 80.3 )
    111 ( 37.0 )
    44.0 ( 69.8 )
        Cycle 1 Day 21 (n= 5,5,6,6,7,8,4,9)
    51.1 ( 74.0 )
    181 ( 134 )
    193 ( 35.0 )
    105 ( 84.5 )
    156 ( 91.2 )
    179 ( 113 )
    172 ( 60.3 )
    116 ( 42 )
    No statistical analyses for this end point

    Secondary: Time to Cmax (Tmax) of Cobimetinib

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    End point title
    		 Time to Cmax (Tmax) of Cobimetinib
    End point description
    Plasma samples for determination of Cobimetinib concentration will be collected prior to dosing and at 2, 4, 6 and 24 hours after dosing on Days 1 and 21 of Cycle 1. The sampling will allow determination of Tmax.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 2, 4, 6, and 24 hours post-dose on Cycle 1 Days 1 and 21 (pre-dose=within 4 hours prior to dose; cycle length=28 days)
    End point values
    		 Phase I (Tablet) Cobimetinib (0.6 mg/kg) (PK Population) Phase I (Tablet) Cobimetinib (0.8 mg/kg) (PK Population) Phase I (Tablet) Cobimetinib (1 mg/kg) (PK Population) Phase I (Suspension) Cobimetinib (0.6 mg/kg) (PK Population) Phase I (Suspension) Cobimetinib (0.8 mg/kg) (PK Population) Phase I (Suspension) Cobimetinib (1 mg/kg) (PK Population) Phase I (Suspension) Cobimetinib (1.33 mg/kg) (PK Population) Phase II (Suspension) Cobimetinib (1 mg/kg) (PK Population)
    Number of subjects analysed
    6
    6
    6
    6
    7
    8
    5
    12
    Units: hr
    median (full range (min-max))
        Cycle 1 Day 1 (n= 6,5,6,6,7,8,4,9)
    4 (2 to 6)
    2 (2 to 6)
    3 (2 to 4)
    4 (2 to 6)
    4 (2 to 6)
    2 (2 to 4)
    5 (2 to 6)
    4 (2 to 6)
        Cycle 1 Day 21 (n= 5,5,5,6,6,8,2,9)
    4 (2 to 6)
    4 (2 to 6)
    2 (2 to 4)
    4 (2 to 6)
    2 (2 to 4)
    3 (2 to 6)
    4 (4 to 4)
    2 (2 to 6)
    No statistical analyses for this end point

    Secondary: Area Under the Concentration-Time Curve From 0 to 24 Hours (AUC0-24) of Cobimetinib

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    End point title
    		 Area Under the Concentration-Time Curve From 0 to 24 Hours (AUC0-24) of Cobimetinib
    End point description
    Plasma samples for determination of Cobimetinib concentration will be collected prior to dosing and at 2, 4, 6 and 24 hours after dosing on Days 1 and 21 of Cycle 1. The sampling will allow determination of AUC0-24.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 2, 4, 6, and 24 hours post-dose on Cycle 1 Days 1 and 21 (pre-dose=within 4 hours prior to dose; cycle length=28 days)
    End point values
    		 Phase I (Tablet) Cobimetinib (0.6 mg/kg) (PK Population) Phase I (Tablet) Cobimetinib (0.8 mg/kg) (PK Population) Phase I (Tablet) Cobimetinib (1 mg/kg) (PK Population) Phase I (Suspension) Cobimetinib (0.6 mg/kg) (PK Population) Phase I (Suspension) Cobimetinib (0.8 mg/kg) (PK Population) Phase I (Suspension) Cobimetinib (1 mg/kg) (PK Population) Phase I (Suspension) Cobimetinib (1.33 mg/kg) (PK Population) Phase II (Suspension) Cobimetinib (1 mg/kg) (PK Population)
    Number of subjects analysed
    6
    6
    6
    6
    7
    8
    5
    12
    Units: hr*ng/mL
    geometric mean (geometric coefficient of variation)
        Cycle 1 Day 1 (n= 6,5,6,6,6,8,3,9)
    865 ( 83.0 )
    1006 ( 100 )
    1432 ( 50.0 )
    743 ( 67.4 )
    1111 ( 144 )
    1627 ( 74.0 )
    1567 ( 33.1 )
    589 ( 79.5 )
        Cycle 1 Day 21 (n= 5,5,5,6,6,8,2,9)
    836 ( 83.5 )
    2802 ( 111 )
    2382 ( 38.4 )
    1624 ( 80.4 )
    1805 ( 109 )
    2562 ( 104 )
    2511 ( 104 )
    1402 ( 59 )
    No statistical analyses for this end point

