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    Clinical Trial Results:
    A Phase 1 Study of the EZH2 Inhibitor Tazemetostat in Pediatric Subjects with Relapsed or Refractory INI1-Negative Tumors or Synovial Sarcoma

    Summary
    EudraCT number
    2015-002468-18
    Trial protocol
    GB   DK   DE   NL   IT  
    Global end of trial date
    19 Jun 2021

    Results information
    Results version number
    v2(current)
    This version publication date
    13 Jul 2024
    First version publication date
    11 Jan 2022
    Other versions
    v1
    Version creation reason
    • Correction of full data set
    Correction of full data set

    Trial information

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    Trial identification
    Sponsor protocol code
    EZH-102
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02601937
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Epizyme, Inc.
    Sponsor organisation address
    400 Technology Square, 4th Floor, Cambridge, United States, 02139
    Public contact
    Shefali Agarwal, MBBS, MPH, MIS, Epizyme, Inc., 001 855500-1011, clinicaltrials@epizyme.com
    Scientific contact
    Shefali Agarwal, MBBS, MPH, MIS, Epizyme, Inc., 001 855500-1011, clinicaltrials@epizyme.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-003055-PIP01-21
    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
    22 Oct 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Jun 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Dose Escalation: To determine the maximum tolerated dose (MTD) or the recommended phase 2 dose (RP2D) of tazemetostat when administered as an oral suspension twice daily (BID) in pediatric subjects with relapsed/refractory rhabdoid tumors, integrase interactor 1 (INI1)-negative tumors or synovial sarcoma. Dose Expansion: To evaluate the antitumor activity of tazemetostat as assessed by overall response rate (ORR) in pediatric subjects with relapsed/refractory atypical teratoid rhabdoid tumor (ATRT) (Cohort 1), non-ATRT rhabdoid tumors (Cohort 2), INI1-negative tumors (Cohort 3), and tumor types eligible for Cohorts 1 through 3 or synovial sarcoma with SS18-SSX rearrangement (Cohort 4) using disease-appropriate standardized response criteria.
    Protection of trial subjects
    The procedures set out in the study protocol pertaining to the conduct, evaluation, and documentation of this study were designed to ensure that the Sponsor and Investigators are by Good Clinical Practice (GCP) as described in the International Conference on Harmonisation (ICH) Tripartite Guideline E6. Compliance with these regulations also constituted compliance with the ethical principles described in the current revision of the Declaration of Helsinki. The study was also carried out in keeping with local legal and regulatory requirements. Subject confidentiality was strictly held in trust by the Sponsor and/or their designee(s), participating Investigators, and site staff.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    07 Jan 2016
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy
    Long term follow-up duration
    2 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 3
    Country: Number of subjects enrolled
    United Kingdom: 7
    Country: Number of subjects enrolled
    Denmark: 12
    Country: Number of subjects enrolled
    France: 14
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    Italy: 7
    Country: Number of subjects enrolled
    Australia: 7
    Country: Number of subjects enrolled
    United States: 55
    Country: Number of subjects enrolled
    Canada: 3
    Worldwide total number of subjects
    109
    EEA total number of subjects
    37
    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)
    17
    Children (2-11 years)
    62
    Adolescents (12-17 years)
    27
    Adults (18-64 years)
    3
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    07 January 2016 – 19 June 2021; Medical clinics, hospitals, and academic research centers.

    Pre-assignment
    Screening details
    A signed, written informed consent (and assent, if applicable) must be obtained prior to any study-specific assessments or procedures being performed. All Screening assessments must be performed within 14 days prior to enrollment (Screening Period extends from Day -14 to Day -1).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Dose Escalation Level 1
    Arm description
    Subjects with relapsed/refractory rhabdoid tumors, INI1-negative tumors, or synovial sarcoma with SS18-SSX rearrangement received oral tazemetostat 240 milligrams per square meter (mg/m^2) BID in continuous 28-day cycles.
    Arm type
    Experimental

    Investigational medicinal product name
    Tazemostat
    Investigational medicinal product code
    EPZ-6438
    Other name
    E7438
    Pharmaceutical forms
    Suspension for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received tazemetostat oral suspension. The amount of tazemetostat oral suspension per dose is calculated based on the subject’s body surface area (BSA) and the assigned dose level. Subjects received oral suspension at the assigned dose twice daily.

    Arm title
    Dose Escalation Level 2
    Arm description
    Subjects with relapsed/refractory rhabdoid tumors, INI1-negative tumors, or synovial sarcoma with SS18-SSX rearrangement received oral tazemetostat 300 mg/m^2 BID in continuous 28-day cycles.
    Arm type
    Experimental

    Investigational medicinal product name
    Tazemostat
    Investigational medicinal product code
    EPZ-6438
    Other name
    E7438
    Pharmaceutical forms
    Suspension for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received tazemetostat oral suspension. The amount of tazemetostat oral suspension per dose is calculated based on the subject’s body surface area (BSA) and the assigned dose level. Subjects received oral suspension at the assigned dose twice daily.

    Arm title
    Dose Escalation Level 3
    Arm description
    Subjects with relapsed/refractory rhabdoid tumors, INI1-negative tumors, or synovial sarcoma with SS18-SSX rearrangement received oral tazemetostat 400 mg/m^2 BID in continuous 28-day cycles.
    Arm type
    Experimental

    Investigational medicinal product name
    Tazemostat
    Investigational medicinal product code
    EPZ-6438
    Other name
    E7438
    Pharmaceutical forms
    Suspension for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received tazemetostat oral suspension. The amount of tazemetostat oral suspension per dose is calculated based on the subject’s body surface area (BSA) and the assigned dose level. Subjects received oral suspension at the assigned dose twice daily.

    Arm title
    Dose Escalation Level 4
    Arm description
    Subjects with relapsed/refractory rhabdoid tumors, INI1-negative tumors, or synovial sarcoma with SS18-SSX rearrangement received oral tazemetostat 520 mg/m^2 BID in continuous 28-day cycles.
    Arm type
    Experimental

    Investigational medicinal product name
    Tazemostat
    Investigational medicinal product code
    EPZ-6438
    Other name
    E7438
    Pharmaceutical forms
    Suspension for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received tazemetostat oral suspension. The amount of tazemetostat oral suspension per dose is calculated based on the subject’s body surface area (BSA) and the assigned dose level. Subjects received oral suspension at the assigned dose twice daily.

    Arm title
    Dose Escalation Level 5
    Arm description
    Subjects with relapsed/refractory rhabdoid tumors, INI1-negative tumors, or synovial sarcoma with SS18-SSX rearrangement received oral tazemetostat 700 mg/m^2 BID in continuous 28-day cycles.
    Arm type
    Experimental

    Investigational medicinal product name
    Tazemostat
    Investigational medicinal product code
    EPZ-6438
    Other name
    E7438
    Pharmaceutical forms
    Suspension for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received tazemetostat oral suspension. The amount of tazemetostat oral suspension per dose is calculated based on the subject’s body surface area (BSA) and the assigned dose level. Subjects received oral suspension at the assigned dose twice daily.

    Arm title
    Dose Escalation Level 6
    Arm description
    Subjects with relapsed/refractory rhabdoid tumors, INI1-negative tumors, or synovial sarcoma with SS18-SSX rearrangement received oral tazemetostat 900 mg/m^2 BID in continuous 28-day cycles.
    Arm type
    Experimental

    Investigational medicinal product name
    Tazemostat
    Investigational medicinal product code
    EPZ-6438
    Other name
    E7438
    Pharmaceutical forms
    Suspension for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received tazemetostat oral suspension. The amount of tazemetostat oral suspension per dose is calculated based on the subject’s body surface area (BSA) and the assigned dose level. Subjects received oral suspension at the assigned dose twice daily.

    Arm title
    Dose Escalation Level 7
    Arm description
    Subjects with relapsed/refractory rhabdoid tumors, INI1-negative tumors, or synovial sarcoma with SS18-SSX rearrangement received oral tazemetostat 1200 mg/m^2 BID in continuous 28-day cycles.
    Arm type
    Experimental

    Investigational medicinal product name
    Tazemostat
    Investigational medicinal product code
    EPZ-6438
    Other name
    E7438
    Pharmaceutical forms
    Suspension for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received tazemetostat oral suspension. The amount of tazemetostat oral suspension per dose is calculated based on the subject’s body surface area (BSA) and the assigned dose level. Subjects received oral suspension at the assigned dose twice daily.

