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    Clinical Trial Results:
    A Phase I/II, multicenter, open-label study of EGFRmut–TKI EGF816 administered orally in adult patients with EGFRmut solid malignancies. Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd. com/CtrdWeb/home.nov for complete trial results Summary

    Summary
    EudraCT number
    2013-004482-14
    Trial protocol
    DE   ES   FR   NL   IT  
    Global end of trial date
    15 Aug 2023

    Results information
    Results version number
    v1(current)
    This version publication date
    31 Aug 2024
    First version publication date
    31 Aug 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CEGF816X2101
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02108964
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Novartis Pharma, AG
    Sponsor organisation address
    CH-4002, Basl, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma, AG, 41 613241111, Novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma, AG, 41 613241111, Novartis.email@novartis.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    15 Aug 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Aug 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Phase I • To estimate the maximum tolerated dose (MTD) or recommended Phase II dose (RP2D) of EGF816. Phase II • To investigate the antitumor activity of EGF816 as measured by overall response rate (ORR) determined by Blinded Independent Review Committee (BIRC) assessment in accordance with RECIST 1.1.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    06 Jun 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 24
    Country: Number of subjects enrolled
    Germany: 14
    Country: Number of subjects enrolled
    Japan: 16
    Country: Number of subjects enrolled
    Korea, Republic of: 40
    Country: Number of subjects enrolled
    Netherlands: 4
    Country: Number of subjects enrolled
    Singapore: 48
    Country: Number of subjects enrolled
    Spain: 15
    Country: Number of subjects enrolled
    Taiwan: 23
    Country: Number of subjects enrolled
    United States: 41
    Worldwide total number of subjects
    225
    EEA total number of subjects
    33
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    133
    From 65 to 84 years
    92
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    This is a 2-part study conducted in 14 investigative sites in 9 countries: Phase I part (dose-escalation) and Phase II part (dose expansion)

    Pre-assignment
    Screening details
    370 subjects were screened for eligibility during the 28 days prior to starting study treatment on Cycle 1 Day 1 (C1D1). The eligibility assessments were performed and ensured that all inclusion and exclusion criteria were satisfied

    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
    EGF816 75 mg (Phase I part)
    Arm description
    Participants with locally advanced or metastatic NSCLC harboring specific EGFR mutations were administered with EGF816 75 mg orally once a day as continuous daily dosing in each cycle (of 28 days) during Phase I part of the study.
    Arm type
    Experimental

    Investigational medicinal product name
    EGF816
    Investigational medicinal product code
    EGF816
    Other name
    Nazartinib
    Pharmaceutical forms
    Capsule, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    EGF816 was administered orally once per day with or without food on a continuous dosing schedule. The dose for this arm in this Phase I-part first cohort of participants was 75 mg administered orally on a continuous, once daily schedule.

    Arm title
    EGF816 100 mg (Phase I part)
    Arm description
    Participants with locally advanced or metastatic NSCLC harboring specific EGFR mutations were administered with EGF816 100 mg orally once a day as continuous daily dosing in each cycle (of 28 days) during Phase I part of the study.
    Arm type
    Experimental

    Investigational medicinal product name
    EGF816
    Investigational medicinal product code
    EGF816
    Other name
    Nazartinib
    Pharmaceutical forms
    Capsule, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    EGF816 was administered orally once per day with or without food on a continuous dosing schedule. The dose for this arm in this Phase I-part first cohort of participants was 100 mg administered orally on a continuous, once daily schedule.

    Arm title
    EGF816 150 mg (Phase I part)
    Arm description
    Participants with locally advanced or metastatic NSCLC harboring specific EGFR mutations were administered with EGF816 150 mg orally once a day as continuous daily dosing in each cycle (of 28 days) during Phase I part of the study.
    Arm type
    Experimental

    Investigational medicinal product name
    EGF816
    Investigational medicinal product code
    EGF816
    Other name
    Nazartinib
    Pharmaceutical forms
    Capsule, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    EGF816 was administered orally once per day with or without food on a continuous dosing schedule. The dose for this arm in this Phase I-part first cohort of participants was 150 mg administered orally on a continuous, once daily schedule.

    Arm title
    EGF816 200 mg (Phase I part)
    Arm description
    Participants with locally advanced or metastatic NSCLC harboring specific EGFR mutations were administered with EGF816 200 mg orally once a day as continuous daily dosing in each cycle (of 28 days) during Phase I part of the study.
    Arm type
    Experimental

    Investigational medicinal product name
    EGF816
    Investigational medicinal product code
    EGF816
    Other name
    Nazartinib
    Pharmaceutical forms
    Capsule, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    EGF816 was administered orally once per day with or without food on a continuous dosing schedule. The dose for this arm in this Phase I-part first cohort of participants was 200 mg administered orally on a continuous, once daily schedule. Note: 200 mg Tablet formulation was supplied to participants from Phase I and not provided to participants in Phase II (RP2D is 150 mg QD) participants.

    Arm title
    EGF816 225 mg (Phase I part)
    Arm description
    Participants with locally advanced or metastatic NSCLC harboring specific EGFR mutations were administered with EGF816 225 mg orally once a day as continuous daily dosing in each cycle (of 28 days) during Phase I part of the study.
    Arm type
    Experimental

    Investigational medicinal product name
    EGF816
    Investigational medicinal product code
    EGF816
    Other name
    Nazartinib
    Pharmaceutical forms
    Capsule, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    EGF816 was administered orally once per day with or without food on a continuous dosing schedule. The dose for this arm in this Phase I-part first cohort of participants was 225 mg administered orally on a continuous, once daily schedule. Note: 200 mg Tablet formulation was supplied to participants from Phase I and not provided to participants in Phase II (RP2D is 150 mg QD) participants.

    Arm title
    EGF816 300 mg (Phase I part)
    Arm description
    Participants with locally advanced or metastatic NSCLC harboring specific EGFR mutations were administered with EGF816 300 mg orally once a day as continuous daily dosing in each cycle (of 28 days) during Phase I part of the study.
    Arm type
    Experimental

    Investigational medicinal product name
    EGF816
    Investigational medicinal product code
    EGF816
    Other name
    Nazartinib
    Pharmaceutical forms
    Capsule, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    EGF816 was administered orally once per day with or without food on a continuous dosing schedule. The dose for this arm in this Phase I-part first cohort of participants was 300 mg administered orally on a continuous, once daily schedule. Note: 200 mg Tablet formulation was supplied to participants from Phase I and not provided to participants in Phase II (RP2D is 150 mg QD) participants.

    Arm title
    EGF816 350 mg (Phase I part)
    Arm description
    Participants with locally advanced or metastatic NSCLC harboring specific EGFR mutations were administered with EGF816 350 mg orally once a day as continuous daily dosing in each cycle (of 28 days) during Phase I part of the study.
    Arm type
    Experimental

    Investigational medicinal product name
    EGF816
    Investigational medicinal product code
    EGF816
    Other name
    Nazartinib
    Pharmaceutical forms
    Capsule, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    EGF816 was administered orally once per day with or without food on a continuous dosing schedule. The dose for this arm in this Phase I-part first cohort of participants was 350 mg administered orally on a continuous, once daily schedule. Note: 200 mg Tablet formulation was supplied to participants from Phase I and not provided to participants in Phase II (RP2D is 150 mg QD) participants.

    Arm title
    EGF816 150 mg (Phase II part)
    Arm description
    Treatment naïve participants with locally advanced or metastatic NSCLC harboring EGFR mutations were administered with 150 mg orally once a day as continuous daily dosing in each cycle (of 28 days) during Phase II part of the study.
    Arm type
    Experimental

    Investigational medicinal product name
    EGF816
    Investigational medicinal product code
    EGF816
    Other name
    Nazartinib
    Pharmaceutical forms
    Capsule, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    EGF816 was administered orally once per day with or without food on a continuous dosing schedule. The dose for this arm in this Phase II-part second cohort of participants was the recommended phase 2 dose (RP2D) of 150 mg administered orally on a continuous, once daily schedule. Note: 200 mg Tablet formulation was supplied to participants from Phase I and not provided to participants in Phase II (RP2D is 150 mg QD) participants.

    Number of subjects in period 1
    EGF816 75 mg (Phase I part) EGF816 100 mg (Phase I part) EGF816 150 mg (Phase I part) EGF816 200 mg (Phase I part) EGF816 225 mg (Phase I part) EGF816 300 mg (Phase I part) EGF816 350 mg (Phase I part) EGF816 150 mg (Phase II part)
    Started
    17
    38
    73
    8
    28
    5
    11
    45
    Completed
    0
    0
    0
    0
    0
    0
    0
    0
    Not completed
    17
    38
    73
    8
    28
    5
    11
    45
         Adverse event, serious fatal
    1
    1
    4
    -
    3
    -
    -
    2
         Physician decision
    1
    5
    7
    1
    2
    1
    1
    3
         Study terminated by Sponsor
    -
    -
    -
    -
    -
    -
    -
    3
         Adverse event, non-fatal
    -
    -
    4
    -
    1
    -
    3
    2
         Subject/Guardian decision
    -
    1
    4
    -
    2
    -
    1
    2
         Progressive disease
    15
    31
    54
    7
    20
    4
    6
    33

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    EGF816 75 mg (Phase I part)
    Reporting group description
    Participants with locally advanced or metastatic NSCLC harboring specific EGFR mutations were administered with EGF816 75 mg orally once a day as continuous daily dosing in each cycle (of 28 days) during Phase I part of the study.

    Reporting group title
    EGF816 100 mg (Phase I part)
    Reporting group description
    Participants with locally advanced or metastatic NSCLC harboring specific EGFR mutations were administered with EGF816 100 mg orally once a day as continuous daily dosing in each cycle (of 28 days) during Phase I part of the study.

    Reporting group title
    EGF816 150 mg (Phase I part)
    Reporting group description
    Participants with locally advanced or metastatic NSCLC harboring specific EGFR mutations were administered with EGF816 150 mg orally once a day as continuous daily dosing in each cycle (of 28 days) during Phase I part of the study.

    Reporting group title
    EGF816 200 mg (Phase I part)
    Reporting group description
    Participants with locally advanced or metastatic NSCLC harboring specific EGFR mutations were administered with EGF816 200 mg orally once a day as continuous daily dosing in each cycle (of 28 days) during Phase I part of the study.

    Reporting group title
    EGF816 225 mg (Phase I part)
    Reporting group description
    Participants with locally advanced or metastatic NSCLC harboring specific EGFR mutations were administered with EGF816 225 mg orally once a day as continuous daily dosing in each cycle (of 28 days) during Phase I part of the study.

    Reporting group title
    EGF816 300 mg (Phase I part)
    Reporting group description
    Participants with locally advanced or metastatic NSCLC harboring specific EGFR mutations were administered with EGF816 300 mg orally once a day as continuous daily dosing in each cycle (of 28 days) during Phase I part of the study.

    Reporting group title
    EGF816 350 mg (Phase I part)
    Reporting group description
    Participants with locally advanced or metastatic NSCLC harboring specific EGFR mutations were administered with EGF816 350 mg orally once a day as continuous daily dosing in each cycle (of 28 days) during Phase I part of the study.

    Reporting group title
    EGF816 150 mg (Phase II part)
    Reporting group description
    Treatment naïve participants with locally advanced or metastatic NSCLC harboring EGFR mutations were administered with 150 mg orally once a day as continuous daily dosing in each cycle (of 28 days) during Phase II part of the study.

    Reporting group values
    EGF816 75 mg (Phase I part) EGF816 100 mg (Phase I part) EGF816 150 mg (Phase I part) EGF816 200 mg (Phase I part) EGF816 225 mg (Phase I part) EGF816 300 mg (Phase I part) EGF816 350 mg (Phase I part) EGF816 150 mg (Phase II part) Total
    Number of subjects
    17 38 73 8 28 5 11 45 225
    Age Categorical
    Units: Participants
        <=18 years
    0 0 0 0 0 0 0 0 0
        Between 18 and 65 years
    10 23 47 6 15 2 7 23 133
        >=65 years
    7 15 26 2 13 3 4 22 92
    Sex: Female, Male
    Units: Participants
        Female
    13 23 50 7 13 3 7 27 143
        Male
    4 15 23 1 15 2 4 18 82
    Race/Ethnicity, Customized
    Units: Subjects
        Asian
    13 22 44 6 21 4 9 28 147
        Caucasian
    2 14 24 2 7 1 2 17 69
        Unknown
    2 2 3 0 0 0 0 0 7
        Black
    0 0 2 0 0 0 0 0 2

    End points

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    End points reporting groups
    Reporting group title
    EGF816 75 mg (Phase I part)
    Reporting group description
    Participants with locally advanced or metastatic NSCLC harboring specific EGFR mutations were administered with EGF816 75 mg orally once a day as continuous daily dosing in each cycle (of 28 days) during Phase I part of the study.