    Secondary: Apparent Clearance (CL/F) of Cobimetinib

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    End point title
    		 Apparent Clearance (CL/F) of Cobimetinib
    End point description
    Plasma samples for determination of Cobimetinib concentration will be collected prior to dosing and at 2, 4, 6 and 24 hours after dosing on Days 1 and 21 of Cycle 1, and within 4 hours prior to dosing on Day 1 of Cycle 2. The sampling will allow determination of CL/F. Please note that for this Outcome Measure, the Apparent Clearance of Cobimetinib could not be calculated/estimated as PK samples were collected only up to 24hr post dosing. 9999999 = Insufficient data to calculate CL/F.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 2, 4, 6, and 24 hours post-dose on Cycle 1 Days 1 and 21; pre-dose on Cycle 2 Day 1 (pre-dose=within 4 hours prior to dose; cycle length=28 days)
    End point values
    		 Phase I (Tablet) Cobimetinib (0.6 mg/kg) (PK Population) Phase I (Tablet) Cobimetinib (0.8 mg/kg) (PK Population) Phase I (Tablet) Cobimetinib (1 mg/kg) (PK Population) Phase I (Suspension) Cobimetinib (0.6 mg/kg) (PK Population) Phase I (Suspension) Cobimetinib (0.8 mg/kg) (PK Population) Phase I (Suspension) Cobimetinib (1 mg/kg) (PK Population) Phase I (Suspension) Cobimetinib (1.33 mg/kg) (PK Population) Phase II (Suspension) Cobimetinib (1 mg/kg) (PK Population)
    Number of subjects analysed
    6
    6
    6
    6
    7
    8
    5
    12
    Units: L/hr
        geometric mean (geometric coefficient of variation)
    9999999 ( 9999999 )
    9999999 ( 9999999 )
    9999999 ( 9999999 )
    9999999 ( 9999999 )
    9999999 ( 9999999 )
    9999999 ( 9999999 )
    9999999 ( 9999999 )
    9999999 ( 9999999 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up until 30 days after the last dose of study drug (up to 5 years, 2 months)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Phase I (Tablet) Cobimetinib (0.6 mg/kg)
    Reporting group description
    		 Dose-Escalation: Participants received 0.6 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

    Reporting group title
    Phase I (Tablet) Cobimetinib (1 mg/kg)
    Reporting group description
    		 Dose-Escalation: Participants received 1 milligram per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

    Reporting group title
    Phase I (Tablet) Cobimetinib (0.8 mg/kg)
    Reporting group description
    		 Dose-Escalation: Participants received 0.8 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

    Reporting group title
    Phase I (Suspension) Cobimetinib (0.6 mg/kg)
    Reporting group description
    		 Dose-Escalation: Participants received 0.6 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

    Reporting group title
    Phase I (Suspension) Cobimetinib (0.8 mg/kg)
    Reporting group description
    		 Dose-Escalation: Participants received 0.8 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

    Reporting group title
    Phase I (Suspension) Cobimetinib (1 mg/kg)
    Reporting group description
    		 Dose-Escalation: Participants received 1 milligram per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

    Reporting group title
    Phase I (Suspension) Cobimetinib (1.33 mg/kg)
    Reporting group description
    		 Dose-Escalation: Participants received 1.33 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