    Arm title
    Dose Expansion Cohort 1
    Arm description
    Subjects with atypical teratoid rhabdoid tumor (ATRT) who participated in the dose expansion portion of the study received 1200 mg/m^2 open-label, tazemetostat BID orally in continuous 28-day cycles.
    Arm type
    Experimental

    Investigational medicinal product name
    Tazemostat
    Investigational medicinal product code
    EPZ-6438
    Other name
    E7438
    Pharmaceutical forms
    Suspension for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received tazemetostat oral suspension. The amount of tazemetostat oral suspension per dose is calculated based on the subject’s body surface area (BSA) and the assigned dose level. Subjects received oral suspension at the assigned dose twice daily.

    Arm title
    Dose Expansion Cohort 2
    Arm description
    Subjects with malignant rhabdoid tumor (MRT)/ rhabdoid tumor of kidney (RTK)/select tumors with rhabdoid features who participated in the dose expansion portion of the study. Subjects whose disease was without central nervous system (CNS) involvement received 520 mg/m^2 open-label, tazemetostat BID orally in continuous 28-day cycles. Subjects whose disease had CNS involvement received 1200 mg/m^2 open-label, tazemetostat BID orally in continuous 28-day cycles.
    Arm type
    Experimental

    Investigational medicinal product name
    Tazemostat
    Investigational medicinal product code
    EPZ-6438
    Other name
    E7438
    Pharmaceutical forms
    Suspension for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received tazemetostat oral suspension. The amount of tazemetostat oral suspension per dose is calculated based on the subject’s body surface area (BSA) and the assigned dose level. Subjects received oral suspension at the assigned dose twice daily.

    Arm title
    Dose Expansion Cohort 3
    Arm description
    Subjects with INI-negative tumors who participated in the dose expansion portion of the study. Subjects whose disease was without central nervous system (CNS) involvement received 520 mg/m^2 open-label, tazemetostat BID orally in continuous 28-day cycles. Subjects whose disease had CNS involvement received 1200 mg/m^2 open-label, tazemetostat BID orally in continuous 28-day cycles.
    Arm type
    Experimental

    Investigational medicinal product name
    Tazemostat
    Investigational medicinal product code
    EPZ-6438
    Other name
    E7438
    Pharmaceutical forms
    Suspension for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received tazemetostat oral suspension. The amount of tazemetostat oral suspension per dose is calculated based on the subject’s body surface area (BSA) and the assigned dose level. Subjects received oral suspension at the assigned dose twice daily.

    Arm title
    Dose Expansion Cohort 4
    Arm description
    Subjects with one of the tumor types defined in Cohorts 1 through 3 or synovial sarcoma with SS18-SSX rearrangement received 800 mg/m^2 tazemetostat three times daily (TID) orally in continuous 28-day cycles.
    Arm type
    Experimental

    Investigational medicinal product name
    Tazemostat
    Investigational medicinal product code
    EPZ-6438
    Other name
    E7438
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects in Dose Expansion Cohort 4 received tazemetostat tablet formulation, 800 mg/m2 three times daily (2400 mg/m2/day equivalent to 1200 mg/m2 BID).

    Number of subjects in period 1
    Dose Escalation Level 1 Dose Escalation Level 2 Dose Escalation Level 3 Dose Escalation Level 4 Dose Escalation Level 5 Dose Escalation Level 6 Dose Escalation Level 7 Dose Expansion Cohort 1 Dose Expansion Cohort 2 Dose Expansion Cohort 3 Dose Expansion Cohort 4
    Started
    8
    6
    6
    7
    6
    6
    7
    19
    20
    18
    6
    Completed
    0
    0
    0
    1
    0
    1
    0
    1
    0
    0
    1
    Not completed
    8
    6
    6
    6
    6
    5
    7
    18
    20
    18
    5
         Physician decision
    -
    -
    -
    -
    -
    -
    -
    -
    -
    1
    1
         death
    -
    -
    -
    -
    -
    -
    -
    -
    1
    -
    -
         unknown
    -
    -
    -
    -
    -
    -
    -
    -
    2
    2
    -
         Adverse event, non-fatal
    -
    -
    -
    -
    -
    1
    -
    -
    -
    1
    -
         Subject refused further treatment of study drug
    1
    -
    -
    -
    -
    -
    1
    2
    -
    -
    -
         Unacceptable toxicity
    -
    -
    1
    -
    -
    -
    -
    -
    -
    -
    -
         Disease Progression
    7
    6
    5
    6
    6
    4
    6
    16
    17
    14
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Dose Escalation Level 1
    Reporting group description
    Subjects with relapsed/refractory rhabdoid tumors, INI1-negative tumors, or synovial sarcoma with SS18-SSX rearrangement received oral tazemetostat 240 milligrams per square meter (mg/m^2) BID in continuous 28-day cycles.

    Reporting group title
    Dose Escalation Level 2
    Reporting group description
    Subjects with relapsed/refractory rhabdoid tumors, INI1-negative tumors, or synovial sarcoma with SS18-SSX rearrangement received oral tazemetostat 300 mg/m^2 BID in continuous 28-day cycles.

    Reporting group title
    Dose Escalation Level 3
    Reporting group description
    Subjects with relapsed/refractory rhabdoid tumors, INI1-negative tumors, or synovial sarcoma with SS18-SSX rearrangement received oral tazemetostat 400 mg/m^2 BID in continuous 28-day cycles.

    Reporting group title
    Dose Escalation Level 4
    Reporting group description
    Subjects with relapsed/refractory rhabdoid tumors, INI1-negative tumors, or synovial sarcoma with SS18-SSX rearrangement received oral tazemetostat 520 mg/m^2 BID in continuous 28-day cycles.

    Reporting group title
    Dose Escalation Level 5
    Reporting group description
    Subjects with relapsed/refractory rhabdoid tumors, INI1-negative tumors, or synovial sarcoma with SS18-SSX rearrangement received oral tazemetostat 700 mg/m^2 BID in continuous 28-day cycles.

    Reporting group title
    Dose Escalation Level 6
    Reporting group description
    Subjects with relapsed/refractory rhabdoid tumors, INI1-negative tumors, or synovial sarcoma with SS18-SSX rearrangement received oral tazemetostat 900 mg/m^2 BID in continuous 28-day cycles.

    Reporting group title
    Dose Escalation Level 7
    Reporting group description
    Subjects with relapsed/refractory rhabdoid tumors, INI1-negative tumors, or synovial sarcoma with SS18-SSX rearrangement received oral tazemetostat 1200 mg/m^2 BID in continuous 28-day cycles.

    Reporting group title
    Dose Expansion Cohort 1
    Reporting group description
    Subjects with atypical teratoid rhabdoid tumor (ATRT) who participated in the dose expansion portion of the study received 1200 mg/m^2 open-label, tazemetostat BID orally in continuous 28-day cycles.

    Reporting group title
    Dose Expansion Cohort 2
    Reporting group description
    Subjects with malignant rhabdoid tumor (MRT)/ rhabdoid tumor of kidney (RTK)/select tumors with rhabdoid features who participated in the dose expansion portion of the study. Subjects whose disease was without central nervous system (CNS) involvement received 520 mg/m^2 open-label, tazemetostat BID orally in continuous 28-day cycles. Subjects whose disease had CNS involvement received 1200 mg/m^2 open-label, tazemetostat BID orally in continuous 28-day cycles.

    Reporting group title
    Dose Expansion Cohort 3
    Reporting group description
    Subjects with INI-negative tumors who participated in the dose expansion portion of the study. Subjects whose disease was without central nervous system (CNS) involvement received 520 mg/m^2 open-label, tazemetostat BID orally in continuous 28-day cycles. Subjects whose disease had CNS involvement received 1200 mg/m^2 open-label, tazemetostat BID orally in continuous 28-day cycles.

    Reporting group title
    Dose Expansion Cohort 4
    Reporting group description
    Subjects with one of the tumor types defined in Cohorts 1 through 3 or synovial sarcoma with SS18-SSX rearrangement received 800 mg/m^2 tazemetostat three times daily (TID) orally in continuous 28-day cycles.