    Reporting group title
    EGF816 100 mg (Phase I part)
    Reporting group description
    Participants with locally advanced or metastatic NSCLC harboring specific EGFR mutations were administered with EGF816 100 mg orally once a day as continuous daily dosing in each cycle (of 28 days) during Phase I part of the study.

    Reporting group title
    EGF816 150 mg (Phase I part)
    Reporting group description
    Participants with locally advanced or metastatic NSCLC harboring specific EGFR mutations were administered with EGF816 150 mg orally once a day as continuous daily dosing in each cycle (of 28 days) during Phase I part of the study.

    Reporting group title
    EGF816 200 mg (Phase I part)
    Reporting group description
    Participants with locally advanced or metastatic NSCLC harboring specific EGFR mutations were administered with EGF816 200 mg orally once a day as continuous daily dosing in each cycle (of 28 days) during Phase I part of the study.

    Reporting group title
    EGF816 225 mg (Phase I part)
    Reporting group description
    Participants with locally advanced or metastatic NSCLC harboring specific EGFR mutations were administered with EGF816 225 mg orally once a day as continuous daily dosing in each cycle (of 28 days) during Phase I part of the study.

    Reporting group title
    EGF816 300 mg (Phase I part)
    Reporting group description
    Participants with locally advanced or metastatic NSCLC harboring specific EGFR mutations were administered with EGF816 300 mg orally once a day as continuous daily dosing in each cycle (of 28 days) during Phase I part of the study.

    Reporting group title
    EGF816 350 mg (Phase I part)
    Reporting group description
    Participants with locally advanced or metastatic NSCLC harboring specific EGFR mutations were administered with EGF816 350 mg orally once a day as continuous daily dosing in each cycle (of 28 days) during Phase I part of the study.

    Reporting group title
    EGF816 150 mg (Phase II part)
    Reporting group description
    Treatment naïve participants with locally advanced or metastatic NSCLC harboring EGFR mutations were administered with 150 mg orally once a day as continuous daily dosing in each cycle (of 28 days) during Phase II part of the study.

    Primary: Number of participants with Dose Limiting Toxicities (DLTs) (Phase I Part)

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    End point title
    Number of participants with Dose Limiting Toxicities (DLTs) (Phase I Part) [1] [2]
    End point description
    Number of participants with DLTs during the first 28 days of therapy. A DLT is defined as an adverse event or abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness, or concomitant medications that occurs within the first cycle of treatment with EGF816 and meets any of the criteria described in the protocol. A participant with multiple occurrences of DLTs under one treatment is counted only once.
    End point type
    Primary
    End point timeframe
    First 28 days of dosing
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistics analysis was done for this endpoint
    [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: No statistics analysis was done for this endpoint
    End point values
    EGF816 75 mg (Phase I part) EGF816 100 mg (Phase I part) EGF816 150 mg (Phase I part) EGF816 200 mg (Phase I part) EGF816 225 mg (Phase I part) EGF816 300 mg (Phase I part) EGF816 350 mg (Phase I part)
    Number of subjects analysed
    16
    38
    69
    7
    23
    2
    9
    Units: Participants
    0
    0
    2
    0
    1
    0
    3
    No statistical analyses for this end point

    Primary: Overall Response Rate (ORR) by Blinded Independent Review Committee (BIRC) (Phase II Part)

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    End point title
    Overall Response Rate (ORR) by Blinded Independent Review Committee (BIRC) (Phase II Part) [3] [4]
    End point description
    ORR is defined as the percentage of patients with a best overall response of complete response (CR) or partial response (PR) determined by BIRC assessment in accordance to Response Evaluation Criteria in Solid Tumors (RECIST 1.1).
    End point type
    Primary
    End point timeframe
    From baseline up to 64 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: No statistics analysis was done for this endpoint
    [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: No statistics analysis was done for this endpoint
    End point values
    EGF816 150 mg (Phase II part)
    Number of subjects analysed
    45
    Units: Percentage of participants
        number (confidence interval 95%)
    64.4 (48.80 to 78.10)
    No statistical analyses for this end point

    Secondary: Progression-free survival (PFS) by Investigator assessment (Phase I & Phase II Parts)

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    End point title
    Progression-free survival (PFS) by Investigator assessment (Phase I & Phase II Parts)
    End point description
    PFS is defined as time from date of first dose of study treatment to date of first documented disease progression or death due to any cause determined by Investigator assessment in accordance to RECIST 1.1
    End point type
    Secondary
    End point timeframe
    At least 24 weeks up to approx. 9 years
    End point values
    EGF816 75 mg (Phase I part) EGF816 100 mg (Phase I part) EGF816 150 mg (Phase I part) EGF816 200 mg (Phase I part) EGF816 225 mg (Phase I part) EGF816 300 mg (Phase I part) EGF816 350 mg (Phase I part) EGF816 150 mg (Phase II part)
    Number of subjects analysed
    12
    34
    68
    8
    24
    5
    11
    45
    Units: Months
        median (confidence interval 95%)
    6.3 (1.54 to 47.80)
    12.1 (7.16 to 16.56)
    7.4 (5.32 to 9.59)
    13.7 (3.52 to 27.47)
    11.1 (7.23 to 23.49)
    11.8 (5.62 to 999)
    11.0 (0.43 to 999)
    18.2 (11.04 to 30.16)
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR) by Investigator assessment (Phase I & II Parts)

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    End point title
    Duration of Response (DOR) by Investigator assessment (Phase I & II Parts)
    End point description
    DOR is defined as the time from first documented response (PR or CR) to the date of first documented disease progression or death due to any cause determined by Investigator assessment in accordance to RECIST 1.1
    End point type
    Secondary
    End point timeframe
    At least 24 weeks up to approx. 9 years
    End point values
    EGF816 75 mg (Phase I part) EGF816 100 mg (Phase I part) EGF816 150 mg (Phase I part) EGF816 200 mg (Phase I part) EGF816 225 mg (Phase I part) EGF816 300 mg (Phase I part) EGF816 350 mg (Phase I part) EGF816 150 mg (Phase II part)
    Number of subjects analysed
    5
    17
    34
    5
    15
    3
    4
    29
    Units: Months
        median (confidence interval 95%)
    46.2 (3.68 to 99)
    11.3 (7.39 to 23.79)
    7.9 (7.39 to 11.04)
    14.9 (9.20 to 999)
    16.5 (5.52 to 29.63)
    10.2 (9.33 to 999)
    17.5 (7.56 to 999)
    20.3 (11.01 to 34.89)
    No statistical analyses for this end point

    Secondary: Observed maximum plasma concentration (Cmax) of EGF816 and metabolite LMI258 (Phase I & Phase II part)

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    End point title
    Observed maximum plasma concentration (Cmax) of EGF816 and metabolite LMI258 (Phase I & Phase II part)
    End point description
    To characterize the PK properties of EGF816 and metabolite LMI258, Cmax will be calculated (Phase I & II parts). Cmax is maximum (peak) observed plasma drug concentration (mass x volume-1).
    End point type
    Secondary
    End point timeframe
    Cycle (C) 1 Day (D) 1 (pre-dose and 0.5,1,2,3,4,6,8,12 and 24 hours (hrs) post-dose), C1D15 (pre-dose and 0.5,1,2,3,4,6,8,12 and 24 hrs post-dose) (for Phase I part only) and C2D1 (pre-dose and 0.5,1,2,3,4,6,8,12 and 24 hrs post-dose).
    End point values
    EGF816 75 mg (Phase I part) EGF816 100 mg (Phase I part) EGF816 150 mg (Phase I part) EGF816 200 mg (Phase I part) EGF816 225 mg (Phase I part) EGF816 300 mg (Phase I part) EGF816 350 mg (Phase I part) EGF816 150 mg (Phase II part)
    Number of subjects analysed
    17
    38
    72
    8
    28
    5
    11
    45
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        EFG816: C1D1(n = 17, 36, 69, 8, 28, 5, 11, 45)
    333 ( 64.9 )
    301 ( 81.8 )
    541 ( 53.2 )
    641 ( 60.2 )
    935 ( 66.1 )
    1070 ( 58.3 )
    1190 ( 50.0 )
    471 ( 41.2 )
        EFG816: C1D15 (n = 14, 36, 63, 7, 21, 1, 6, 0)
    402 ( 62.3 )
    477 ( 53.0 )
    765 ( 50.1 )
    939 ( 45.4 )
    1320 ( 46.0 )
    2670 ( 999 )
    1530 ( 23.5 )
    999 ( 999 )
        EFG816: C2D1 (n = 12, 24, 59, 7, 20, 3, 9, 26)
    348 ( 43.4 )
    426 ( 50.1 )
    767 ( 46.7 )
    938 ( 53.9 )
    1270 ( 61.0 )
    1700 ( 41.3 )
    1270 ( 30.4 )
    648 ( 50.9 )
        LMI258: C1D1 (n= 17, 36, 68, 8, 28, 5, 11, 38)
    14.1 ( 174.8 )
    11.4 ( 76.1 )
    25.2 ( 61.7 )
    30.9 ( 64.6 )
    42.0 ( 63.1 )
    62.2 ( 40.5 )
    52.7 ( 42.1 )
    24.3 ( 46.6 )
        LMI258: C1D15 (n = 13, 34, 61, 7, 20, 1, 5, 0)
    31.2 ( 94.7 )
    34.1 ( 81.8 )
    72.2 ( 64.0 )
    113 ( 54.1 )
    131 ( 56.8 )
    292 ( 999 )
    164 ( 22.7 )
    999 ( 999 )
        LMI258: C2D1 (n = 10, 30, 54, 6, 16, 3, 7, 13)
    23.9 ( 59.5 )
    32.4 ( 76.0 )
    81.4 ( 55.4 )
    114 ( 75.1 )
    101 ( 72.8 )
    142 ( 55.1 )
    116 ( 68.7 )
    62.5 ( 60.7 )
    No statistical analyses for this end point

    Secondary: Time to Maximum Plasma concentration (Tmax) of EGF816 and metabolite LMI258 (Phase I & Phase II part). Tmax is the time to reach maximum (peak) plasma drug concentration (time).

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    End point title
    Time to Maximum Plasma concentration (Tmax) of EGF816 and metabolite LMI258 (Phase I & Phase II part). Tmax is the time to reach maximum (peak) plasma drug concentration (time).
    End point description
    To characterize the PK properties of EGF816 and metabolite LMI258, Tmax will be calculated (Phase I & II parts). Tmax is the time to reach maximum (peak) plasma drug concentration (time).
    End point type
    Secondary
    End point timeframe
    Cycle (C) 1 Day (D) 1 (pre-dose and 0.5,1,2,3,4,6,8,12 and 24 hours (hrs) post-dose), C1D15 (pre-dose and 0.5,1,2,3,4,6,8,12 and 24 hrs post-dose) (for Phase I part only) and C2D1 (pre-dose and 0.5,1,2,3,4,6,8,12 and 24 hrs post-dose).
    End point values
    EGF816 75 mg (Phase I part) EGF816 100 mg (Phase I part) EGF816 150 mg (Phase I part) EGF816 200 mg (Phase I part) EGF816 225 mg (Phase I part) EGF816 300 mg (Phase I part) EGF816 350 mg (Phase I part) EGF816 150 mg (Phase II part)
    Number of subjects analysed
    17
    38
    69
    8
    28
    5
    11
    43
    Units: hour (hr)
    geometric mean (geometric coefficient of variation)
        EFG816: C1D1 (n =17,36,69,8,28,5,11,43)
    2.83 ( 63.0 )
    3.24 ( 42.7 )
    2.74 ( 54.7 )
    3.66 ( 74.1 )
    2.64 ( 64.9 )
    3.37 ( 41.0 )
    3.45 ( 22.4 )
    2.81 ( 43.4 )
        EFG816: C1D15 (n = 14, 36, 63, 7, 21, 1, 6, 0)
    2.91 ( 57.7 )
    2.75 ( 75.8 )
    3.11 ( 46.4 )
    3.52 ( 44.3 )
    3.46 ( 36.1 )
    6.08 ( 999 )
    4.45 ( 35.4 )
    999 ( 999 )
        EFG816: C2D1 (n = 12, 34, 59, 7, 20, 3, 9, 26)
    3.13 ( 44.7 )
    2.81 ( 49.0 )
    3.14 ( 54.0 )
    3.53 ( 35.3 )
    3.17 ( 38.2 )
    2.99 ( 0.6 )
    3.97 ( 44.1 )
    3.48 ( 52.7 )
        LMI258: C1D1 (n= 17, 36, 68, 8, 28, 5, 11, 38)
    2.54 ( 65.7 )
    3.14 ( 43.6 )
    2.78 ( 65.2 )
    3.19 ( 73.6 )
    2.99 ( 71.4 )
    3.37 ( 41.5 )
    3.53 ( 31.8 )
    2.70 ( 43.3 )
        LMI258: C1D15 (n = 13, 34, 61, 7, 20, 1, 5, 0)
    2.89 ( 55.1 )
    2.76 ( 63.8 )
    3.32 ( 54.7 )
    4.05 ( 32.6 )
    4.03 ( 38.7 )
    7.12 ( 999 )
    4.54 ( 39.3 )
    999 ( 999 )
        LMI258: C2D1 (n = 10, 33, 57, 7, 19, 3, 8, 13)
    3.38 ( 64.7 )
    3.04 ( 57.6 )
    3.43 ( 55.0 )
    5.00 ( 56.1 )
    3.26 ( 46.6 )
    3.77 ( 42.4 )
    4.13 ( 47.8 )
    3.92 ( 45.5 )
    No statistical analyses for this end point