    Reporting group title
    Phase II (Suspension) Cobimetinib (1 mg/kg)
    Reporting group description
    		 Dose-Expansion: Participants received 1 milligram per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

    Serious adverse events
    		 Phase I (Tablet) Cobimetinib (0.6 mg/kg) Phase I (Tablet) Cobimetinib (1 mg/kg) Phase I (Tablet) Cobimetinib (0.8 mg/kg) Phase I (Suspension) Cobimetinib (0.6 mg/kg) Phase I (Suspension) Cobimetinib (0.8 mg/kg) Phase I (Suspension) Cobimetinib (1 mg/kg) Phase I (Suspension) Cobimetinib (1.33 mg/kg) Phase II (Suspension) Cobimetinib (1 mg/kg)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 6 (33.33%)
    2 / 6 (33.33%)
    2 / 6 (33.33%)
    2 / 6 (33.33%)
    1 / 7 (14.29%)
    2 / 8 (25.00%)
    2 / 5 (40.00%)
    5 / 12 (41.67%)
         number of deaths (all causes)
    2
    1
    2
    2
    2
    2
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    0
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    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
    Injury, poisoning and procedural complications
    Femoral neck fracture
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    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
    Cardiac disorders
    Cardiac ventricular thrombosis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    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
    Pericardial effusion
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    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
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    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
    Somnolence
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    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
    Hydrocephalus
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    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
    Encephalopathy
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    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
    Seizure
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neuralgia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    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
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    1 / 5 (20.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    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
    Eye disorders
    Chorioretinopathy
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    1 / 5 (20.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    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
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    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
    Abdominal pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    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
    Respiratory, thoracic and mediastinal disorders
    Pneumothorax
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    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
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    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
    Infections and infestations
    Infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    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
    Paronychia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    1 / 5 (20.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    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
    Pneumonia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    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
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 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
    Gastroenteritis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    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
    Vascular device infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    1 / 5 (20.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    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
    Catheter site infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    1 / 5 (20.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    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
    Skin infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Phase I (Tablet) Cobimetinib (0.6 mg/kg) Phase I (Tablet) Cobimetinib (1 mg/kg) Phase I (Tablet) Cobimetinib (0.8 mg/kg) Phase I (Suspension) Cobimetinib (0.6 mg/kg) Phase I (Suspension) Cobimetinib (0.8 mg/kg) Phase I (Suspension) Cobimetinib (1 mg/kg) Phase I (Suspension) Cobimetinib (1.33 mg/kg) Phase II (Suspension) Cobimetinib (1 mg/kg)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 6 (100.00%)
    6 / 6 (100.00%)
    6 / 6 (100.00%)
    6 / 6 (100.00%)
    7 / 7 (100.00%)
    8 / 8 (100.00%)
    5 / 5 (100.00%)
    12 / 12 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Hair follicle tumour benign
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Skin papilloma
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    1
    General disorders and administration site conditions
    Gait disturbance
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Chest pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    2
    0
    0
    Fatigue
         subjects affected / exposed
    2 / 6 (33.33%)
    3 / 6 (50.00%)
    2 / 6 (33.33%)
    2 / 6 (33.33%)
    2 / 7 (28.57%)
    3 / 8 (37.50%)
    1 / 5 (20.00%)
    2 / 12 (16.67%)
         occurrences all number
    2
    5
    2
    2
    3
    3
    1
    2
    Inflammation
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Localised oedema
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    1 / 5 (20.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Oedema peripheral
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Xerosis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Nodule
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Asthenia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    2
    Extravasation
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    1 / 5 (20.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Mucosal inflammation
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Malaise
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Pyrexia
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    2 / 8 (25.00%)
    2 / 5 (40.00%)
    3 / 12 (25.00%)
         occurrences all number
    2
    3
    2
    1
    1
    2
    3
    5
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Reproductive system and breast disorders
    Balanoposthitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Scrotal ulcer
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Vulvovaginal pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    1 / 5 (20.00%)
    4 / 12 (33.33%)
         occurrences all number
    3
    2
    1
    1
    1
    0
    1
    5
    Dyspnoea
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    2 / 8 (25.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    3
    0
    0
    0