    Reporting group values
    Dose Escalation Level 1 Dose Escalation Level 2 Dose Escalation Level 3 Dose Escalation Level 4 Dose Escalation Level 5 Dose Escalation Level 6 Dose Escalation Level 7 Dose Expansion Cohort 1 Dose Expansion Cohort 2 Dose Expansion Cohort 3 Dose Expansion Cohort 4 Total
    Number of subjects
    8 6 6 7 6 6 7 19 20 18 6 109
    Age categorical
    Units: Subjects
        Infants and toddlers (28 days-23 months)
    4 1 1 1 0 1 2 2 5 0 0 17
        Children (2-11 years)
    4 0 4 6 4 5 4 15 13 5 2 62
        Adolescents (12-17 years)
    0 5 1 0 2 0 1 2 2 12 2 27
        Adults (18-64 years)
    0 0 0 0 0 0 0 0 0 1 2 3
    Gender categorical
    Units: Subjects
        Female
    4 4 5 5 2 4 2 12 7 11 3 59
        Male
    4 2 1 2 4 2 5 7 13 7 3 50
    Race
    Units: Subjects
        Asian
    0 0 1 1 0 1 0 0 1 0 0 4
        Black or African American
    1 0 0 1 1 1 1 2 0 1 0 8
        White
    7 6 4 5 4 4 5 14 12 14 4 79
        Unknown or Not Reported
    0 0 1 0 1 0 1 3 7 3 2 18
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    0 0 3 0 1 0 1 5 2 4 1 17
        Not Hispanic or Latino
    8 4 2 7 4 5 5 13 14 12 5 79
        Unknown or Not Reported
    0 2 1 0 1 1 1 1 4 2 0 13

    End points

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    End points reporting groups
    Reporting group title
    Dose Escalation Level 1
    Reporting group description
    Subjects with relapsed/refractory rhabdoid tumors, INI1-negative tumors, or synovial sarcoma with SS18-SSX rearrangement received oral tazemetostat 240 milligrams per square meter (mg/m^2) BID in continuous 28-day cycles.

    Reporting group title
    Dose Escalation Level 2
    Reporting group description
    Subjects with relapsed/refractory rhabdoid tumors, INI1-negative tumors, or synovial sarcoma with SS18-SSX rearrangement received oral tazemetostat 300 mg/m^2 BID in continuous 28-day cycles.

    Reporting group title
    Dose Escalation Level 3
    Reporting group description
    Subjects with relapsed/refractory rhabdoid tumors, INI1-negative tumors, or synovial sarcoma with SS18-SSX rearrangement received oral tazemetostat 400 mg/m^2 BID in continuous 28-day cycles.

    Reporting group title
    Dose Escalation Level 4
    Reporting group description
    Subjects with relapsed/refractory rhabdoid tumors, INI1-negative tumors, or synovial sarcoma with SS18-SSX rearrangement received oral tazemetostat 520 mg/m^2 BID in continuous 28-day cycles.

    Reporting group title
    Dose Escalation Level 5
    Reporting group description
    Subjects with relapsed/refractory rhabdoid tumors, INI1-negative tumors, or synovial sarcoma with SS18-SSX rearrangement received oral tazemetostat 700 mg/m^2 BID in continuous 28-day cycles.

    Reporting group title
    Dose Escalation Level 6
    Reporting group description
    Subjects with relapsed/refractory rhabdoid tumors, INI1-negative tumors, or synovial sarcoma with SS18-SSX rearrangement received oral tazemetostat 900 mg/m^2 BID in continuous 28-day cycles.

    Reporting group title
    Dose Escalation Level 7
    Reporting group description
    Subjects with relapsed/refractory rhabdoid tumors, INI1-negative tumors, or synovial sarcoma with SS18-SSX rearrangement received oral tazemetostat 1200 mg/m^2 BID in continuous 28-day cycles.

    Reporting group title
    Dose Expansion Cohort 1
    Reporting group description
    Subjects with atypical teratoid rhabdoid tumor (ATRT) who participated in the dose expansion portion of the study received 1200 mg/m^2 open-label, tazemetostat BID orally in continuous 28-day cycles.

    Reporting group title
    Dose Expansion Cohort 2
    Reporting group description
    Subjects with malignant rhabdoid tumor (MRT)/ rhabdoid tumor of kidney (RTK)/select tumors with rhabdoid features who participated in the dose expansion portion of the study. Subjects whose disease was without central nervous system (CNS) involvement received 520 mg/m^2 open-label, tazemetostat BID orally in continuous 28-day cycles. Subjects whose disease had CNS involvement received 1200 mg/m^2 open-label, tazemetostat BID orally in continuous 28-day cycles.

    Reporting group title
    Dose Expansion Cohort 3
    Reporting group description
    Subjects with INI-negative tumors who participated in the dose expansion portion of the study. Subjects whose disease was without central nervous system (CNS) involvement received 520 mg/m^2 open-label, tazemetostat BID orally in continuous 28-day cycles. Subjects whose disease had CNS involvement received 1200 mg/m^2 open-label, tazemetostat BID orally in continuous 28-day cycles.

    Reporting group title
    Dose Expansion Cohort 4
    Reporting group description
    Subjects with one of the tumor types defined in Cohorts 1 through 3 or synovial sarcoma with SS18-SSX rearrangement received 800 mg/m^2 tazemetostat three times daily (TID) orally in continuous 28-day cycles.

    Subject analysis set title
    Overall Dose Escalation
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Subjects with relapsed/refractory rhabdoid tumors, INI1-negative tumors, or synovial sarcoma with SS18-SSX rearrangement received oral tazemetostat at dose Level 1: 240 mg/m^2 BID, dose level 2: 300 mg/m^2 BID, dose level 3: 400 mg/m^2 BID, dose level 4: 520 mg/m^2 BID, dose level 5: 700 mg/m^2 BID, dose level 6: 900 mg/m^2 BID and dose level 7: 1200 mg/m^2 BID in continuous 28-day cycles.

    Primary: Number of Dose-limiting Toxicities (Dose Escalation Only)

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    End point title
    Number of Dose-limiting Toxicities (Dose Escalation Only) [1] [2]
    End point description
    The RP2D in pediatric subjects treated with tazemetostat as determined by the incidence and severity of treatment-emergent adverse events qualifying as protocol-defined dose-limiting toxicities that occurred during the first month of treatment. Dose-Limiting Toxicity (DLT) population included all subjects in the safety population set who experienced a DLT during Cycle 1 or were not removed from Cycle 1 for reasons other than toxicity and did not have an interruption in study treatment for more than 14 days during Cycle 1. Only those subjects with data collected at Cycle 1 are reported.
    End point type
    Primary
    End point timeframe
    Cycle 1, from the start of study treatment (Day 1) until the end of the first Cycle (Day 28) of treatment
    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: Summary statistics were provided for this study. This was a signal findings study that was not powered to make statistical comparisons.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: There are 8 different phases in the trial (7 dose escalation phases and the dose expansion phase with 4 cohorts) within the same period (overall study). All 8 phases are encompassed within the baseline period but the dose escalation and dose expansion phases have different end points.
    End point values
    Dose Escalation Level 1 Dose Escalation Level 2 Dose Escalation Level 3 Dose Escalation Level 4 Dose Escalation Level 5 Dose Escalation Level 6 Dose Escalation Level 7
    Number of subjects analysed
    5
    6
    6
    6
    6
    6
    6
    Units: number
    0
    1
    0
    0
    0
    1
    0
    No statistical analyses for this end point

    Primary: Overall Response Rate (ORR) (dose expansion only)

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    End point title
    Overall Response Rate (ORR) (dose expansion only) [3] [4]
    End point description
    ORR is defined as the percentage of subjects who achieved a confirmed CR and/or PR defined by RECIST or RANO criteria from the start of tazemetostat treatment until disease progression or the start of subsequent anticancer therapy, whichever occurs first. CR is defined as disappearance of all target and non-target lesions (with all lymph nodes must be non-pathological in size or under 10 millimeters [mm] in short axis) and PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. ORR= CR+PR. The ITT population included all subjects who received at least one dose of tazemetostat.
    End point type
    Primary
    End point timeframe
    RECIST assessments performed at screening (within 14 days before start of study intervention) and every 8 weeks post start of dosing, approximately up to 302 weeks
    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: Summary statistics were provided for this study. This was a signal findings study that was not powered to make statistical comparisons.
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: There are 8 different phases in the trial (7 dose escalation phases and the dose expansion phase with 4 cohorts) within the same period (overall study). All 8 phases are encompassed within the baseline period but the dose escalation and dose expansion phases have different end points.
    End point values
    Dose Expansion Cohort 1 Dose Expansion Cohort 2 Dose Expansion Cohort 3 Dose Expansion Cohort 4
    Number of subjects analysed
    19
    20
    18
    6
    Units: Percentage of participants
        number (not applicable)
    26.3
    0
    16.7
    16.7
    No statistical analyses for this end point

    Primary: Recommended phase 2 dose (RP2D) (dose escalation only)