    Secondary: Area Under the Serum Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau (AUCtau) of EGF816 and metabolite LMI258 (Phase I & Phase II part)

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    End point title
    Area Under the Serum Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau (AUCtau) of EGF816 and metabolite LMI258 (Phase I & Phase II part)
    End point description
    To characterize the PK properties of EGF816 and metabolite LMI258, AUCtau will be calculated (Phase I & II parts). AUCtau is the AUC calculated to the end of a dosing interval (tau) (amount x time x volume-1).
    End point type
    Secondary
    End point timeframe
    Cycle (C) 1 Day (D) 1 (pre-dose and 0.5,1,2,3,4,6,8,12 and 24 hours (hrs) post-dose), C1D15 (pre-dose and 0.5,1,2,3,4,6,8,12 and 24 hrs post-dose) (for Phase I part only) and C2D1 (pre-dose and 0.5,1,2,3,4,6,8,12 and 24 hrs post-dose).
    End point values
    EGF816 75 mg (Phase I part) EGF816 100 mg (Phase I part) EGF816 150 mg (Phase I part) EGF816 200 mg (Phase I part) EGF816 225 mg (Phase I part) EGF816 300 mg (Phase I part) EGF816 350 mg (Phase I part) EGF816 150 mg (Phase II part)
    Number of subjects analysed
    17
    38
    72
    8
    28
    5
    11
    45
    Units: ng*hr/mL
    geometric mean (geometric coefficient of variation)
        EFG816: C1D1 (n = 16, 35, 66, 8, 26, 5, 11, 41)
    4340 ( 68.2 )
    4000 ( 83.1 )
    6880 ( 53.3 )
    8310 ( 51.2 )
    12100 ( 64.7 )
    15000 ( 61.0 )
    16900 ( 51.0 )
    5720 ( 42.7 )
        EFG816: C1D15 (n = 13, 31, 57, 7, 18, 1, 5, 0)
    6370 ( 61.1 )
    6770 ( 66.0 )
    11300 ( 53.2 )
    13500 ( 44.1 )
    20300 ( 54.6 )
    51200 ( 999 )
    25700 ( 26.1 )
    999 ( 999 )
        EFG816: C2D1 (n = 12, 30, 56, 6, 17, 3, 7, 25)
    5670 ( 44.7 )
    6150 ( 58.6 )
    11800 ( 50.3 )
    15800 ( 10.6 )
    18600 ( 66.5 )
    26100 ( 53.0 )
    22300 ( 19.0 )
    9830 ( 51.3 )
        LMI258: C1D1 (n= 15, 33, 65, 8, 26, 5, 11, 37)
    182 ( 56.8 )
    162 ( 78.0 )
    330 ( 62.1 )
    424 ( 56.0 )
    559 ( 62.4 )
    859 ( 50.0 )
    810 ( 47.0 )
    291 ( 45.3 )
        LMI258: C1D15 (n = 13, 31, 57, 7, 19, 1, 5, 0)
    466 ( 82.1 )
    523 ( 111.1 )
    1170 ( 69.5 )
    1810 ( 58.6 )
    2460 ( 65.2 )
    5940 ( 999 )
    3420 ( 45.6 )
    999 ( 999 )
        LMI258: C2D1 (n = 10, 30, 54, 6, 16, 3, 7, 13)
    402 ( 65.7 )
    499 ( 97.7 )
    1380 ( 58.6 )
    2340 ( 45.2 )
    1760 ( 90.3 )
    2360 ( 65.9 )
    2820 ( 34.8 )
    1060 ( 67.7 )
    No statistical analyses for this end point

    Secondary: Percentage change from baseline in H-score for immunohistochemistry (IHC) biomarkers from tumor tissue samples (Phase I part)

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    End point title
    Percentage change from baseline in H-score for immunohistochemistry (IHC) biomarkers from tumor tissue samples (Phase I part) [5]
    End point description
    Changes in EGFR signaling pathway of newly obtained tumor samples following EGF816 treatment were evaluated by IHC of three pharmacodynamics (PD) biomarkers: p-EGFR, p-AKT and p-ERK. The assigned H-score semi-quantitatively assessed the expression level of these protein markers and their phosphorylated forms.
    End point type
    Secondary
    End point timeframe
    Baseline and Cycle 1 Day 15
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistics analysis was done for this endpoint
    End point values
    EGF816 75 mg (Phase I part) EGF816 100 mg (Phase I part) EGF816 150 mg (Phase I part) EGF816 200 mg (Phase I part) EGF816 225 mg (Phase I part) EGF816 300 mg (Phase I part) EGF816 350 mg (Phase I part)
    Number of subjects analysed
    17
    38
    73
    8
    28
    5
    11
    Units: percentage change
    arithmetic mean (standard deviation)
        PD: P_AKT: Change from BL (n=1,5,10,4,9,2,4,0)
    -10.0 ( 999 )
    -39.0 ( 78.2 )
    -31.8 ( 47.7 )
    3.5 ( 14.5 )
    16.1 ( 65.3 )
    -2.5 ( 3.5 )
    -51.3 ( 71.9 )
        PD: p-EGFR: Change from BL (n=1,5,10,4,9,2,4,0)
    -165.0 ( 999 )
    -21.8 ( 43.9 )
    -19.5 ( 34.7 )
    -38.8 ( 50.1 )
    2.2 ( 23.7 )
    -32.5 ( 38.9 )
    -12.5 ( 18.9 )
        PD: p-ERK: Change from BL (n=1,5,10,4,8,2,4,0)
    -60.0 ( 999 )
    -113.4 ( 84.2 )
    -2.4 ( 128.3 )
    33.5 ( 86.7 )
    8.8 ( 68.0 )
    -65.0 ( 35.4 )
    -1.3 ( 46.6 )
    No statistical analyses for this end point

    Secondary: Overall Response Rate (ORR) by Investigator assessment (Phase I & II Parts)

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    End point title
    Overall Response Rate (ORR) by Investigator assessment (Phase I & II Parts)
    End point description
    ORR is defined as percentage of patients with best overall response of partial response (PR)+ complete response (CR) determined by Investigator assessment in accordance to RECIST 1.1
    End point type
    Secondary
    End point timeframe
    At least 24 weeks up to approx. 4 years
    End point values
    EGF816 75 mg (Phase I part) EGF816 100 mg (Phase I part) EGF816 150 mg (Phase I part) EGF816 200 mg (Phase I part) EGF816 225 mg (Phase I part) EGF816 300 mg (Phase I part) EGF816 350 mg (Phase I part) EGF816 150 mg (Phase II part)
    Number of subjects analysed
    12
    34
    68
    8
    24
    5
    11
    45
    Units: Percentage of participants
        number (not applicable)
    41.7
    50.0
    50.0
    62.5
    62.5
    60.0
    36.4
    55.6
    No statistical analyses for this end point

    Secondary: Disease Control Rate (DCR) by Investigator assessment (Phase I & II Parts)

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    End point title
    Disease Control Rate (DCR) by Investigator assessment (Phase I & II Parts)
    End point description
    DCR is defined as the proportion of patients with best overall response of CR, PR, or SD determined by Investigator assessment in accordance to RECIST 1.1
    End point type
    Secondary
    End point timeframe
    At least 24 weeks up to approx. 4 years
    End point values
    EGF816 75 mg (Phase I part) EGF816 100 mg (Phase I part) EGF816 150 mg (Phase I part) EGF816 200 mg (Phase I part) EGF816 225 mg (Phase I part) EGF816 300 mg (Phase I part) EGF816 350 mg (Phase I part) EGF816 150 mg (Phase II part)
    Number of subjects analysed
    12
    34
    68
    8
    24
    5
    11
    45
    Units: Percentage of participants
        number (not applicable)
    83.3
    97.1
    83.3
    100.0
    95.8
    100.0
    72.7
    91.1
    No statistical analyses for this end point

    Secondary: Time to Response (TTR) by Investigator assessment (Phase I & II Parts)

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    End point title
    Time to Response (TTR) by Investigator assessment (Phase I & II Parts)
    End point description
    TTR is defined as the time from the date of the first dose to the date of first documented response (CR or PR) determined by Investigator assessment in accordance to RECIST 1.1
    End point type
    Secondary
    End point timeframe
    At least 24 weeks up to approx. 9 years
    End point values
    EGF816 75 mg (Phase I part) EGF816 100 mg (Phase I part) EGF816 150 mg (Phase I part) EGF816 200 mg (Phase I part) EGF816 225 mg (Phase I part) EGF816 300 mg (Phase I part) EGF816 350 mg (Phase I part) EGF816 150 mg (Phase II part)
    Number of subjects analysed
    12
    34
    68
    8
    24
    5
    11
    45
    Units: Months
        median (confidence interval 95%)
    999 (1.64 to 999)
    5.5 (1.81 to 999)
    11.6 (1.87 to 999)
    4.5 (1.64 to 999)
    1.9 (1.68 to 999)
    1.7 (1.61 to 999)
    999 (1.64 to 999)
    1.9 (1.84 to 7.16)
    No statistical analyses for this end point

    Secondary: Number of participants with dose interruptions and dose reductions (Phase I & II Parts)

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    End point title
    Number of participants with dose interruptions and dose reductions (Phase I & II Parts)
    End point description
    Assessment of the tolerability of EGF816 will be performed continuously during the treatment phase
    End point type
    Secondary
    End point timeframe
    At least 24 weeks up to approx. 9 years
    End point values
    EGF816 75 mg (Phase I part) EGF816 100 mg (Phase I part) EGF816 150 mg (Phase I part) EGF816 200 mg (Phase I part) EGF816 225 mg (Phase I part) EGF816 300 mg (Phase I part) EGF816 350 mg (Phase I part) EGF816 150 mg (Phase II part)
    Number of subjects analysed
    17
    38
    73
    8
    28
    5
    11
    45
    Units: Participants
        Participants with any dose Interruption
    3
    17
    35
    5
    20
    5
    6
    19
        Participants with at least one dose reductions
    0
    1
    9
    1
    17
    4
    6
    9
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR) by BIRC (Phase II Part)

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    End point title
    Duration of Response (DOR) by BIRC (Phase II Part) [6]
    End point description
    DOR is defined as the time from first documented response (PR or CR) to the date of first documented disease progression or death due to any cause determined by BIRC in accordance to RECIST 1.1
    End point type
    Secondary
    End point timeframe
    At least 24 weeks up to approx. 9 years
    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: No statistics analysis was done for this endpoint
    End point values
    EGF816 150 mg (Phase II part)
    Number of subjects analysed
    30
    Units: Months
        median (confidence interval 95%)
    18.6 (14.88 to 31.41)
    No statistical analyses for this end point

    Secondary: Disease Control Rate (DCR) by BIRC (Phase II Part)

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    End point title
    Disease Control Rate (DCR) by BIRC (Phase II Part) [7]
    End point description
    DCR is defined as the percentage of patients with best overall response of CR, PR, or SD determined by BIRC in accordance to RECIST 1.1
    End point type
    Secondary
    End point timeframe
    At least 24 weeks up to approx. 9 years
    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: No statistics analysis was done for this endpoint
    End point values
    EGF816 150 mg (Phase II part)
    Number of subjects analysed
    45
    Units: Percentage of participants
        number (confidence interval 95%)
    93.3 (81.70 to 98.60)
    No statistical analyses for this end point