    0
    2
    0
    0
    Nasal congestion
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    2 / 6 (33.33%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    2
    2
    0
    0
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    1 / 5 (20.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    2
    1
    0
    0
    0
    1
    1
    Pleural effusion
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Rhinorrhoea
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    0
    0
    Cough
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    2 / 6 (33.33%)
    2 / 6 (33.33%)
    1 / 7 (14.29%)
    1 / 8 (12.50%)
    0 / 5 (0.00%)
    3 / 12 (25.00%)
         occurrences all number
    3
    1
    4
    2
    1
    1
    0
    5
    Sputum decreased
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Psychiatric disorders
    Behaviour disorder
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Insomnia
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    1 / 5 (20.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    1
    1
    0
    Inappropriate affect
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    2
    Anxiety
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    1 / 5 (20.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    1
    0
    Bradyphrenia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Investigations
    Blood bicarbonate decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    2
    Ejection fraction decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 8 (12.50%)
    1 / 5 (20.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    3
    1
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    2
    Blood chloride increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    3
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    1 / 5 (20.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    2
    1
    White blood cell count decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    2 / 7 (28.57%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    0
    9
    0
    3
    0
    0
    8
    Blood creatinine decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    1 / 5 (20.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    Anion gap increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    3
    Lymphocyte count decreased
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    1 / 8 (12.50%)
    0 / 5 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    1
    0
    0
    4
    1
    1
    0
    4
    Weight decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Body temperature decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Platelet count increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    2
    Cortisol decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Intraocular pressure increased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    1
    1
    0
    0
    0
    Transaminases increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    2 / 7 (28.57%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    7
    0
    3
    0
    0
    5
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Protein total decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    3
    Blood creatinine increased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 8 (12.50%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    1
    0
    0
    Mean cell volume increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    2 / 7 (28.57%)
    1 / 8 (12.50%)
    0 / 5 (0.00%)
    4 / 12 (33.33%)
         occurrences all number
    0
    3
    0
    1
    3
    1
    0
    8
    Lymphocyte count increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    White blood cell count increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    1 / 5 (20.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Body temperature increased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Oxygen saturation decreased
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Weight increased
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    2
    Blood cholesterol increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Platelet count decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    2 / 5 (40.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    3
    0
    Neutrophil count increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    1 / 5 (20.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    1
    Injury, poisoning and procedural complications
    Face injury
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Skin abrasion
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 8 (12.50%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    2
    1
    0
    1
    1
    0
    1
    Thermal burn
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Wrist fracture
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    1 / 5 (20.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    1
    Foreign body in ear
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Contusion
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    3
    0
    0
    0
    1
    0
    0
    Hand fracture
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Limb injury
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    3
    0
    0
    0
    0
    0
    0
    Arthropod bite
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Ligament sprain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    1 / 5 (20.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Foot fracture
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Head injury
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    5
    0
    0
    0
    0
    0
    0
    Skin laceration
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    1 / 5 (20.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Tooth fracture
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Fall
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    1 / 5 (20.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    4
    0
    0
    0
    1
    1
    1
    Abdominal injury
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Skin wound
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Congenital, familial and genetic disorders
    Iris hamartoma
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    0
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    1 / 5 (20.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    2
    0
    0
    0
    0
    1
    0
    Headache
         subjects affected / exposed
    3 / 6 (50.00%)
    2 / 6 (33.33%)
    3 / 6 (50.00%)
    2 / 6 (33.33%)
    3 / 7 (42.86%)
    4 / 8 (50.00%)
    3 / 5 (60.00%)
    7 / 12 (58.33%)
         occurrences all number
    5
    2
    4
    4
    8
    4
    5
    11
    Paraesthesia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    4
    1
    0
    0
    0
    0
    0
    Tremor
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    2 / 8 (25.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    0