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    End point title
    Recommended phase 2 dose (RP2D) (dose escalation only) [5]
    End point description
    The incidence and severity of treatment-emergent adverse events qualifying as protocol-defined dose-limiting toxicities that occurred during the first month of treatment was used to determine the RP2D and/or MTD in pediatric subjects treated with tazemetostat. The ITT population included all subjects who received at least one dose of tazemetostat.
    End point type
    Primary
    End point timeframe
    Cycle 1, from the start of study treatment (Day 1) until the end of the first Cycle (Day 28) of treatment
    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: Summary statistics were provided for this study. This was a signal findings study that was not powered to make statistical comparisons.
    End point values
    Overall Dose Escalation
    Number of subjects analysed
    46
    Units: mg/m^2 BID
    number (not applicable)
        RP2D for subjects with ATRT or CNS involvement
    1200
        RP2D for subjects without CNS involvement
    520
    No statistical analyses for this end point

    Secondary: ORR (dose escalation only)

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    End point title
    ORR (dose escalation only) [6]
    End point description
    ORR is defined as the percentage of subjects who achieved a confirmed complete response (CR) and/or partial response (PR) defined by response evaluation criteria in solid tumors (RECIST) or response assessment in neuro-oncology (RANO) criteria from the start of tazemetostat treatment until disease progression or the start of subsequent anticancer therapy, whichever occurs first. CR is defined as disappearance of all target and non-target lesions (with all lymph nodes must be non-pathological in size or under 10 mm in short axis) and PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. ORR= CR+PR. The ITT population included all subjects who received at least one dose of tazemetostat.
    End point type
    Secondary
    End point timeframe
    RECIST assessments performed at screening (within 14 days before start of study intervention) and every 8 weeks post start of dosing, approximately up to 302 weeks
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: There are 8 different phases in the trial (7 dose escalation phases and the dose expansion phase with 4 cohorts) within the same period (overall study). All 8 phases are encompassed within the baseline period but the dose escalation and dose expansion phases have different end points.
    End point values
    Dose Escalation Level 1 Dose Escalation Level 2 Dose Escalation Level 3 Dose Escalation Level 4 Dose Escalation Level 5 Dose Escalation Level 6 Dose Escalation Level 7
    Number of subjects analysed
    8
    6
    6
    7
    6
    6
    7
    Units: Percentage of participants
        number (not applicable)
    0
    0
    0
    14.3
    16.7
    16.7
    0
    No statistical analyses for this end point

    Secondary: Progression Free Survival (PFS) (dose expansion only)

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    End point title
    Progression Free Survival (PFS) (dose expansion only) [7]
    End point description
    PFS was defined as the interval of time (in weeks) from the date of first dose of study drug and the earliest date of disease progression or death, from any cause defined by RECIST or RANO criteria. Disease progression is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (including at least a 5 mm absolute increase). The presence of new lesions also constitutes to disease progression. The ITT population included all subjects who received at least one dose of tazemetostat.
    End point type
    Secondary
    End point timeframe
    RECIST assessments performed at screening (within 14 days before start of study intervention) and every 8 weeks post start of dosing, approximately up to 302 weeks
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: There are 8 different phases in the trial (7 dose escalation phases and the dose expansion phase with 4 cohorts) within the same period (overall study). All 8 phases are encompassed within the baseline period but the dose escalation and dose expansion phases have different end points.
    End point values
    Dose Expansion Cohort 1 Dose Expansion Cohort 2 Dose Expansion Cohort 3 Dose Expansion Cohort 4
    Number of subjects analysed
    19
    20
    18
    6
    Units: weeks
        median (confidence interval 95%)
    7.9 (6.0 to 24.3)
    7.7 (3.4 to 8.0)
    15.9 (8.0 to 21.3)
    28.3 (7.9 to 145.4)
    No statistical analyses for this end point

    Secondary: Overall survival (OS) (dose expansion Only)

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    End point title
    Overall survival (OS) (dose expansion Only) [8]
    End point description
    Overall survival was defined as the time (in weeks) from the first dose of study drug to the date of death due to any cause. The ITT population included all subjects who received at least one dose of tazemetostat.
    End point type
    Secondary
    End point timeframe
    RECIST assessments performed at screening (within 14 days before start of study intervention) and every 8 weeks post start of dosing, approximately up to 302 weeks
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: There are 8 different phases in the trial (7 dose escalation phases and the dose expansion phase with 4 cohorts) within the same period (overall study). All 8 phases are encompassed within the baseline period but the dose escalation and dose expansion phases have different end points.
    End point values
    Dose Expansion Cohort 1 Dose Expansion Cohort 2 Dose Expansion Cohort 3 Dose Expansion Cohort 4
    Number of subjects analysed
    19
    20
    18
    6
    Units: weeks
        median (confidence interval 95%)
    21.4 (11.0 to 50.3)
    14.1 (6.9 to 22.4)
    41.8 (18.6 to 55.6)
    103.1 (12.3 to 185.6)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    TEAEs:Day 1 until earlier of either 30 days after discontinuation of study treatment or until initiation of subsequent anticancer therapy, approximately 114 weeks (dose escalation phase) and 138.7 weeks (dose expansion phase). Deaths:Day 1 up to 302 weeks
    Adverse event reporting additional description
    The safety population consists of all subjects in the ITT population who had at least one post-dose safety observation recorded.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Dose Escalation Level 1
    Reporting group description
    Subjects with relapsed/refractory rhabdoid tumors, INI1-negative tumors, or synovial sarcoma with SS18-SSX rearrangement received oral tazemetostat 240 mg/m^2 BID in continuous 28-day cycles.

    Reporting group title
    Dose Escalation Level 2
    Reporting group description
    Subjects with relapsed/refractory rhabdoid tumors, INI1-negative tumors, or synovial sarcoma with SS18-SSX rearrangement received oral tazemetostat 300 mg/m^2 BID in continuous 28-day cycles.

    Reporting group title
    Dose Escalation Level 3
    Reporting group description
    Subjects with relapsed/refractory rhabdoid tumors, INI1-negative tumors, or synovial sarcoma with SS18-SSX rearrangement received oral tazemetostat 400 mg/m^2 BID in continuous 28-day cycles.

    Reporting group title
    Dose Escalation Level 4
    Reporting group description
    Subjects with relapsed/refractory rhabdoid tumors, INI1-negative tumors, or synovial sarcoma with SS18-SSX rearrangement received oral tazemetostat 520 mg/m^2 BID in continuous 28-day cycles.

    Reporting group title
    Dose Escalation Level 5
    Reporting group description
    Subjects with relapsed/refractory rhabdoid tumors, INI1-negative tumors, or synovial sarcoma with SS18-SSX rearrangement received oral tazemetostat 700 mg/m^2 BID in continuous 28-day cycles.

    Reporting group title
    Dose Escalation Level 6
    Reporting group description
    Subjects with relapsed/refractory rhabdoid tumors, INI1-negative tumors, or synovial sarcoma with SS18-SSX rearrangement received oral tazemetostat 900 mg/m^2 BID in continuous 28-day cycles.

    Reporting group title
    Dose Escalation Level 7
    Reporting group description
    Subjects with relapsed/refractory rhabdoid tumors, INI1-negative tumors, or synovial sarcoma with SS18-SSX rearrangement received oral tazemetostat 1200 mg/m^2 BID in continuous 28-day cycles.

    Reporting group title
    Dose Expansion Cohort 1
    Reporting group description
    Subjects with ATRT who participated in the dose expansion portion of the study received 1200 mg/m^2 open-label, tazemetostat BID orally in continuous 28-day cycles.

    Reporting group title
    Dose Expansion Cohort 2
    Reporting group description
    Subjects with MRT/ RTK/select tumors with rhabdoid features who participated in the dose expansion portion of the study. Subjects whose disease was without CNS involvement received 520 mg/m^2 open-label, tazemetostat BID orally in continuous 28-day cycles. Subjects whose disease had CNS involvement received 1200 mg/m^2 open-label, tazemetostat BID orally in continuous 28-day cycles

    Reporting group title
    Dose Expansion Cohort 3
    Reporting group description
    Subjects with INI-negative tumors who participated in the dose expansion portion of the study. Subjects whose disease was without CNS involvement received 520 mg/m^2 open-label, tazemetostat BID orally in continuous 28-day cycles. Subjects whose disease had CNS involvement received 1200 mg/m^2 open-label, tazemetostat BID orally in continuous 28-day cycles.