    Secondary: Progression-Free Survival (PFS) by BIRC (Phase II Part)

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    End point title
    Progression-Free Survival (PFS) by BIRC (Phase II Part) [8]
    End point description
    PFS is defined as time from date of first dose of study treatment to date of first documented disease progression or death due to any cause determined by BIRC in accordance to RECIST 1.1
    End point type
    Secondary
    End point timeframe
    At least 24 weeks up to approx. 9 years
    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: No statistics analysis was done for this endpoint
    End point values
    EGF816 150 mg (Phase II part)
    Number of subjects analysed
    45
    Units: months
        median (confidence interval 95%)
    18.9 (14.75 to 29.44)
    No statistical analyses for this end point

    Secondary: Time to Response (TTR) by BIRC (Phase II Part)

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    End point title
    Time to Response (TTR) by BIRC (Phase II Part) [9]
    End point description
    TTR is defined as as the time from the date of first dose of study treatment to the date of first documented response (CR or PR) determined by by BIRC in accordance to RECIST 1.1
    End point type
    Secondary
    End point timeframe
    At least 24 weeks up to approx. 9 years
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistics analysis was done for this endpoint
    End point values
    EGF816 150 mg (Phase II part)
    Number of subjects analysed
    45
    Units: Months
        median (confidence interval 95%)
    48.3 (22.93 to 58.84)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS) (Phase II Part)

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    End point title
    Overall Survival (OS) (Phase II Part) [10]
    End point description
    OS is defined as the time from first dose of the study treatment to the date of death due to any cause.
    End point type
    Secondary
    End point timeframe
    At least 24 weeks up to approx. 9 years
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistics analysis was done for this endpoint
    End point values
    EGF816 150 mg (Phase II part)
    Number of subjects analysed
    45
    Units: Months
        median (confidence interval 95%)
    48.3 (22.93 to 58.84)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events (AEs) are collected from first dose of study treatment until end of study treatment plus 30 days post treatment. AEs reported in this record are from first dose of study treatment until 30 days after end of treatment, approx. 9 years.
    Adverse event reporting additional description
    Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    75 mg
    Reporting group description
    75 mg

    Reporting group title
    100 mg
    Reporting group description
    100 mg

    Reporting group title
    150 mg
    Reporting group description
    150 mg

    Reporting group title
    200 mg
    Reporting group description
    200 mg

    Reporting group title
    All@subjects
    Reporting group description
    All@subjects

    Reporting group title
    300 mg
    Reporting group description
    300 mg

    Reporting group title
    350 mg
    Reporting group description
    350 mg

    Reporting group title
    RP2D (150 mg - 1L)
    Reporting group description
    RP2D (150 mg - 1L)