    Lethargy
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Neuralgia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Sciatica
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Lymphadenopathy
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Anaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    3 / 12 (25.00%)
         occurrences all number
    0
    0
    7
    3
    0
    0
    0
    6
    Leukopenia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    2 / 8 (25.00%)
    0 / 5 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    1
    1
    1
    0
    3
    0
    2
    Eye disorders
    Retinal detachment
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Vision blurred
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Conjunctivitis allergic
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Ocular hyperaemia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    0
    Punctate keratitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    1
    Ocular hypertension
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Miosis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Visual acuity reduced transiently
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Optic disc disorder
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Detachment of retinal pigment epithelium
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    1 / 5 (20.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Serous retinal detachment
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    1 / 5 (20.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    2
    0
    Retinal disorder
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Corneal neovascularisation
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Optic atrophy
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Dry eye
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    0
    Visual impairment
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Eye pain
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    Visual field defect
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Eye disorder
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Eyelid skin dryness
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Chorioretinopathy
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    1 / 5 (20.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    0
    Eyelid ptosis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Gastrointestinal disorders
    Toothache
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Dyspepsia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Tongue ulceration
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    1 / 5 (20.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    0
    1
    0
    4
    2
    Lip haemorrhage
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Vomiting
         subjects affected / exposed
    1 / 6 (16.67%)
    4 / 6 (66.67%)
    2 / 6 (33.33%)
    2 / 6 (33.33%)
    2 / 7 (28.57%)
    4 / 8 (50.00%)
    2 / 5 (40.00%)
    7 / 12 (58.33%)
         occurrences all number
    1
    9
    4
    2
    9
    7
    2
    14
    Anal haemorrhage
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Dysphagia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Lip ulceration
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Constipation
         subjects affected / exposed
    3 / 6 (50.00%)
    3 / 6 (50.00%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    2 / 8 (25.00%)
    1 / 5 (20.00%)
    3 / 12 (25.00%)
         occurrences all number
    3
    5
    3
    0
    0
    3
    1
    3
    Glossodynia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    0
    0
    Oesophagitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Haematochezia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Proctalgia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Dry mouth
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Nausea
         subjects affected / exposed
    2 / 6 (33.33%)
    3 / 6 (50.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    2 / 7 (28.57%)
    3 / 8 (37.50%)
    0 / 5 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    2
    3
    1
    0
    7
    5
    0
    2
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    0
    0
    Gastritis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Dental caries
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Abdominal distension
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Stomatitis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    1 / 5 (20.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    0
    0
    1
    0
    1
    0
    Faeces hard
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Tooth impacted
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Abdominal pain
         subjects affected / exposed
    2 / 6 (33.33%)
    2 / 6 (33.33%)
    3 / 6 (50.00%)
    1 / 6 (16.67%)
    2 / 7 (28.57%)
    1 / 8 (12.50%)
    2 / 5 (40.00%)
    3 / 12 (25.00%)
         occurrences all number
    2
    2
    3
    1
    2
    1
    2
    7
    Diarrhoea
         subjects affected / exposed
    3 / 6 (50.00%)
    5 / 6 (83.33%)
    4 / 6 (66.67%)
    4 / 6 (66.67%)
    2 / 7 (28.57%)
    4 / 8 (50.00%)
    4 / 5 (80.00%)
    4 / 12 (33.33%)
         occurrences all number
    5
    8
    17
    6
    3
    6
    10
    11
    Mouth ulceration
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    1 / 5 (20.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    1
    0
    Aphthous ulcer
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Anorectal discomfort
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Papule
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Rash
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    2 / 7 (28.57%)
    1 / 8 (12.50%)
    1 / 5 (20.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    2
    5
    1
    2
    1
    1
    2
    Skin fissures
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    1 / 5 (20.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Hyperkeratosis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Pruritus
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    1 / 5 (20.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    1
    1
    0
    Rash papular
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    0
    2
    Dermatitis atopic
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    1
    Telangiectasia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Rash erythematous
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    Skin lesion
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Eczema
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    1 / 8 (12.50%)
    0 / 5 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    1
    1
    1
    1
    1
    0
    2
    Rash maculo-papular
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    0
    1
    0
    5
    0
    1
    Dermatitis contact