    Reporting group title
    Dose Expansion Cohort 4
    Reporting group description
    Subjects with one of the tumor types defined in Cohorts 1 through 3 or synovial sarcoma with SS18-SSX rearrangement received 800 mg/m^2 tazemetostat TID orally in continuous 28-day cycles.

    Serious adverse events
    Dose Escalation Level 1 Dose Escalation Level 2 Dose Escalation Level 3 Dose Escalation Level 4 Dose Escalation Level 5 Dose Escalation Level 6 Dose Escalation Level 7 Dose Expansion Cohort 1 Dose Expansion Cohort 2 Dose Expansion Cohort 3 Dose Expansion Cohort 4
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 8 (50.00%)
    1 / 6 (16.67%)
    3 / 6 (50.00%)
    2 / 7 (28.57%)
    3 / 6 (50.00%)
    4 / 6 (66.67%)
    2 / 7 (28.57%)
    12 / 19 (63.16%)
    10 / 20 (50.00%)
    9 / 18 (50.00%)
    3 / 6 (50.00%)
         number of deaths (all causes)
    7
    6
    4
    4
    5
    4
    7
    15
    18
    16
    4
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Second primary malignancy
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rhabdoid tumour
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Vascular disorders
    Superior vena cava syndrome
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subclavian vein thrombosis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 3
    0 / 0
    0 / 7
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Hypoxia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    2 / 20 (10.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    3 / 20 (15.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 3
    0 / 1
    0 / 0
    Apnoea
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract inflammation
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung consolidation
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Platelet count decreased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Unintentional medical device removal
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint injury
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Hydrocephalus
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    4 / 19 (21.05%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 5
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    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
    0 / 0
    0 / 0
    0 / 0
    Cerebrospinal fluid leakage
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Visual impairment
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    2 / 19 (10.53%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary tract obstruction
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    2 / 19 (10.53%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CNS ventriculitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Laryngitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mastoid abscess
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oral herpes
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Otitis externa
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Otitis media
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumococcal bacteraemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Streptococcal bacteraemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular device infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vulval abscess
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Dose Escalation Level 1 Dose Escalation Level 2 Dose Escalation Level 3 Dose Escalation Level 4 Dose Escalation Level 5 Dose Escalation Level 6 Dose Escalation Level 7 Dose Expansion Cohort 1 Dose Expansion Cohort 2 Dose Expansion Cohort 3 Dose Expansion Cohort 4
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 8 (100.00%)
    5 / 6 (83.33%)
    6 / 6 (100.00%)
    7 / 7 (100.00%)
    6 / 6 (100.00%)
    6 / 6 (100.00%)
    6 / 7 (85.71%)
    19 / 19 (100.00%)
    19 / 20 (95.00%)
    18 / 18 (100.00%)
    6 / 6 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    0
    4
    3
    0
    0
    0
    0
    0
    0
    Tumour pain
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    2 / 19 (10.53%)
    2 / 20 (10.00%)
    3 / 18 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    3
    0
    2
    0
    0
    3
    2
    3
    0
    Melanocytic naevus
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Skin papilloma
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Peritumoural oedema
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Tumour haemorrhage
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    2
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 19 (5.26%)
    3 / 20 (15.00%)
    2 / 18 (11.11%)
    1 / 6 (16.67%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    1
    1
    3
    3
    3
    Embolism
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    1
    0
    Hot flush
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    2 / 18 (11.11%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    2
    0
    Hypotension
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    1
    0
    1
    0
    Lymphoedema
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Venous thrombosis limb
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 8 (0.00%)
    3 / 6 (50.00%)
    2 / 6 (33.33%)
    1 / 7 (14.29%)
    2 / 6 (33.33%)
    3 / 6 (50.00%)
    1 / 7 (14.29%)
    4 / 19 (21.05%)
    2 / 20 (10.00%)
    5 / 18 (27.78%)
    2 / 6 (33.33%)
         occurrences all number
    0
    3
    3
    1
    2
    3
    1
    4
    2
    7
    3
    Pyrexia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    2 / 7 (28.57%)
    3 / 6 (50.00%)
    2 / 6 (33.33%)
    1 / 7 (14.29%)
    4 / 19 (21.05%)
    5 / 20 (25.00%)
    7 / 18 (38.89%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    1
    2
    5
    4
    1
    6
    8
    16
    0
    Oedema peripheral
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    2 / 19 (10.53%)
    1 / 20 (5.00%)
    5 / 18 (27.78%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    2
    1
    6
    0
    Asthenia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    1 / 20 (5.00%)
    1 / 18 (5.56%)
    3 / 6 (50.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    1
    1
    3
    Gait disturbance
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    2 / 19 (10.53%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    2
    0
    0
    1
    Catheter site swelling
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Chest pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    1
    1
    Chills
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Face oedema
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    1
    0
    0
    Feeling cold
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Localised oedema
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    3
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Malaise
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    1 / 18 (5.56%)
    1 / 6 (16.67%)
         occurrences all number
    0
    2
    0
    0
    1
    0
    0
    0
    1
    1
    1
    Catheter site pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Influenza like illness
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Axillary pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Catheter site erosion
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Generalised oedema
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Peripheral swelling
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    1
    0
    0
    Reproductive system and breast disorders
    Vulvovaginal rash
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Vulvovaginal pruritus
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Breast pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Dysmenorrhoea
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Menorrhagia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    2
    0
    Menstruation irregular
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    3 / 6 (50.00%)
    3 / 6 (50.00%)
    2 / 7 (28.57%)
    6 / 19 (31.58%)
    4 / 20 (20.00%)
    6 / 18 (33.33%)
    3 / 6 (50.00%)
         occurrences all number
    0
    4
    1
    0
    5
    9
    2
    11
    5
    8
    4
    Nasal congestion
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    2 / 7 (28.57%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    2 / 7 (28.57%)
    2 / 19 (10.53%)
    1 / 20 (5.00%)
    2 / 18 (11.11%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    2
    0
    3
    2
    2
    1
    2
    0
    Dyspnoea
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    3 / 6 (50.00%)
         occurrences all number
    0
    4
    0
    0
    2
    0
    0
    2
    2
    0
    4
    Hypoxia
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    2 / 20 (10.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    1
    0
    0
    0
    0
    1
    3
    3
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    3 / 18 (16.67%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    0
    0
    4
    1
    Pleural effusion
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Tachypnoea
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    2 / 20 (10.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    0
    0
    2
    0
    0
    Atelectasis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    1
    0
    0
    Dysphonia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Epistaxis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    0
    1
    0
    1
    0
    Productive cough
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    1
    0
    0
    Rales
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Rhinitis allergic
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    2 / 19 (10.53%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    2
    0
    0
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    2
    0
    0
    0
    0
    0
    Interstitial lung disease
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Lung consolidation
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Stridor
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    1
    0
    Yawning
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Increased bronchial secretion
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Pneumothorax
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Wheezing
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Psychiatric disorders
    Irritability
         subjects affected / exposed
    3 / 8 (37.50%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    2 / 19 (10.53%)
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    4
    0
    0
    0
    0
    0
    2
    2
    1
    0
    0
    Insomnia
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    3 / 18 (16.67%)
    1 / 6 (16.67%)
         occurrences all number
    1
    2
    0
    0
    0
    1
    0
    2
    0
    3
    1
    Anxiety
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    2 / 18 (11.11%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    1
    0
    2
    0
    Restlessness
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Behaviour disorder
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Fear
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Agitation
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    1
    0
    Delirium
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Depressed mood
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Depression
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    2 / 18 (11.11%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    2
    0
    Euphoric mood
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Mental disorder
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Mental status changes
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Nightmare
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Investigations
    Platelet count decreased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    3 / 6 (50.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    2 / 20 (10.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    2
    5
    0
    6
    0
    4
    7
    0
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    2 / 19 (10.53%)
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    0
    1
    0
    1
    1
    3
    1