    Reporting group title
    225 mg
    Reporting group description
    225 mg

    Serious adverse events
    75 mg 100 mg 150 mg 200 mg All@subjects 300 mg 350 mg RP2D (150 mg - 1L) 225 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 17 (41.18%)
    11 / 38 (28.95%)
    40 / 73 (54.79%)
    2 / 8 (25.00%)
    107 / 225 (47.56%)
    4 / 5 (80.00%)
    5 / 11 (45.45%)
    22 / 45 (48.89%)
    16 / 28 (57.14%)
         number of deaths (all causes)
    3
    1
    13
    0
    31
    0
    1
    6
    7
         number of deaths resulting from adverse events
    0
    0
    0
    0
    1
    0
    0
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Pancreatic carcinoma
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    2 / 225 (0.89%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 45 (2.22%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymphangiosis carcinomatosa
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    1 / 73 (1.37%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Follicular lymphoma
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cancer pain
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 38 (2.63%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    2 / 225 (0.89%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    1 / 73 (1.37%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Aortic dissection
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 45 (2.22%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    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
    Hypertension
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    1 / 73 (1.37%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymphoedema
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Face oedema
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    1 / 73 (1.37%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    2 / 225 (0.89%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    2 / 45 (4.44%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    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
    Reproductive system and breast disorders
    Vaginal prolapse
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 38 (2.63%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Choking
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    1 / 73 (1.37%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    1 / 73 (1.37%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 38 (2.63%)
    4 / 73 (5.48%)
    0 / 8 (0.00%)
    7 / 225 (3.11%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    1 / 7
    0 / 0
    1 / 10
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    1 / 73 (1.37%)
    0 / 8 (0.00%)
    3 / 225 (1.33%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 45 (2.22%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    3 / 3
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    1 / 73 (1.37%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    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
    Haemoptysis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    1 / 73 (1.37%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    3 / 73 (4.11%)
    0 / 8 (0.00%)
    5 / 225 (2.22%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    2 / 45 (4.44%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 0
    0 / 5
    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
    Pulmonary haemorrhage
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 38 (0.00%)
    1 / 73 (1.37%)
    0 / 8 (0.00%)
    2 / 225 (0.89%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    1 / 5 (20.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    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
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 38 (2.63%)
    3 / 73 (4.11%)
    0 / 8 (0.00%)
    4 / 225 (1.78%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 3
    0 / 0
    0 / 4
    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
    Major depression
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    1 / 73 (1.37%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 45 (2.22%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    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
    Investigations
    Hepatitis B DNA assay positive
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 38 (2.63%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    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
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    1 / 73 (1.37%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    2 / 73 (2.74%)
    0 / 8 (0.00%)
    2 / 225 (0.89%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fracture
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    1 / 8 (12.50%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    Hip fracture
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 45 (2.22%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    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
    Spinal fracture
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    2 / 225 (0.89%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    1 / 45 (2.22%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    1 / 8 (12.50%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    Post procedural fever
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    1 / 5 (20.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    1 / 73 (1.37%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    1 / 73 (1.37%)
    1 / 8 (12.50%)
    3 / 225 (1.33%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 3
    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
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 45 (2.22%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    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
    Atrial fibrillation
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial tachycardia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    1 / 73 (1.37%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    2 / 225 (0.89%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    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
    Nervous system disorders
    Ataxia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    1 / 73 (1.37%)
    0 / 8 (0.00%)
    2 / 225 (0.89%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 45 (2.22%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 2
    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
    Cerebrovascular accident
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    1 / 73 (1.37%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Altered state of consciousness
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 45 (2.22%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    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
    Dizziness
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    1 / 73 (1.37%)
    0 / 8 (0.00%)
    3 / 225 (1.33%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    2 / 28 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 45 (2.22%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    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
    Hydrocephalus
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    1 / 73 (1.37%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    1 / 73 (1.37%)
    0 / 8 (0.00%)
    2 / 225 (0.89%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 45 (2.22%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    2 / 73 (2.74%)
    1 / 8 (12.50%)
    4 / 225 (1.78%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 1
    0 / 4
    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
    Paraesthesia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 38 (0.00%)
    1 / 73 (1.37%)
    0 / 8 (0.00%)
    2 / 225 (0.89%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    1 / 73 (1.37%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    3 / 73 (4.11%)
    0 / 8 (0.00%)
    6 / 225 (2.67%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    2 / 45 (4.44%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 3
    0 / 0
    3 / 6
    0 / 0
    0 / 0
    0 / 2
    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
    Abdominal pain
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 45 (2.22%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    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
    Duodenal ulcer
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    1 / 73 (1.37%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    2 / 73 (2.74%)
    0 / 8 (0.00%)
    2 / 225 (0.89%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic ascites
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    1 / 73 (1.37%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    1 / 73 (1.37%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    1 / 73 (1.37%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Biliary obstruction
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 45 (2.22%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    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
    Cholestasis
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 38 (2.63%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    1 / 73 (1.37%)
    0 / 8 (0.00%)
    2 / 225 (0.89%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    2 / 2
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 38 (2.63%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    1 / 73 (1.37%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 38 (2.63%)
    2 / 73 (2.74%)
    0 / 8 (0.00%)
    5 / 225 (2.22%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 45 (2.22%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 0
    0 / 5
    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
    Bone pain
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 38 (0.00%)
    1 / 73 (1.37%)
    0 / 8 (0.00%)
    2 / 225 (0.89%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 38 (2.63%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 38 (2.63%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    1 / 73 (1.37%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    2 / 225 (0.89%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    2 / 45 (4.44%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    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
    Cellulitis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Empyema
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    2 / 225 (0.89%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 45 (2.22%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis B reactivation
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 38 (2.63%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    4 / 225 (1.78%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 45 (2.22%)
    2 / 28 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    4 / 4
    0 / 0
    0 / 0
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 45 (2.22%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    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
    Meningitis
         subjects affected / exposed
    0 / 17 (0.00%)
    2 / 38 (5.26%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    2 / 225 (0.89%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Perihepatic abscess
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    1 / 5 (20.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 17 (5.88%)
    4 / 38 (10.53%)
    6 / 73 (8.22%)
    0 / 8 (0.00%)
    21 / 225 (9.33%)
    1 / 5 (20.00%)
    3 / 11 (27.27%)
    2 / 45 (4.44%)
    4 / 28 (14.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 6
    0 / 0
    0 / 24
    0 / 3
    0 / 3
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 3
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 45 (2.22%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    1 / 73 (1.37%)
    0 / 8 (0.00%)
    2 / 225 (0.89%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    1 / 73 (1.37%)
    0 / 8 (0.00%)
    2 / 225 (0.89%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 2
    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
    Pneumonia influenzal
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 45 (2.22%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    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
    Sepsis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 38 (0.00%)
    3 / 73 (4.11%)
    0 / 8 (0.00%)
    4 / 225 (1.78%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 3
    0 / 0
    0 / 4
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    1 / 73 (1.37%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    2 / 8 (25.00%)
    2 / 225 (0.89%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suspected COVID-19
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    1 / 73 (1.37%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    1 / 73 (1.37%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    1 / 73 (1.37%)
    0 / 8 (0.00%)
    4 / 225 (1.78%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    2 / 45 (4.44%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 4
    0 / 0
    0 / 0
    0 / 2
    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
    Hypervolaemia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    1 / 73 (1.37%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    75 mg 100 mg 150 mg 200 mg All@subjects 300 mg 350 mg RP2D (150 mg - 1L) 225 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    17 / 17 (100.00%)
    36 / 38 (94.74%)
    73 / 73 (100.00%)
    8 / 8 (100.00%)
    220 / 225 (97.78%)
    5 / 5 (100.00%)
    11 / 11 (100.00%)
    42 / 45 (93.33%)
    28 / 28 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 38 (0.00%)
    2 / 73 (2.74%)
    0 / 8 (0.00%)
    5 / 225 (2.22%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    2
    0
    2
    0
    5
    0
    0
    0
    1
    Vascular disorders
    Flushing
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    1 / 5 (20.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    0
    0
    Hypertension
         subjects affected / exposed
    2 / 17 (11.76%)
    4 / 38 (10.53%)
    2 / 73 (2.74%)
    1 / 8 (12.50%)
    20 / 225 (8.89%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    8 / 45 (17.78%)
    2 / 28 (7.14%)
         occurrences all number
    2
    4
    4
    1
    24
    0
    1
    10
    2
    Hot flush
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    0
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 38 (2.63%)
    5 / 73 (6.85%)
    0 / 8 (0.00%)
    13 / 225 (5.78%)
    1 / 5 (20.00%)
    1 / 11 (9.09%)
    3 / 45 (6.67%)
    1 / 28 (3.57%)
         occurrences all number
    1
    1
    5
    0
    19
    1
    1
    4
    6
    Chest discomfort
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 38 (0.00%)
    3 / 73 (4.11%)
    0 / 8 (0.00%)
    9 / 225 (4.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    3 / 45 (6.67%)
    2 / 28 (7.14%)
         occurrences all number
    2
    0
    4
    0
    12
    0
    0
    4
    2
    Chills
         subjects affected / exposed
    0 / 17 (0.00%)
    4 / 38 (10.53%)
    2 / 73 (2.74%)
    0 / 8 (0.00%)
    9 / 225 (4.00%)
    0 / 5 (0.00%)
    2 / 11 (18.18%)
    0 / 45 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    4
    2
    0
    9
    0
    2
    0
    1
    Early satiety
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    0
    0
    Fatigue
         subjects affected / exposed
    8 / 17 (47.06%)
    8 / 38 (21.05%)
    21 / 73 (28.77%)
    3 / 8 (37.50%)
    59 / 225 (26.22%)
    3 / 5 (60.00%)
    3 / 11 (27.27%)
    5 / 45 (11.11%)
    8 / 28 (28.57%)
         occurrences all number
    9
    8
    21
    6
    67
    3
    5
    6
    9
    Oedema peripheral
         subjects affected / exposed
    1 / 17 (5.88%)
    5 / 38 (13.16%)
    11 / 73 (15.07%)
    2 / 8 (25.00%)
    27 / 225 (12.00%)
    2 / 5 (40.00%)
    0 / 11 (0.00%)
    5 / 45 (11.11%)
    1 / 28 (3.57%)
         occurrences all number
    1
    8
    16
    2
    36
    2
    0
    6
    1
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 17 (5.88%)
    2 / 38 (5.26%)
    10 / 73 (13.70%)
    0 / 8 (0.00%)
    18 / 225 (8.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    3 / 45 (6.67%)
    2 / 28 (7.14%)
         occurrences all number
    1
    2
    11
    0
    19
    0
    0
    3
    2
    Influenza like illness
         subjects affected / exposed
    0 / 17 (0.00%)
    2 / 38 (5.26%)
    3 / 73 (4.11%)
    1 / 8 (12.50%)
    9 / 225 (4.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 45 (2.22%)
    2 / 28 (7.14%)
         occurrences all number
    0
    6
    9
    1
    21
    0
    0
    1
    4
    Gait disturbance
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    1 / 8 (12.50%)
    3 / 225 (1.33%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 45 (2.22%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    1
    4
    0
    0
    2
    1
    Peripheral swelling
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    1 / 73 (1.37%)
    0 / 8 (0.00%)
    2 / 225 (0.89%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    1
    0
    2
    0
    1
    0
    0
    Xerosis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    2 / 73 (2.74%)
    1 / 8 (12.50%)
    5 / 225 (2.22%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    0
    3
    1
    6
    0
    0
    0
    2
    Swelling face
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 38 (0.00%)
    1 / 73 (1.37%)
    0 / 8 (0.00%)
    2 / 225 (0.89%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    1
    0
    2
    0
    0
    0
    0
    Pyrexia
         subjects affected / exposed
    0 / 17 (0.00%)
    3 / 38 (7.89%)
    8 / 73 (10.96%)
    1 / 8 (12.50%)
    34 / 225 (15.11%)
    2 / 5 (40.00%)
    2 / 11 (18.18%)
    12 / 45 (26.67%)
    6 / 28 (21.43%)
         occurrences all number
    0
    4
    10
    1
    46
    3
    2
    18
    8
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    1 / 8 (12.50%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    0
    Seasonal allergy
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    1 / 73 (1.37%)
    1 / 8 (12.50%)
    2 / 225 (0.89%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    1
    1
    2
    0
    0
    0
    0
    Reproductive system and breast disorders
    Vulvovaginal dryness
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    1 / 5 (20.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    0
    0
    Pelvic pain
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    2 / 225 (0.89%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 45 (2.22%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    0
    0
    2
    0
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    0
    0
    Cough
         subjects affected / exposed
    5 / 17 (29.41%)
    7 / 38 (18.42%)
    21 / 73 (28.77%)
    3 / 8 (37.50%)
    64 / 225 (28.44%)
    2 / 5 (40.00%)
    2 / 11 (18.18%)
    14 / 45 (31.11%)
    10 / 28 (35.71%)
         occurrences all number
    7
    7
    27
    3
    81
    2
    3
    20
    12
    Dyspnoea exertional
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 38 (0.00%)
    2 / 73 (2.74%)
    1 / 8 (12.50%)
    9 / 225 (4.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    2 / 45 (4.44%)
    2 / 28 (7.14%)
         occurrences all number
    1
    0
    2
    1
    9
    0
    1
    2
    2
    Dyspnoea
         subjects affected / exposed
    6 / 17 (35.29%)
    1 / 38 (2.63%)
    13 / 73 (17.81%)
    0 / 8 (0.00%)
    36 / 225 (16.00%)
    1 / 5 (20.00%)
    1 / 11 (9.09%)
    6 / 45 (13.33%)
    8 / 28 (28.57%)
         occurrences all number
    7
    1
    13
    0
    40
    1
    1
    8
    9
    Dysphonia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    1 / 73 (1.37%)
    0 / 8 (0.00%)
    4 / 225 (1.78%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    1 / 45 (2.22%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    1
    0
    4
    0
    1
    1
    1
    Dry throat
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    1 / 5 (20.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    0
    0
    Epistaxis
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 38 (2.63%)
    6 / 73 (8.22%)
    0 / 8 (0.00%)
    11 / 225 (4.89%)
    2 / 5 (40.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    1
    6
    0
    11
    2
    0
    0
    2
    Haemoptysis
         subjects affected / exposed
    3 / 17 (17.65%)
    0 / 38 (0.00%)
    5 / 73 (6.85%)
    1 / 8 (12.50%)
    16 / 225 (7.11%)
    1 / 5 (20.00%)
    3 / 11 (27.27%)
    1 / 45 (2.22%)
    2 / 28 (7.14%)
         occurrences all number
    6
    0
    5
    1
    20
    1
    3
    2
    2
    Hiccups
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 38 (0.00%)
    2 / 73 (2.74%)
    0 / 8 (0.00%)
    3 / 225 (1.33%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    2
    0
    3
    0
    0
    0
    0
    Laryngeal inflammation
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    1 / 73 (1.37%)
    0 / 8 (0.00%)
    2 / 225 (0.89%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    1
    0
    2
    0
    1
    0
    0
    Pharyngeal inflammation
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    1 / 73 (1.37%)
    0 / 8 (0.00%)
    3 / 225 (1.33%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    0
    1
    0
    3
    0
    0
    0
    2
    Oropharyngeal pain
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    3 / 73 (4.11%)
    0 / 8 (0.00%)
    9 / 225 (4.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    3 / 45 (6.67%)
    3 / 28 (10.71%)
         occurrences all number
    0
    0
    3
    0
    9
    0
    0
    3
    3
    Nasal dryness
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 38 (2.63%)
    3 / 73 (4.11%)
    0 / 8 (0.00%)
    5 / 225 (2.22%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    1
    3
    0
    5
    0
    1