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    1 / 5 (20.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Acne
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    1 / 5 (20.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    1
    0
    Eczema asteatotic
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    1 / 5 (20.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Photosensitivity reaction
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Xeroderma
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Hirsutism
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Skin ulcer
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    Onychomadesis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    0
    Ingrowing nail
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    0
    Hand dermatitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    1 / 5 (20.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Miliaria
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Rash macular
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Dandruff
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    2
    Skin mass
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Alopecia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    1 / 5 (20.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    1
    0
    Hyperhidrosis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Seborrhoea
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Purpura
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    2
    Dermatitis acneiform
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    1 / 8 (12.50%)
    3 / 5 (60.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    0
    1
    1
    1
    3
    1
    Dry skin
         subjects affected / exposed
    2 / 6 (33.33%)
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    3 / 7 (42.86%)
    2 / 8 (25.00%)
    1 / 5 (20.00%)
    1 / 12 (8.33%)
         occurrences all number
    6
    2
    2
    0
    3
    2
    2
    1
    Erythema
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    1
    1
    1
    0
    0
    0
    Pityriasis alba
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Renal and urinary disorders
    Urinary incontinence
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    0
    0
    Urinary hesitation
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Acute kidney injury
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    2
    Micturition urgency
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    0
    0
    Urinary tract pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    0
    Pollakiuria
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    0
    1
    Urinary retention
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    0
    0
    Polyuria
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    1 / 5 (20.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Dysuria
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    Endocrine disorders
    Precocious puberty
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Neck pain
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 7 (28.57%)
    1 / 8 (12.50%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    2
    0
    0
    2
    1
    0
    0
    Back pain
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    2 / 8 (25.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    6
    0
    0
    1
    2
    0
    0
    Pain in extremity
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    2 / 7 (28.57%)
    0 / 8 (0.00%)
    1 / 5 (20.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    6
    1
    0
    3
    0
    1
    0
    Arthralgia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    2 / 8 (25.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    4
    0
    1
    0
    2
    0
    0
    Groin pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Joint swelling
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Muscle spasms
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Myalgia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    Pain in jaw
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Spinal deformity
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Flank pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Infections and infestations
    Rhinitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    1 / 5 (20.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Scarlet fever
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    1 / 5 (20.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    1
    2
    Anorectal infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Catheter site infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    1 / 5 (20.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    1
    Hand-foot-and-mouth disease
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    1 / 5 (20.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Conjunctivitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    0
    0
    Viral tonsillitis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Viral infection
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    1
    0
    0
    COVID-19
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Tonsillitis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Fungal skin infection
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    0
    0
    Paronychia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    1 / 7 (14.29%)
    1 / 8 (12.50%)
    1 / 5 (20.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    0
    0
    2
    1
    1
    1
    2
    Rash pustular
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    1
    Urinary tract infection
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    1 / 5 (20.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    5
    0
    0
    0
    0
    2
    0
    Varicella
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 8 (12.50%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    1
    Bronchitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Respiratory tract infection
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    2
    Localised infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Rhinovirus infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Skin infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    1 / 5 (20.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    2
    0
    Ear infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 8 (12.50%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    1 / 5 (20.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Oral herpes
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 8 (12.50%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    0
    H1N1 influenza
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Folliculitis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    0
    1
    1
    0
    0
    0
    Oral candidiasis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    0 / 12 (0