    0
    1
    Lymphocyte count decreased
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    2 / 19 (10.53%)
    3 / 20 (15.00%)
    2 / 18 (11.11%)
    0 / 6 (0.00%)
         occurrences all number
    3
    0
    0
    1
    0
    1
    1
    4
    3
    2
    0
    Weight decreased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    3 / 20 (15.00%)
    0 / 18 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    3
    0
    8
    Blood bromide increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    2 / 19 (10.53%)
    1 / 20 (5.00%)
    1 / 18 (5.56%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    3
    1
    1
    2
    Bacterial test positive
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    2 / 19 (10.53%)
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    4
    1
    0
    0
    0
    2
    1
    0
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    4
    0
    0
    0
    0
    0
    2
    0
    Blood creatinine increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    3
    0
    2
    Weight increased
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    2 / 18 (11.11%)
    0 / 6 (0.00%)
         occurrences all number
    0
    3
    0
    0
    0
    0
    0
    0
    1
    2
    0
    White blood cell count decreased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    2 / 19 (10.53%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    2
    0
    1
    0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    2
    0
    0
    1
    Neutrophil count decreased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    C-reactive protein increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    1
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    2 / 7 (28.57%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    1
    4
    0
    0
    0
    0
    0
    0
    0
    Skin laceration
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    1
    0
    0
    0
    Skin abrasion
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Ligament sprain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Arthropod sting
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Fracture
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Spinal fracture
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    1 / 19 (5.26%)
    2 / 20 (10.00%)
    1 / 18 (5.56%)
    1 / 6 (16.67%)
         occurrences all number
    2
    0
    1
    0
    0
    1
    2
    1
    2
    1
    2
    Left ventricular dysfunction
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    1
    0
    0
    Wolff-Parkinson-White syndrome
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Defect conduction intraventricula
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Sinus bradycardia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Tachycardia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    2 / 20 (10.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    2
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 6 (33.33%)
    3 / 6 (50.00%)
    2 / 7 (28.57%)
    2 / 6 (33.33%)
    2 / 6 (33.33%)
    1 / 7 (14.29%)
    4 / 19 (21.05%)
    1 / 20 (5.00%)
    7 / 18 (38.89%)
    3 / 6 (50.00%)
         occurrences all number
    0
    2
    3
    2
    3
    2
    1
    6
    1
    9
    3
    Dizziness
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    2 / 18 (11.11%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    0
    0
    0
    2
    2
    0
    0
    2
    2
    Paraesthesia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    1
    1
    0
    0
    0
    0
    0
    1
    0
    Dysmetria
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Auditory nerve disorder
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Facial nerve disorder
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Facial paresis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    1
    0
    IIIrd nerve paralysis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    IVth nerve paralysis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Lethargy
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Tremor
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    0
    0
    0
    1
    1
    VIth nerve paralysis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Disturbance in attention
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Drooling
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Dysgeusia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    2
    1
    0
    1
    Dyskinesia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    1
    1
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Hemiparesis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Ataxia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Hyperaesthesia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Neuralgia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Neuromyopathy
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Seizure
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Sensory loss
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Somnolence
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    VIth nerve disorder
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    2 / 7 (28.57%)
    4 / 19 (21.05%)
    8 / 20 (40.00%)
    5 / 18 (27.78%)
    0 / 6 (0.00%)
         occurrences all number
    3
    1
    2
    1
    1
    3
    4
    29
    18
    13
    0
    Lymphopenia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    3 / 6 (50.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    3
    1
    0
    0
    10
    Thrombocytopenia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    2 / 6 (33.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    4
    1
    0
    1
    7
    Leukopenia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    3
    0
    0
    0
    1
    Lymphadenopathy
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Neutropenia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    2
    0
    0
    1
    0
    Neutrophilia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Leukocytosis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    3
    0
    Ear and labyrinth disorders
    Deafness
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Ear discomfort
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Ear pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    3
    0
    1
    0
    2
    0
    Motion sickness
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Tympanic membrane perforation
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Hypoacusis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    2 / 19 (10.53%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    3
    0
    0
    0
    External ear inflammation
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Otorrhoea
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Deafness transitory
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Deafness unilateral
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Tinnitus
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Eye disorders
    Dry eye
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    1
    0
    0
    1
    0
    Eye pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Eyelid function disorder
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Conjunctivitis allergic
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Corneal epithelium defect
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Exophthalmos
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Gaze palsy
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Neurotrophic keratopathy
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Papilloedema
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Photophobia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    1 / 8 (12.50%)
    2 / 6 (33.33%)
    3 / 6 (50.00%)
    2 / 7 (28.57%)
    3 / 6 (50.00%)
    2 / 6 (33.33%)
    6 / 7 (85.71%)
    11 / 19 (57.89%)
    9 / 20 (45.00%)
    11 / 18 (61.11%)
    5 / 6 (83.33%)
         occurrences all number
    1
    3
    5
    4
    7
    4
    12
    19
    14
    34
    19
    Nausea
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 6 (33.33%)
    3 / 6 (50.00%)
    1 / 7 (14.29%)
    3 / 6 (50.00%)
    2 / 6 (33.33%)
    1 / 7 (14.29%)
    6 / 19 (31.58%)
    5 / 20 (25.00%)
    11 / 18 (61.11%)
    3 / 6 (50.00%)
         occurrences all number
    0
    2
    6
    1
    5
    3
    1
    6
    5
    16
    3
    Constipation
         subjects affected / exposed
    1 / 8 (12.50%)
    2 / 6 (33.33%)
    3 / 6 (50.00%)
    1 / 7 (14.29%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    2 / 19 (10.53%)
    4 / 20 (20.00%)
    3 / 18 (16.67%)
    2 / 6 (33.33%)
         occurrences all number
    1
    2
    4
    1
    1
    1
    1
    2
    4
    3
    2
    Diarrhoea
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    2 / 7 (28.57%)
    4 / 6 (66.67%)
    2 / 6 (33.33%)
    1 / 7 (14.29%)
    7 / 19 (36.84%)
    3 / 20 (15.00%)
    7 / 18 (38.89%)
    2 / 6 (33.33%)
         occurrences all number
    0
    3
    0
    3
    6
    6
    1
    12
    3
    11
    4
    Abdominal pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    3 / 6 (50.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    4 / 20 (20.00%)
    3 / 18 (16.67%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    2
    4
    2
    0
    1
    4
    6
    1
    Stomatitis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    1 / 20 (5.00%)
    3 / 18 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    1
    4
    0
    Abdominal distension
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    1
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    0
    0
    1
    Chapped lips
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Dyspepsia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    1
    0
    Flatulence
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    0
    1
    0
    0
    0
    Gastritis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    2
    0
    0
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    1
    0
    Lip blister
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Teething
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Cheilitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    2
    0
    0
    0
    Dysphagia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Haemorrhoids
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Abdominal discomfort
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Ascites
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    2 / 20 (10.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    2
    0
    0
    Duodenal obstruction
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Haematemesis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Melaena
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Mouth ulceration
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Odynophagia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Oesophagitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Tongue erythema
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Tooth development disorder
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Toothache
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    1
    Hepatobiliary disorders
    Hepatitis toxic
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Cholestasis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Hepatocellular injury
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    3
    0
    Jaundice
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    1
    0
    0
    0
    1
    1
    0
    0
    0
    1
    Erythema
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    2 / 19 (10.53%)
    2 / 20 (10.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    1
    2
    2
    0
    0
    Pruritus
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    3 / 20 (15.00%)
    2 / 18 (11.11%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    1
    0
    0
    0
    1
    3
    3
    0
    Alopecia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    3 / 18 (16.67%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    3
    1
    Blister
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Hyperhidrosis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Skin hyperpigmentation