    0
    0
    Nasal congestion
         subjects affected / exposed
    1 / 17 (5.88%)
    2 / 38 (5.26%)
    2 / 73 (2.74%)
    0 / 8 (0.00%)
    6 / 225 (2.67%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    1
    2
    2
    0
    6
    0
    0
    0
    1
    Orthopnoea
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    0
    0
    Rhinitis allergic
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    2 / 73 (2.74%)
    1 / 8 (12.50%)
    4 / 225 (1.78%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    2
    1
    4
    0
    0
    0
    1
    Pulmonary embolism
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    3 / 225 (1.33%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 45 (2.22%)
    1 / 28 (3.57%)
         occurrences all number
    1
    0
    0
    0
    3
    0
    0
    1
    1
    Productive cough
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 38 (2.63%)
    2 / 73 (2.74%)
    0 / 8 (0.00%)
    8 / 225 (3.56%)
    1 / 5 (20.00%)
    0 / 11 (0.00%)
    2 / 45 (4.44%)
    1 / 28 (3.57%)
         occurrences all number
    1
    3
    2
    0
    12
    1
    0
    2
    3
    Pleural effusion
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    3 / 73 (4.11%)
    0 / 8 (0.00%)
    6 / 225 (2.67%)
    1 / 5 (20.00%)
    0 / 11 (0.00%)
    2 / 45 (4.44%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    3
    0
    6
    1
    0
    2
    0
    Rhinorrhoea
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 38 (2.63%)
    8 / 73 (10.96%)
    2 / 8 (25.00%)
    19 / 225 (8.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 45 (2.22%)
    6 / 28 (21.43%)
         occurrences all number
    3
    1
    8
    2
    24
    0
    0
    3
    7
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 17 (0.00%)
    2 / 38 (5.26%)
    1 / 73 (1.37%)
    1 / 8 (12.50%)
    6 / 225 (2.67%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    2 / 45 (4.44%)
    0 / 28 (0.00%)
         occurrences all number
    0
    2
    1
    2
    7
    0
    0
    2
    0
    Depressed mood
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    0
    0
    Depression
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 38 (2.63%)
    2 / 73 (2.74%)
    0 / 8 (0.00%)
    5 / 225 (2.22%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    1 / 45 (2.22%)
    0 / 28 (0.00%)
         occurrences all number
    0
    1
    2
    0
    5
    0
    1
    1
    0
    Insomnia
         subjects affected / exposed
    2 / 17 (11.76%)
    2 / 38 (5.26%)
    8 / 73 (10.96%)
    3 / 8 (37.50%)
    22 / 225 (9.78%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    5 / 45 (11.11%)
    2 / 28 (7.14%)
         occurrences all number
    3
    2
    9
    3
    25
    0
    0
    5
    3
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 38 (2.63%)
    1 / 73 (1.37%)
    0 / 8 (0.00%)
    5 / 225 (2.22%)
    1 / 5 (20.00%)
    0 / 11 (0.00%)
    1 / 45 (2.22%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    1
    0
    7
    1
    0
    1
    3
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 17 (0.00%)
    2 / 38 (5.26%)
    1 / 73 (1.37%)
    0 / 8 (0.00%)
    6 / 225 (2.67%)
    1 / 5 (20.00%)
    0 / 11 (0.00%)
    2 / 45 (4.44%)
    0 / 28 (0.00%)
         occurrences all number
    0
    4
    1
    0
    9
    1
    0
    3
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 17 (11.76%)
    2 / 38 (5.26%)
    5 / 73 (6.85%)
    0 / 8 (0.00%)
    18 / 225 (8.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    5 / 45 (11.11%)
    3 / 28 (10.71%)
         occurrences all number
    2
    2
    5
    0
    23
    0
    1
    9
    4
    Amylase increased
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    9 / 225 (4.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    6 / 45 (13.33%)
    1 / 28 (3.57%)
         occurrences all number
    2
    0
    0
    0
    14
    0
    1
    10
    1
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 17 (11.76%)
    4 / 38 (10.53%)
    4 / 73 (5.48%)
    0 / 8 (0.00%)
    17 / 225 (7.56%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    4 / 45 (8.89%)
    2 / 28 (7.14%)
         occurrences all number
    3
    5
    4
    0
    20
    0
    1
    4
    3
    Platelet count decreased
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 38 (0.00%)
    3 / 73 (4.11%)
    0 / 8 (0.00%)
    12 / 225 (5.33%)
    1 / 5 (20.00%)
    0 / 11 (0.00%)
    3 / 45 (6.67%)
    4 / 28 (14.29%)
         occurrences all number
    1
    0
    5
    0
    18
    4
    0
    3
    5
    Neutrophil count decreased
         subjects affected / exposed
    1 / 17 (5.88%)
    2 / 38 (5.26%)
    1 / 73 (1.37%)
    0 / 8 (0.00%)
    6 / 225 (2.67%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    2 / 45 (4.44%)
    0 / 28 (0.00%)
         occurrences all number
    1
    3
    2
    0
    8
    0
    0
    2
    0
    Lipase increased
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 38 (0.00%)
    3 / 73 (4.11%)
    0 / 8 (0.00%)
    11 / 225 (4.89%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    6 / 45 (13.33%)
    1 / 28 (3.57%)
         occurrences all number
    2
    0
    4
    0
    17
    0
    0
    10
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 17 (0.00%)
    3 / 38 (7.89%)
    1 / 73 (1.37%)
    0 / 8 (0.00%)
    8 / 225 (3.56%)
    1 / 5 (20.00%)
    0 / 11 (0.00%)
    3 / 45 (6.67%)
    0 / 28 (0.00%)
         occurrences all number
    0
    4
    1
    0
    9
    1
    0
    3
    0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 38 (2.63%)
    1 / 73 (1.37%)
    0 / 8 (0.00%)
    5 / 225 (2.22%)
    2 / 5 (40.00%)
    0 / 11 (0.00%)
    1 / 45 (2.22%)
    0 / 28 (0.00%)
         occurrences all number
    0
    1
    1
    0
    7
    4
    0
    1
    0
    Blood creatinine increased
         subjects affected / exposed
    1 / 17 (5.88%)
    2 / 38 (5.26%)
    5 / 73 (6.85%)
    1 / 8 (12.50%)
    16 / 225 (7.11%)
    1 / 5 (20.00%)
    1 / 11 (9.09%)
    1 / 45 (2.22%)
    4 / 28 (14.29%)
         occurrences all number
    1
    2
    13
    1
    28
    1
    1
    4
    5
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 17 (0.00%)
    2 / 38 (5.26%)
    1 / 73 (1.37%)
    0 / 8 (0.00%)
    8 / 225 (3.56%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 45 (2.22%)
    4 / 28 (14.29%)
         occurrences all number
    0
    5
    1
    0
    13
    0
    0
    1
    6
    Weight decreased
         subjects affected / exposed
    1 / 17 (5.88%)
    2 / 38 (5.26%)
    3 / 73 (4.11%)
    0 / 8 (0.00%)
    13 / 225 (5.78%)
    0 / 5 (0.00%)
    2 / 11 (18.18%)
    1 / 45 (2.22%)
    4 / 28 (14.29%)
         occurrences all number
    1
    2
    4
    0
    14
    0
    2
    1
    4
    Injury, poisoning and procedural complications
    Fracture
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    0
    0
    Face injury
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    1 / 8 (12.50%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    0
    Contusion
         subjects affected / exposed
    0 / 17 (0.00%)
    3 / 38 (7.89%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    5 / 225 (2.22%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    2 / 45 (4.44%)
    0 / 28 (0.00%)
         occurrences all number
    0
    4
    0
    0
    6
    0
    0
    2
    0
    Ligament sprain
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    2 / 225 (0.89%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    1 / 45 (2.22%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    1
    1
    0
    Procedural pain
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    4 / 73 (5.48%)
    0 / 8 (0.00%)
    10 / 225 (4.44%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    2 / 45 (4.44%)
    3 / 28 (10.71%)
         occurrences all number
    0
    0
    4
    0
    10
    0
    1
    2
    3
    Radius fracture
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    0
    0
    Vascular access site haematoma
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    1 / 73 (1.37%)
    0 / 8 (0.00%)
    3 / 225 (1.33%)
    1 / 5 (20.00%)
    0 / 11 (0.00%)
    1 / 45 (2.22%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    1
    0
    3
    1
    0
    1
    0
    Subdural haematoma
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    1 / 73 (1.37%)
    1 / 8 (12.50%)
    2 / 225 (0.89%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    1
    1
    2
    0
    0
    0
    0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    2 / 225 (0.89%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    1
    0
    0
    0
    2
    0
    0
    0
    1
    Cardiac failure congestive
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    1 / 5 (20.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    0
    0
    Angina pectoris
         subjects affected / exposed
    0 / 17 (0.00%)
    2 / 38 (5.26%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    2 / 225 (0.89%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    2
    0
    0
    2
    0
    0
    0
    0
    Sinus tachycardia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    2 / 73 (2.74%)
    0 / 8 (0.00%)
    3 / 225 (1.33%)
    1 / 5 (20.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    2
    0
    3
    1
    0
    0
    0
    Left ventricular dysfunction
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    1 / 5 (20.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    0
    0
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 38 (2.63%)
    2 / 73 (2.74%)
    1 / 8 (12.50%)
    4 / 225 (1.78%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    1
    2
    1
    4
    0
    0
    0
    0
    Amnesia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 38 (2.63%)
    0 / 73 (0.00%)
    1 / 8 (12.50%)
    3 / 225 (1.33%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 45 (2.22%)
    0 / 28 (0.00%)
         occurrences all number
    0
    1
    0
    1
    3
    0
    0
    1
    0
    Ataxia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 38 (2.63%)
    2 / 73 (2.74%)
    1 / 8 (12.50%)
    4 / 225 (1.78%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    1
    2
    1
    4
    0
    0
    0
    0
    Hypoaesthesia
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 38 (2.63%)
    1 / 73 (1.37%)
    1 / 8 (12.50%)
    4 / 225 (1.78%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    1
    2
    1
    1
    5
    0
    0
    0
    0
    Hyperaesthesia
         subjects affected / exposed
    0 / 17 (0.00%)
    2 / 38 (5.26%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    2 / 225 (0.89%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    2
    0
    0
    2
    0
    0
    0
    0
    Headache
         subjects affected / exposed
    1 / 17 (5.88%)
    7 / 38 (18.42%)
    13 / 73 (17.81%)
    3 / 8 (37.50%)
    41 / 225 (18.22%)
    1 / 5 (20.00%)
    1 / 11 (9.09%)
    9 / 45 (20.00%)
    6 / 28 (21.43%)
         occurrences all number
    1
    10
    14
    5
    54
    1
    1
    14
    8
    Dysgeusia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 38 (2.63%)
    1 / 73 (1.37%)
    0 / 8 (0.00%)
    7 / 225 (3.11%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    4 / 45 (8.89%)
    0 / 28 (0.00%)
         occurrences all number
    0
    1
    1
    0
    12
    0
    1
    9
    0
    Dizziness
         subjects affected / exposed
    5 / 17 (29.41%)
    6 / 38 (15.79%)
    9 / 73 (12.33%)
    1 / 8 (12.50%)
    32 / 225 (14.22%)
    2 / 5 (40.00%)
    1 / 11 (9.09%)
    4 / 45 (8.89%)
    4 / 28 (14.29%)
         occurrences all number
    5
    7
    10
    1
    34
    2
    1
    4
    4
    Dementia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    1 / 8 (12.50%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    0
    Cognitive disorder
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    1 / 73 (1.37%)
    1 / 8 (12.50%)
    2 / 225 (0.89%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    1
    1
    2
    0
    0
    0
    0
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    0
    0
    Tremor
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    0
    0
    Taste disorder
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 38 (2.63%)
    1 / 73 (1.37%)
    0 / 8 (0.00%)
    4 / 225 (1.78%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 45 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    1
    0
    4
    0
    1
    0
    1
    Seizure
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 38 (2.63%)
    1 / 73 (1.37%)
    1 / 8 (12.50%)
    5 / 225 (2.22%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 45 (2.22%)
    0 / 28 (0.00%)
         occurrences all number
    1
    1
    1
    1
    5
    0
    0
    1
    0
    Petit mal epilepsy
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    1 / 8 (12.50%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    0
    Paraesthesia
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 38 (2.63%)
    2 / 73 (2.74%)
    0 / 8 (0.00%)
    5 / 225 (2.22%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 45 (2.22%)
    0 / 28 (0.00%)
         occurrences all number
    1
    1
    2
    0
    5
    0
    0
    1
    0
    Neuropathy peripheral
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    2 / 8 (25.00%)
    6 / 225 (2.67%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 45 (2.22%)
    2 / 28 (7.14%)
         occurrences all number
    1
    0
    0
    2
    6
    0
    0
    1
    2
    Memory impairment
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    1 / 8 (12.50%)
    2 / 225 (0.89%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    1
    2
    0
    1
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 17 (5.88%)
    5 / 38 (13.16%)
    10 / 73 (13.70%)
    0 / 8 (0.00%)
    35 / 225 (15.56%)
    3 / 5 (60.00%)
    4 / 11 (36.36%)
    5 / 45 (11.11%)
    7 / 28 (25.00%)
         occurrences all number
    1
    7
    12
    0
    43
    3
    4
    8
    8
    Neutropenia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 38 (2.63%)
    4 / 73 (5.48%)
    1 / 8 (12.50%)
    10 / 225 (4.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    3 / 45 (6.67%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    5
    1
    17
    0
    0
    9
    1
    Immune thrombocytopenia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    1 / 5 (20.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    0
    0
    Lymphadenopathy
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 38 (2.63%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    2 / 225 (0.89%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    1
    1
    0
    0
    2
    0
    0
    0
    0
    Disseminated intravascular coagulation
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    0
    0
    Eosinophilia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    1 / 8 (12.50%)
    2 / 225 (0.89%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    1
    2
    0
    0
    0
    1
    Thrombocytopenia
         subjects affected / exposed
    0 / 17 (0.00%)
    2 / 38 (5.26%)
    2 / 73 (2.74%)
    1 / 8 (12.50%)
    7 / 225 (3.11%)
    1 / 5 (20.00%)
    0 / 11 (0.00%)
    1 / 45 (2.22%)
    0 / 28 (0.00%)
         occurrences all number
    0
    2
    6
    1
    12
    2
    0
    1
    0
    Ear and labyrinth disorders
    Ear haemorrhage
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    0
    0
    Eye disorders
    Eye discharge
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    0
    0
    Dry eye
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 38 (2.63%)
    4 / 73 (5.48%)
    0 / 8 (0.00%)
    9 / 225 (4.00%)
    1 / 5 (20.00%)
    0 / 11 (0.00%)
    2 / 45 (4.44%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    4
    0
    11
    1
    0
    4
    1
    Ocular hyperaemia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    1 / 73 (1.37%)
    0 / 8 (0.00%)
    2 / 225 (0.89%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    1
    0
    2
    0
    1
    0
    0
    Lacrimation increased
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    0
    0
    Vision blurred
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    5 / 73 (6.85%)
    2 / 8 (25.00%)
    9 / 225 (4.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    0
    5
    2
    9
    0
    0
    0
    2
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    3 / 17 (17.65%)
    2 / 38 (5.26%)
    4 / 73 (5.48%)
    0 / 8 (0.00%)
    16 / 225 (7.11%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    4 / 45 (8.89%)
    2 / 28 (7.14%)
         occurrences all number
    3
    3
    4
    0
    17
    0
    1
    4
    2
    Abdominal distension
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 38 (2.63%)
    3 / 73 (4.11%)
    0 / 8 (0.00%)
    8 / 225 (3.56%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 45 (2.22%)
    2 / 28 (7.14%)
         occurrences all number
    1
    1
    3
    0
    9
    0
    0
    2
    2
    Abdominal discomfort
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    3 / 225 (1.33%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 45 (2.22%)
    1 / 28 (3.57%)
         occurrences all number
    1
    0
    0
    0
    3
    0
    0
    1
    1
    Abdominal pain upper
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 38 (2.63%)
    2 / 73 (2.74%)
    0 / 8 (0.00%)
    13 / 225 (5.78%)
    1 / 5 (20.00%)
    2 / 11 (18.18%)
    5 / 45 (11.11%)
    1 / 28 (3.57%)
         occurrences all number
    1
    1
    2
    0
    17
    2
    4
    6
    1
    Aphthous ulcer
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 38 (2.63%)
    2 / 73 (2.74%)
    0 / 8 (0.00%)
    4 / 225 (1.78%)
    1 / 5 (20.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    1
    4
    0
    6
    1
    0
    0
    0
    Ascites
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 38 (0.00%)
    1 / 73 (1.37%)
    0 / 8 (0.00%)
    2 / 225 (0.89%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    1
    0
    2
    0
    0
    0
    0
    Cheilitis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    2 / 225 (0.89%)
    0 / 5 (0.00%)
    2 / 11 (18.18%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    2
    0
    0
    Dry mouth
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 38 (2.63%)
    5 / 73 (6.85%)
    0 / 8 (0.00%)
    9 / 225 (4.00%)
    1 / 5 (20.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    1
    5
    0
    9
    1
    0
    0
    2
    Diarrhoea
         subjects affected / exposed
    4 / 17 (23.53%)
    13 / 38 (34.21%)
    29 / 73 (39.73%)
    4 / 8 (50.00%)
    102 / 225 (45.33%)
    5 / 5 (100.00%)
    9 / 11 (81.82%)
    21 / 45 (46.67%)
    17 / 28 (60.71%)
         occurrences all number
    7
    21
    50
    10
    179
    8
    17
    36
    30
    Constipation
         subjects affected / exposed
    2 / 17 (11.76%)
    10 / 38 (26.32%)
    17 / 73 (23.29%)
    1 / 8 (12.50%)
    42 / 225 (18.67%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    8 / 45 (17.78%)
    4 / 28 (14.29%)
         occurrences all number
    2
    15
    23
    1
    59
    0
    0
    10
    8
    Dyspepsia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 38 (0.00%)
    5 / 73 (6.85%)
    0 / 8 (0.00%)
    15 / 225 (6.67%)
    1 / 5 (20.00%)
    1 / 11 (9.09%)
    4 / 45 (8.89%)
    3 / 28 (10.71%)
         occurrences all number
    4
    0
    6
    0
    21
    1
    1
    6
    3
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 17 (0.00%)
    3 / 38 (7.89%)
    4 / 73 (5.48%)
    0 / 8 (0.00%)
    11 / 225 (4.89%)
    1 / 5 (20.00%)
    0 / 11 (0.00%)
    2 / 45 (4.44%)
    1 / 28 (3.57%)
         occurrences all number
    0
    3
    4
    0
    12
    1
    0
    3
    1
    Gastritis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 38 (0.00%)
    1 / 73 (1.37%)
    1 / 8 (12.50%)
    6 / 225 (2.67%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    2 / 45 (4.44%)
    1 / 28 (3.57%)
         occurrences all number
    1
    0
    3
    1
    10
    0
    0
    4
    1
    Flatulence
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    2 / 73 (2.74%)
    0 / 8 (0.00%)
    5 / 225 (2.22%)
    1 / 5 (20.00%)
    0 / 11 (0.00%)
    2 / 45 (4.44%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    2
    0
    5
    1
    0
    2
    0
    Enterocolitis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    1 / 73 (1.37%)
    0 / 8 (0.00%)
    3 / 225 (1.33%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 45 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    1
    0
    3
    0
    1
    0
    1
    Haemorrhoids
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    1 / 73 (1.37%)
    0 / 8 (0.00%)
    4 / 225 (1.78%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    2 / 45 (4.44%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    1
    0
    4
    0
    1
    2
    0
    Odynophagia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    3 / 225 (1.33%)
    1 / 5 (20.00%)
    0 / 11 (0.00%)
    2 / 45 (4.44%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    3
    1
    0
    2
    0
    Nausea
         subjects affected / exposed
    4 / 17 (23.53%)
    8 / 38 (21.05%)
    15 / 73 (20.55%)
    2 / 8 (25.00%)
    54 / 225 (24.00%)
    2 / 5 (40.00%)
    3 / 11 (27.27%)
    10 / 45 (22.22%)
    10 / 28 (35.71%)
         occurrences all number
    5
    8
    21
    3
    73
    5
    4
    14
    13
    Ileus
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    0
    0
    Vomiting
         subjects affected / exposed
    6 / 17 (35.29%)
    6 / 38 (15.79%)
    10 / 73 (13.70%)
    0 / 8 (0.00%)
    38 / 225 (16.89%)
    1 / 5 (20.00%)
    2 / 11 (18.18%)
    5 / 45 (11.11%)
    8 / 28 (28.57%)
         occurrences all number
    9
    6
    13
    0
    48
    3
    2
    5
    10
    Stomatitis
         subjects affected / exposed
    8 / 17 (47.06%)
    9 / 38 (23.68%)
    20 / 73 (27.40%)
    3 / 8 (37.50%)
    67 / 225 (29.78%)
    1 / 5 (20.00%)
    3 / 11 (27.27%)
    12 / 45 (26.67%)
    11 / 28 (39.29%)