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    0
    0
    1
    0
    Dermatitis acneiform
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    2
    0
    Hair texture abnormal
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Onychoclasis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Rash
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    0
    0
    1
    0
    Rash erythematous
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Rash macular
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Rash papular
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Urticaria
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    4
    0
    Dermatitis diaper
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    2 / 19 (10.53%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    2
    0
    0
    0
    Scab
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Skin lesion
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    2
    0
    0
    0
    Acne
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Dermatitis bullous
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Dermatitis contact
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Eczema
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Nail disorder
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Rash maculo-papular
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    2
    0
    Telangiectasia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Renal and urinary disorders
    Urinary incontinence
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Proteinuria
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    3
    0
    0
    1
    0
    0
    0
    Urine odour abnormal
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Acute kidney injury
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Haematuria
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    2
    Nephrolithiasis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    4 / 18 (22.22%)
    2 / 6 (33.33%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    4
    2
    Pain in extremity
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    2 / 20 (10.00%)
    1 / 18 (5.56%)
    1 / 6 (16.67%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    2
    2
    1
    1
    Facial asymmetry
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Myalgia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    1
    0
    0
    0
    1
    Arthralgia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    2
    0
    0
    1
    Joint range of motion decreased
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Muscle spasms
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Muscular weakness
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    1
    1
    0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    0
    3
    0
    0
    0
    0
    0
    1
    1
    Neck pain
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    2 / 18 (11.11%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    0
    2
    0
    Bone pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Fracture pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    2
    0
    0
    Groin pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    2
    0
    Infections and infestations
    Otitis media
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    3 / 19 (15.79%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    2
    0
    2
    1
    1
    0
    3
    0
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 7 (28.57%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    2 / 19 (10.53%)
    1 / 20 (5.00%)
    3 / 18 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    9
    1
    2
    1
    3
    1
    3
    0
    Rhinitis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    2 / 20 (10.00%)
    1 / 18 (5.56%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    1
    0
    0
    5
    0
    4
    2
    2
    1
    Urinary tract infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    2 / 20 (10.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    2
    1
    0
    Oral candidiasis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    0
    1
    1
    0
    Candida infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Hordeolum
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    0
    0
    0
    0
    Mucosal infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    1
    0
    1
    0
    Otitis externa
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    5
    0
    0
    0
    Otitis media acute
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Pharyngitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Pharyngitis streptococcal
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    1
    0
    0
    Pneumonia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    2 / 20 (10.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    0
    0
    3
    0
    0
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Sinusitis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Skin infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    1
    1
    0
    Tinea pedis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Viral rash
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Conjunctivitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    1
    Escherichia urinary tract infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    2
    0
    0
    0
    Fungal skin infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Herpes simplex
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    4
    0
    0
    0
    Impetigo
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    3
    0
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    1
    1
    Parainfluenzae virus infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Pneumonia pneumococcal
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Respiratory syncytial virus infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Rhinovirus infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    1
    0
    0
    Skin candida
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Viral infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Viral rhinitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Body tinea
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    COVID-19
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Coronavirus infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Device related infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    1
    0
    Enterovirus infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Gastrointestinal viral infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Influenza
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Urinary tract infection pseudomonal
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    3 / 7 (42.86%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    5 / 19 (26.32%)
    4 / 20 (20.00%)
    4 / 18 (22.22%)
    1 / 6 (16.67%)
         occurrences all number
    1
    0
    2
    3
    2
    0
    1
    5
    4
    4
    1
    Hypokalaemia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    3 / 19 (15.79%)
    2 / 20 (10.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    0
    1
    0
    0
    1
    0
    5
    2
    0
    2
    Hypertriglyceridaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    2 / 19 (10.53%)
    1 / 20 (5.00%)
    2 / 18 (11.11%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    2
    1
    3
    0
    Hypophosphataemia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    1 / 20 (5.00%)
    1 / 18 (5.56%)
    2 / 6 (33.33%)
         occurrences all number
    1
    0
    0
    0
    6
    0
    0
    4
    1
    1
    2
    Hypermagnesaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    1 / 20 (5.00%)
    1 / 18 (5.56%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    2
    1
    1
    1
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    2 / 19 (10.53%)
    2 / 20 (10.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    3
    0
    0
    0
    0
    4
    2
    0
    0
    Hyponatraemia
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    2 / 20 (10.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    1
    2
    0
    0
    Dehydration
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    1
    0
    0
    1
    Hyperchloraemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    1
    0
    1
    0
    Hyperglycaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Hyperkalaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    1
    0
    2
    0
    Hyperuricaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Hypomagnesaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    2 / 19 (10.53%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    3
    0
    0
    1
    Hypercalcaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    1
    0
    0
    Hypoglycaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Vitamin D deficiency
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 19 (5.26%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    1
    0
    Hypernatraemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    1 / 20 (5.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Hypocalcaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 19 (0.00%)
    0 / 20 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Jul 2015
    Original Protocol submitted to FDA, never submitted to sites.
    24 Aug 2015
    Amendment v1.0 – submitted to all sites. Key changes: - Added a dose level to start at a lower dose (240mg/m2 vs. original 300mg/m2) and effectively increasing the dose escalation phase numbers from 18 to 24 subjects. - Additional details on blood sampling volumes added. - Removed mandatory requirement to collect date of birth.
    02 Oct 2015
    Amendment v2.0 – submitted to all sites. Key changes: - Added selected tumors with rhabdoid features that responses were seen in Phase 1 (SMARCA4 loss in MRTO or SCCOHT). - Removed requirement for fasting based upon data in food-effect study. - Removed restriction for pregnancy prevention 30 days prior to entry.
    12 Oct 2015
    Amendment v2.1 – Country-specific for Germany Key changes: - Upper age limit changes to <12 years old due to inability to do Panorex films in Germany (radiation exposure an issue). - Removed MUGA scan as it is not performed in Germany. - Removed bone monitoring and Karnofsky performance due to age change.
    03 Dec 2015
    Amendment v2.2 – Country-specific for United Kingdom Key changes: - Lower age limit increased to >1 year old (vs. 6 mos for rest of world). - No subjects <5 years old in UK will be enrolled until 4 subjects study wide have received at least 4 weeks of study drug. - Pregnancy prevention in females and males updated to reflect UK law.
    31 Mar 2016
    Amendment v2.3 – Country-specific for Germany Key changes: - Removal of synovial and other INI1-negative/SMARCA4 negative tumors
    11 May 2016
    Amendment v3.0 – submitted to all sites. Key changes: - Changes to include treated brain mets. - Remove Panorex. - Remove baseline visit and other changes made to 202. - Add cohorts - Cohort 1: atypical teratoid rhabdoid tumor (ATRT), Cohort 2: non-ATRT rhabdoid tumors and Cohort 3: INI1-negative tumors or synovial sarcoma.
    22 Jun 2016
    Amendment v3.1 – Country-specific for Germany Key changes: - Incorporating all changes from amendment v3.0
    13 Jul 2016
    Amendment v3.2 – Country-specific for United Kingdom Key changes: - Incorporating all changes from amendment v3.0
    27 Jul 2016
    Amendment v4.0 – submitted to all sites Key changes: - Four dose expansion levels added. - Number of subjects changed from 84 to 108. - Allow replacement of subjects who discontinue in absence of a dose-limiting toxicity [DLT] prior to the completing of the DLT evaluation period.
    02 Aug 2016
    Amendment v4.1 – Country-specific for Germany Key changes: - All changes from v4.0 incorporated
    21 Oct 2016
    Amendment v4.3 – Country-specific for United Kingdom Key changes: - All changes from v4.0 incorporated
    20 Jul 2017
    Amendment v5.0 – submitted to all sites Key changes: - RP2D was determined to be 1200 mg/m2 BID and will be used in the dose expansion portion of the study. - New cohort 4 added for subjects ≥10 years to ≤21 years to receive tazemetostat tablets. - Number of subjects changed from 108 to 120. - Information on hydrobromide salt, hyperchloremia and potential associated toxicities added. - Cycle length and study procedure timings changed for Cycles 13 and beyond to 21 days.
    26 Jul 2017
    Amendment v5.3 – Country-specific for United Kingdom Key changes: - Tablet formulation cohort added; this cohort (Cohort 4) will not enroll subjects in Germany - The RP2D was determined to be 1200 mg/m2 BID and will be the dose used in the dose expansion portion of the study - New cohort added to Dose Expansion phase of study (outside of Germany): Cohort 4 to received tazemetostat tablets 800 mg/m2 TID [2400 mg/m2/day]); Subjects are to be ≥10 years to ≤21 years with one of the tumor types defined in Cohorts 1 through 3 or synovial sarcoma with SS18-SSX rearrangement and able to swallow tablets) - Information on hydrobromide salt, hyperchloremia, and potential associated toxicities had been added; also, bromide measurements have been added - Number of subjects increased from 108 to 120 - Additional preliminary PK data added - Additional prohibited medications added - Cycle length for Cycles 13 and beyond changed to 21 days. - Study procedure timings updated for Cycles 13 and beyond to reflect 21-day cycle - Dose modification information has been updated - Expansion of requirements for additional biopsies for subjects who progress to include all subjects (including SD) not just subjects who experienced PR or better. - Safety section has been updated - New appendix added for Cohort 4 dosing and dose modification - Minor corrections
    03 Aug 2017
    Amendment v5.1 – Country-specific for Germany Key changes: - Tablet formulation cohort added; this cohort (Cohort 4) will not enroll subjects in Germany - The RP2D was determined to be 1200 mg/m2 BID and will be the dose used in the dose expansion portion of the study - New cohort added to Dose Expansion phase of study (outside of Germany): Cohort 4 to received tazemetostat tablets 800 mg/m2 TID [2400 mg/m2/day]); Subjects are to be ≥10 years to ≤21 years with one of the tumor types defined in Cohorts 1 through 3 or synovial sarcoma with SS18-SSX rearrangement and able to swallow tablets) - Information on hydrobromide salt, hyperchloremia, and potential associated toxicities had been added; also, bromide measurements have been added - Number of subjects increased from 108 to 120 - Additional preliminary PK data added - Additional prohibited medications added - Cycle length for Cycles 13 and beyond changed to 21 days. - Study procedure timings updated for Cycles 13 and beyond to reflect 21-day cycle - Dose modification information has been updated - Expansion of requirements for additional biopsies for subjects who progress to include all subjects (including SD) not just subjects who experienced PR or better. - Safety section has been updated - New appendix added for Cohort 4 dosing and dose modification - Minor corrections
    31 Oct 2017
    Amendment v5.4 – Country-specific for France Key changes: - Updated text on phototoxicity. - Updated text to clarify chloride levels are assessed at every visit locally and centrally and bromide levels will be analyzed centrally. - Added additional prohibited meds. - Removed PD samples at C13 and beyond. - Correct inconsistency in Exclusion criteria #11 in two different sections of the protocol. - Remove PD blood sample collection from procedures and assessments conducted at Cycle 13 and beyond. Add language about stopping PD sample collection after 20 evaluable PD samples are collected through Day 15 upon Sponsor notification. - Minor corrections
    01 Feb 2018
    Amendment v5.5 – Country-specific for France Key changes: - Option to change from suspension to tablets
    28 Sep 2018
    Amendment v6.0 – submitted to all sites Key changes: - All changes from v5.5 - Updated with 2 new AESIs – T-LBL/T-ALL and MDS. - Added exclusion criteria to exclude patients with thrombocytopenia, neutropenia, anemia of Grade ≥3 and history of MDS and T-LBL and MDS. - Hold treatment to either modify or discontinue if patient develop MDS/AML. - Patients have a maximum of cumulative 2 years on the study. - Updated dose modification or discontinuation section. - Changed age from ≤21 years to <18 years. - Addition of assessments – blood smear morphology and annual PK. - Removed Cycle 13 and beyond study design. - Allow patients to change to tablet dosing after completion of Cycle 1
    10 Oct 2018
    Amendment v6.2 – Country-specific for United Kingdom - All changes from v6.0 incorporated
    07 Nov 2018
    Amendment v6.1 – Country-specific for Germany - All changes from v6.0 incorporated
    13 Dec 2018
    Amendment v7.2 – Country-specific for United Kingdom - All changes from v7.0 incorporated
    17 Dec 2018
    Amendment v7.0 – submitted to all sites. Key changes: - Addition of the option to discontinue treatment if the Investigator determines the dose of tazemetostat must be modified for subjects enrolled in the dose expansion part of the study. - Alignment of the disease assessment frequency of bone scans with the RECIST guidelines in Appendix 4. - Update of dose rationale language with the starting dose of 520 mg/m2 BID for newly enrolled subjects with non-ATRT tumors to align with the new dosing requirements. - Cohort 1 enrollment has been closed as there has been sufficient data collected in pediatric subjects with ATRT. - Cohort 4 enrollment has been closed as there has been sufficient pharmacokinetic data collected in pediatric subjects who were administered tazemetostat in tablet form. - Removal of language allowing subjects who do not have clinical or radiographic disease progression and do not experience unacceptable toxicity to receive tazemetostat beyond cycle 1. Removal of language allowing subjects who have modest disease progression in the absence of clinical deterioration to remain on study. - Addition of the definition of adverse drug reaction to the overall definitions section. - Addition of the definition of a suspected unexpected serious adverse reaction (SUSAR) to the overall definitions section. - Addition of safety language to suggest that rapid communication of adverse events of special interest should be communicated to the Sponsor to allow the event to be understood and characterized in a timely manner. - Removal of dose escalation from interim analysis section of the statistical analysis plan, as this was added in error. - Change in the confidence interval from 90% to 95% when calculating overall survival, and from 80% to 95% when calculating objective response rate.
    15 Mar 2019
    Amendment v6.3 – Country-specific for Germany Key changes: - Removal of the option of tablet dosing as dose reduction, if needed, is not possible with the tablet formulations currently in use. - Removal of the requirement of Karnofsky Performance Status >50% for subjects ≥12 years of age as all subjects in Germany are <12 years of age upon enrollment, and the Lansky Performance Scale is used for subjects <12 years of age. - Removal of the requirement specific to French subjects, that they be affiliated with or a beneficiary or a social security category, as this protocol only applies to subjects in Germany. - Removal of the requirement of SMARCA4 loss from IHC or molecular confirmation of SMARCA4 loss as this gene is associated with SCCOHT tumors, which will not be studied in Germany. - Removal of the requirement for subjects enrolled in cohort 4 (not open in Germany) to be able to swallow tablets as tablet dosing options will no longer be permitted. - Removal of language stating that for subjects who have modest disease progression in the absence of clinical deterioration and are receiving clinical benefit in the opinion of the Investigator, the Investigator should contact the Medical Monitor to discuss keeping the subject on study as subjects must come off study in the event of disease progression.
    20 Feb 2020
    Amendment v8.0 – submitted to all sites. Key changes: - Updated the study period to reflect the first subject’s first visit and current projections for last subject last visit. - Updated the anticipated safety profile to align with the current IB. - Included T-LBL/T-ALL with other events that will trigger convening of safety committees and to clarify that consequences of an event of T-LBL/T-ALL will occur regardless of dose level. - Modified dose modification text to state that for MDS, AML or any myeloid malignancy like MPN, tazemetostat will be discontinued. - Removed dose modification sub-section for dose modifications due to MDS. - Adjusted and clarified dose modifications for subjects in dose expansion starting at 1200mg/m2 and for subjects starting at 520mg/m2. - Removed blood chemistry collection at Day 15 of Cycles 2 and beyond to reduce the amount of blood drawn for unnecessary testing. - Modified requirement for the timing of screening disease assessments to allow for assessments done more than 14 days before enrollment. - Updated contraception requirements to reflect current expectations and to align with approved labeling in the US. - Added genitourinary exam to comprehensive physical exam to ensure abnormalities and malignancies are not missed. - Specified that elevated bromide is considered an event of clinical interest, and that events of clinical interest are to be reported in the same manner as SAEs. - Corrected the confidence internal from 90% to 95% to be estimated in the case of sufficient number of deaths to trigger survival endpoint assessments by Brookneyer-Crowley.
    03 Apr 2020
    Amendment v8.2 – Country-specific for United Kingdom - All changed from v8.0 incorporated
    03 Apr 2020
    Amendment v8.3 – Country-specific for Germany - All changed from v8.0 incorporated
    01 Jul 2020
    Amendment v8.4 – Country-specific for Germany Key changes: - Clarification of the roles of existing safety committees. - Corrected an inaccuracy in wording that was made to clarify that if enrollment of new patients is suspended in the event of a new case of T-LBL/T-ALL, patients on study who continue to derive clinical benefit “may” (rather than “will”) be maintained on therapy.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    06 Apr 2018
    On 06 April 2018, an event of T-LBL was observed in a pediatric subject on study EZH-102. The SUSAR of T-LBL resulted in the Sponsor initiating a temporary global halt in enrollment for the pediatric study EZH-102. In addition, this event led to a partial clinical hold (PCH) on new subject enrollment for tazemetostat by the U.S. (FDA), France (ANSM), and Germany (BfArM) across all studies of the Tazemetostat Development Program. Following this report, Epizyme conducted a comprehensive evaluation. Based on this evaluation, we continued to believe that tazemetostat is a clinically active drug and has the potential to benefit both adult and pediatric patients across different tumor types where there are unmet medical needs. We also concluded that the risk assessment identifies a possible direct association between tazemetostat and T-LBL/T-ALL. Epizyme considers the risk for T-LBL/T-ALL in tazemetostat clinical trials to be largely concentrated in pediatric patients based on 1) higher AUC0-24h exposures in pediatric patients, 2) increases over time in age-related thymic involution, and 3) the known epidemiology/pathophysiology of T-LBL/ALL. The risk of T-LBL/T-ALL in adults is not known, however the incidence of treatment-related T-LBL/T-ALL in adults is expected to be uncommon. Heightened surveillance was and continues to be conducted to monitor and identify early signs and symptoms (per local practice/standard of care) of T-LBL/T-ALL so that tazemetostat may be discontinued in the subject and treatment can be initiated for these malignancies. If a case of adult T-LBL/T-ALL occurs, enrollment will be suspended and the benefit-risk of the drug will be assessed by the Tazemetostat Safety Committee and will be communicated to all Health Authorities and Ethics Committees. To date, no adult T-LBL/T-ALL cases have occurred.
    28 Sep 2018

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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