         occurrences all number
    10
    23
    45
    6
    129
    1
    4
    16
    24
    Oral pain
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    3 / 225 (1.33%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    2 / 45 (4.44%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    3
    0
    1
    2
    0
    Hepatobiliary disorders
    Hepatic function abnormal
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    1 / 73 (1.37%)
    0 / 8 (0.00%)
    4 / 225 (1.78%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 45 (2.22%)
    2 / 28 (7.14%)
         occurrences all number
    0
    0
    1
    0
    4
    0
    0
    1
    2
    Skin and subcutaneous tissue disorders
    Cutaneous vasculitis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    0
    0
    Blister
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    0
    0
    Alopecia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 38 (2.63%)
    1 / 73 (1.37%)
    0 / 8 (0.00%)
    9 / 225 (4.00%)
    1 / 5 (20.00%)
    0 / 11 (0.00%)
    5 / 45 (11.11%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    1
    0
    9
    1
    0
    5
    1
    Acne
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    3 / 73 (4.11%)
    1 / 8 (12.50%)
    4 / 225 (1.78%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    3
    1
    4
    0
    0
    0
    0
    Dermatitis acneiform
         subjects affected / exposed
    3 / 17 (17.65%)
    4 / 38 (10.53%)
    8 / 73 (10.96%)
    1 / 8 (12.50%)
    34 / 225 (15.11%)
    0 / 5 (0.00%)
    3 / 11 (27.27%)
    10 / 45 (22.22%)
    5 / 28 (17.86%)
         occurrences all number
    4
    4
    10
    1
    40
    0
    3
    12
    6
    Dermatitis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    1 / 8 (12.50%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    0
    Decubitus ulcer
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    2 / 73 (2.74%)
    1 / 8 (12.50%)
    4 / 225 (1.78%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 45 (2.22%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    4
    1
    6
    0
    0
    1
    0
    Dry skin
         subjects affected / exposed
    3 / 17 (17.65%)
    9 / 38 (23.68%)
    15 / 73 (20.55%)
    1 / 8 (12.50%)
    52 / 225 (23.11%)
    3 / 5 (60.00%)
    5 / 11 (45.45%)
    5 / 45 (11.11%)
    11 / 28 (39.29%)
         occurrences all number
    3
    9
    15
    1
    52
    3
    5
    5
    11
    Onychomadesis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    1 / 8 (12.50%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    0
    Eczema asteatotic
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    1 / 73 (1.37%)
    0 / 8 (0.00%)
    2 / 225 (0.89%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    1
    0
    2
    0
    1
    0
    0
    Hyperhidrosis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 38 (0.00%)
    1 / 73 (1.37%)
    0 / 8 (0.00%)
    2 / 225 (0.89%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    1
    0
    2
    0
    0
    0
    0
    Nail ridging
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    1 / 73 (1.37%)
    0 / 8 (0.00%)
    3 / 225 (1.33%)
    1 / 5 (20.00%)
    0 / 11 (0.00%)
    1 / 45 (2.22%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    1
    0
    3
    1
    0
    1
    0
    Night sweats
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    2
    0
    0
    0
    2
    0
    0
    0
    0
    Eczema
         subjects affected / exposed
    0 / 17 (0.00%)
    3 / 38 (7.89%)
    3 / 73 (4.11%)
    2 / 8 (25.00%)
    10 / 225 (4.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 45 (2.22%)
    1 / 28 (3.57%)
         occurrences all number
    0
    3
    4
    3
    12
    0
    0
    1
    1
    Rash
         subjects affected / exposed
    3 / 17 (17.65%)
    4 / 38 (10.53%)
    4 / 73 (5.48%)
    0 / 8 (0.00%)
    24 / 225 (10.67%)
    1 / 5 (20.00%)
    2 / 11 (18.18%)
    8 / 45 (17.78%)
    2 / 28 (7.14%)
         occurrences all number
    4
    4
    6
    0
    31
    1
    3
    11
    2
    Pruritus
         subjects affected / exposed
    4 / 17 (23.53%)
    11 / 38 (28.95%)
    28 / 73 (38.36%)
    5 / 8 (62.50%)
    82 / 225 (36.44%)
    3 / 5 (60.00%)
    6 / 11 (54.55%)
    13 / 45 (28.89%)
    12 / 28 (42.86%)
         occurrences all number
    7
    18
    31
    5
    110
    5
    6
    17
    21
    Petechiae
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    1 / 5 (20.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    0
    0
    Rash erythematous
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    1 / 73 (1.37%)
    2 / 8 (25.00%)
    5 / 225 (2.22%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    1 / 45 (2.22%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    1
    2
    6
    0
    1
    2
    0
    Skin discolouration
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    3 / 225 (1.33%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 45 (2.22%)
    1 / 28 (3.57%)
         occurrences all number
    1
    0
    0
    0
    3
    0
    0
    1
    1
    Rash papular
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 38 (2.63%)
    2 / 73 (2.74%)
    1 / 8 (12.50%)
    8 / 225 (3.56%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 45 (2.22%)
    3 / 28 (10.71%)
         occurrences all number
    0
    1
    2
    1
    9
    0
    0
    1
    4
    Rash maculo-papular
         subjects affected / exposed
    4 / 17 (23.53%)
    9 / 38 (23.68%)
    29 / 73 (39.73%)
    4 / 8 (50.00%)
    89 / 225 (39.56%)
    5 / 5 (100.00%)
    6 / 11 (54.55%)
    17 / 45 (37.78%)
    15 / 28 (53.57%)
         occurrences all number
    5
    16
    39
    6
    124
    7
    7
    20
    24
    Rash macular
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 38 (2.63%)
    5 / 73 (6.85%)
    0 / 8 (0.00%)
    15 / 225 (6.67%)
    2 / 5 (40.00%)
    0 / 11 (0.00%)
    2 / 45 (4.44%)
    4 / 28 (14.29%)
         occurrences all number
    2
    2
    9
    0
    21
    2
    0
    2
    4
    Skin exfoliation
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 38 (2.63%)
    1 / 73 (1.37%)
    0 / 8 (0.00%)
    5 / 225 (2.22%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    1 / 45 (2.22%)
    0 / 28 (0.00%)
         occurrences all number
    1
    1
    1
    0
    5
    0
    1
    1
    0
    Skin fissures
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    3 / 73 (4.11%)
    0 / 8 (0.00%)
    8 / 225 (3.56%)
    1 / 5 (20.00%)
    0 / 11 (0.00%)
    1 / 45 (2.22%)
    3 / 28 (10.71%)
         occurrences all number
    0
    0
    4
    0
    9
    1
    0
    1
    3
    Skin hyperpigmentation
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    1 / 8 (12.50%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    0
    Skin mass
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    0
    0
    Toxic skin eruption
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    1 / 8 (12.50%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    0
    Urticaria
         subjects affected / exposed
    3 / 17 (17.65%)
    1 / 38 (2.63%)
    5 / 73 (6.85%)
    1 / 8 (12.50%)
    19 / 225 (8.44%)
    0 / 5 (0.00%)
    2 / 11 (18.18%)
    3 / 45 (6.67%)
    4 / 28 (14.29%)
         occurrences all number
    3
    1
    6
    1
    22
    0
    2
    3
    6
    Vasculitic rash
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    1 / 8 (12.50%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    0
    Skin striae
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    0
    0
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    2 / 73 (2.74%)
    1 / 8 (12.50%)
    4 / 225 (1.78%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    2
    1
    4
    0
    0
    0
    1
    Hypertonic bladder
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    1 / 8 (12.50%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    0
    Urinary incontinence
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 38 (2.63%)
    1 / 73 (1.37%)
    2 / 8 (25.00%)
    4 / 225 (1.78%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    1
    1
    2
    4
    0
    0
    0
    0
    Nocturia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    1 / 8 (12.50%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    0
    Pollakiuria
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 38 (2.63%)
    1 / 73 (1.37%)
    0 / 8 (0.00%)
    4 / 225 (1.78%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    2
    1
    1
    0
    5
    0
    0
    0
    1
    Polyuria
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    1 / 8 (12.50%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    0
    Micturition urgency
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    1 / 8 (12.50%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    0
    Urinary retention
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    2 / 225 (0.89%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    0
    2
    Musculoskeletal and connective tissue disorders
    Muscular weakness
         subjects affected / exposed
    0 / 17 (0.00%)
    3 / 38 (7.89%)
    1 / 73 (1.37%)
    1 / 8 (12.50%)
    9 / 225 (4.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    1 / 45 (2.22%)
    2 / 28 (7.14%)
         occurrences all number
    0
    5
    1
    1
    13
    0
    2
    2
    2
    Muscle spasms
         subjects affected / exposed
    1 / 17 (5.88%)
    6 / 38 (15.79%)
    11 / 73 (15.07%)
    3 / 8 (37.50%)
    26 / 225 (11.56%)
    1 / 5 (20.00%)
    0 / 11 (0.00%)
    3 / 45 (6.67%)
    1 / 28 (3.57%)
         occurrences all number
    2
    8
    13
    4
    32
    1
    0
    3
    1
    Flank pain
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 38 (2.63%)
    3 / 73 (4.11%)
    0 / 8 (0.00%)
    6 / 225 (2.67%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    1
    1
    3
    0
    6
    0
    0
    0
    1
    Bone pain
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    1 / 73 (1.37%)
    1 / 8 (12.50%)
    3 / 225 (1.33%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    1
    1
    3
    0
    0
    0
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 17 (5.88%)
    7 / 38 (18.42%)
    5 / 73 (6.85%)
    0 / 8 (0.00%)
    17 / 225 (7.56%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    4 / 45 (8.89%)
    0 / 28 (0.00%)
         occurrences all number
    1
    8
    5
    0
    18
    0
    0
    4
    0
    Arthralgia
         subjects affected / exposed
    1 / 17 (5.88%)
    6 / 38 (15.79%)
    9 / 73 (12.33%)
    0 / 8 (0.00%)
    26 / 225 (11.56%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    7 / 45 (15.56%)
    3 / 28 (10.71%)
         occurrences all number
    1
    6
    10
    0
    30
    0
    0
    10
    3
    Back pain
         subjects affected / exposed
    4 / 17 (23.53%)
    6 / 38 (15.79%)
    11 / 73 (15.07%)
    2 / 8 (25.00%)
    34 / 225 (15.11%)
    1 / 5 (20.00%)
    1 / 11 (9.09%)
    4 / 45 (8.89%)
    5 / 28 (17.86%)
         occurrences all number
    4
    7
    11
    2
    35
    1
    1
    4
    5
    Pain in extremity
         subjects affected / exposed
    1 / 17 (5.88%)
    6 / 38 (15.79%)
    8 / 73 (10.96%)
    0 / 8 (0.00%)
    20 / 225 (8.89%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    3 / 45 (6.67%)
    2 / 28 (7.14%)
         occurrences all number
    1
    6
    9
    0
    21
    0
    0
    3
    2
    Osteoporosis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    0
    0
    Neck pain
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    6 / 73 (8.22%)
    0 / 8 (0.00%)
    8 / 225 (3.56%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    2 / 45 (4.44%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    6
    0
    8
    0
    0
    2
    0
    Myalgia
         subjects affected / exposed
    1 / 17 (5.88%)
    2 / 38 (5.26%)
    6 / 73 (8.22%)
    1 / 8 (12.50%)
    16 / 225 (7.11%)
    0 / 5 (0.00%)
    2 / 11 (18.18%)
    1 / 45 (2.22%)
    3 / 28 (10.71%)
         occurrences all number
    4
    3
    6
    1
    20
    0
    2
    1
    3
    Musculoskeletal discomfort
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 38 (2.63%)
    0 / 73 (0.00%)
    1 / 8 (12.50%)
    3 / 225 (1.33%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 45 (2.22%)
    0 / 28 (0.00%)
         occurrences all number
    0
    1
    0
    1
    3
    0
    0
    1
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 17 (0.00%)
    2 / 38 (5.26%)
    0 / 73 (0.00%)
    1 / 8 (12.50%)
    3 / 225 (1.33%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    3
    0
    1
    4
    0
    0
    0
    0
    Genital herpes
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    0
    0
    Conjunctivitis viral
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    2 / 225 (0.89%)
    2 / 5 (40.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    2
    0
    0
    0
    Dermatitis infected
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    1 / 5 (20.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    0
    0
    Folliculitis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    3 / 225 (1.33%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    1 / 45 (2.22%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    4
    0
    2
    1
    1
    Conjunctivitis
         subjects affected / exposed
    0 / 17 (0.00%)
    3 / 38 (7.89%)
    2 / 73 (2.74%)
    1 / 8 (12.50%)
    10 / 225 (4.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    3 / 45 (6.67%)
    1 / 28 (3.57%)
         occurrences all number
    0
    3
    2
    1
    10
    0
    0
    3
    1
    Herpes zoster
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 38 (2.63%)
    2 / 73 (2.74%)
    0 / 8 (0.00%)
    10 / 225 (4.44%)
    1 / 5 (20.00%)
    0 / 11 (0.00%)
    4 / 45 (8.89%)
    1 / 28 (3.57%)
         occurrences all number
    1
    1
    2
    0
    10
    1
    0
    4
    1
    Herpes zoster reactivation
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    1 / 8 (12.50%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    0
    Influenza
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    3 / 225 (1.33%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 45 (2.22%)
    2 / 28 (7.14%)
         occurrences all number
    0
    0
    0
    0
    3
    0
    0
    1
    2
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    3 / 225 (1.33%)
    1 / 5 (20.00%)
    0 / 11 (0.00%)
    1 / 45 (2.22%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    0
    0
    3
    1
    0
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    2 / 17 (11.76%)
    4 / 38 (10.53%)
    5 / 73 (6.85%)
    1 / 8 (12.50%)
    22 / 225 (9.78%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    6 / 45 (13.33%)
    4 / 28 (14.29%)
         occurrences all number
    5
    5
    6
    1
    36
    0
    0
    10
    9
    Onychomycosis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    2 / 225 (0.89%)
    1 / 5 (20.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    2
    1
    0
    0
    1
    Oral candidiasis
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 38 (2.63%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    2 / 225 (0.89%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    1
    0
    0
    2
    0
    1
    0
    0
    Paronychia
         subjects affected / exposed
    1 / 17 (5.88%)
    3 / 38 (7.89%)
    12 / 73 (16.44%)
    2 / 8 (25.00%)
    32 / 225 (14.22%)
    1 / 5 (20.00%)
    4 / 11 (36.36%)
    5 / 45 (11.11%)
    4 / 28 (14.29%)
         occurrences all number
    2
    3
    15
    2
    43
    1
    8
    5
    7
    Tuberculosis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    0
    0
    Tonsillitis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    2 / 225 (0.89%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 45 (2.22%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    0
    0
    2
    0
    0
    1
    0
    Skin infection
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 38 (2.63%)
    0 / 73 (0.00%)
    1 / 8 (12.50%)
    4 / 225 (1.78%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    1 / 45 (2.22%)
    0 / 28 (0.00%)
         occurrences all number
    0
    1
    0
    1
    4
    0
    1
    1
    0
    Rhinitis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    1 / 8 (12.50%)
    3 / 225 (1.33%)
    1 / 5 (20.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    1
    3
    1
    0
    0
    1
    Respiratory tract infection
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 38 (2.63%)
    3 / 73 (4.11%)
    0 / 8 (0.00%)
    7 / 225 (3.11%)
    1 / 5 (20.00%)
    0 / 11 (0.00%)
    2 / 45 (4.44%)
    0 / 28 (0.00%)
         occurrences all number
    0
    1
    3
    0
    7
    1
    0
    2
    0
    Rash pustular
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    2 / 225 (0.89%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    0
    0
    2
    0
    1
    0
    0
    Pneumonia
         subjects affected / exposed
    0 / 17 (0.00%)
    2 / 38 (5.26%)
    4 / 73 (5.48%)
    0 / 8 (0.00%)
    12 / 225 (5.33%)
    1 / 5 (20.00%)
    1 / 11 (9.09%)
    2 / 45 (4.44%)
    2 / 28 (7.14%)
         occurrences all number
    0
    3
    5
    0
    14
    1
    1
    2
    2
    Pharyngitis
         subjects affected / exposed
    1 / 17 (5.88%)
    2 / 38 (5.26%)
    2 / 73 (2.74%)
    1 / 8 (12.50%)
    8 / 225 (3.56%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 45 (2.22%)
    1 / 28 (3.57%)
         occurrences all number
    1
    2
    2
    1
    8
    0
    0
    1
    1
    Wound infection
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    0
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 38 (2.63%)
    1 / 73 (1.37%)
    1 / 8 (12.50%)
    4 / 225 (1.78%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    1 / 45 (2.22%)
    0 / 28 (0.00%)
         occurrences all number
    0
    1
    1
    2
    5
    0
    0
    1
    0
    Viral infection
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    1 / 8 (12.50%)
    1 / 225 (0.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    0
    Urinary tract infection
         subjects affected / exposed
    2 / 17 (11.76%)
    3 / 38 (7.89%)
    4 / 73 (5.48%)
    2 / 8 (25.00%)
    19 / 225 (8.44%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    7 / 45 (15.56%)
    1 / 28 (3.57%)
         occurrences all number
    2
    4
    7
    6
    29
    0
    0
    9
    1
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 17 (5.88%)
    9 / 38 (23.68%)
    7 / 73 (9.59%)
    3 / 8 (37.50%)
    36 / 225 (16.00%)
    0 / 5 (0.00%)
    2 / 11 (18.18%)
    7 / 45 (15.56%)
    7 / 28 (25.00%)
         occurrences all number
    2
    10
    9
    5
    48
    0
    2
    9
    11
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    5 / 17 (29.41%)
    4 / 38 (10.53%)
    16 / 73 (21.92%)
    2 / 8 (25.00%)
    54 / 225 (24.00%)
    2 / 5 (40.00%)
    5 / 11 (45.45%)
    13 / 45 (28.89%)
    7 / 28 (25.00%)
         occurrences all number
    7
    5
    17
    2
    62
    3
    6
    15
    7
    Dehydration
         subjects affected / exposed
    0 / 17 (0.00%)
    3 / 38 (7.89%)
    1 / 73 (1.37%)
    0 / 8 (0.00%)
    5 / 225 (2.22%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    0 / 45 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    3
    1
    0
    6
    0
    2
    0
    0
    Hyperglycaemia
         subjects affected / exposed
    0 / 17 (0.00%)
    2 / 38 (5.26%)
    2 / 73 (2.74%)
    0 / 8 (0.00%)
    5 / 225 (2.22%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    0 / 45 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    2
    2
    0
    5
    0
    0
    0
    1
    Hyperkalaemia
         subjects affected / exposed
    1 / 17 (5.88%)
    3 / 38 (7.89%)
    4 / 73 (5.48%)
    0 / 8 (0.00%)
    11 / 225 (4.89%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    1 / 45 (2.22%)
    1 / 28 (3.57%)
         occurrences all number
    1
    5
    10
    0
    22
    0
    1
    4
    1
    Hyperuricaemia
         subjects affected / exposed
    0 / 17 (0.00%)
    2 / 38 (5.26%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    8 / 225 (3.56%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    3 / 45 (6.67%)
    2 / 28 (7.14%)
         occurrences all number
    0
    2
    0
    0
    10
    0
    1
    4
    3
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    5 / 225 (2.22%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
    4 / 45 (8.89%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    6
    0
    0
    5
    1
    Hypocalcaemia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 38 (2.63%)
    1 / 73 (1.37%)
    0 / 8 (0.00%)
    5 / 225 (2.22%)
    1 / 5 (20.00%)
    0 / 11 (0.00%)
    2 / 45 (4.44%)
    0 / 28 (0.00%)
         occurrences all number
    0
    1
    1
    0
    5
    1
    0
    2
    0
    Hypokalaemia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    0 / 8 (0.00%)
    10 / 225 (4.44%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
    5 / 45 (11.11%)
    3 / 28 (10.71%)
         occurrences all number
    1
    0
    0
    0
    14
    0
    1
    7
    5
    Hypomagnesaemia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    1 / 73 (1.37%)
    1 / 8 (12.50%)
    7 / 225 (3.11%)
    2 / 5 (40.00%)
    0 / 11 (0.00%)
    1 / 45 (2.22%)
    2 / 28 (7.14%)
         occurrences all number
    0
    0
    1
    1
    11
    2
    0
    1
    6
    Hypophosphataemia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    1 / 73 (1.37%)
    0 / 8 (0.00%)
    6 / 225 (2.67%)
    1 / 5 (20.00%)
    0 / 11 (0.00%)
    3 / 45 (6.67%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    1
    0
    7
    2
    0
    3
    1
    Hyponatraemia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 38 (0.00%)
    0 / 73 (0.00%)
    1 / 8 (12.50%)
    6 / 225 (2.67%)
    1 / 5 (20.00%)
    0 / 11 (0.00%)
    2 / 45 (4.44%)
    2 / 28 (7.14%)
         occurrences all number
    0
    0
    0
    1
    10
    1
    0
    5
    3

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Apr 2014
    Amendment 1: - Inclusion of a generic statement to comply with health authority’s request to add a generic statement to this first-in-man trial: “that all participants participating in this clinical trial must have recurred or progressed following standard therapy, unless no standard therapy exists, is tolerated or appropriate”. - Modifications to specific inclusion criteria that all participants participating in this clinical trial must have recurred or progressed following standard therapy, unless no standard therapy exists, is tolerated or appropriate; Phase I part to recruit NSCLC participants harboring a documented EGFR T790M mutation; The group 1 in Phase II part to recruit participants had advanced NSCLC with EGFR mutation (L858R or ex19del, not T790M) and were intolerant to an approved EGFR TKI (e.g., erlotinib, gefitinib, afatinib); and/or for whom these drugs were not appropriate.
    04 Jun 2014
    Amendment 2: The rational for the amendment was to address the changes requested by health authority (i.e. Japan PMDA) and included the following: Clarify the definition of “women of childbearing potential”, Add “glucose” into chemistry panel in laboratory parameters, Clarify that results of biomarker will be returned to investigators.
    21 Aug 2014
    Amendment 3: The main purpose of this amendment was to allow for the possibility of a formulation change during dose escalation from capsule to tablet, and the determination of a MTD and/or RP2D with either formulation.
    05 May 2015
    Amendment 4: The primary purpose of this amendment was to revise the participant populations and/or the number of participants to be enrolled in each group in the Phase II part. In addition, the number of groups in the Phase II part was revised from four groups (as per Amendment 3) to six groups (Amendment 4). Each group had a distinctive participant population, determined by the specific EGFR mutations and the number of prior lines of systemic antineoplastic therapy, including prior EGFR TKIs. Throughout this amendment, advanced NSCLC referred to participants with either locally advanced or metastatic NSCLC. Locally advanced NSCLC was defined as stage IIIB NSCLC not amenable to definitive multi-modality therapy including surgery. Metastatic NSCLC referred to stage IV NSCLC.
    31 Aug 2015
    Amendment 5: As of 23-July-2015, 121 participants had been enrolled in the Phase I part (dose-escalation) of the study at nine sites in eight countries in Asia, Europe, and North America. As of 08-July-2015, two SAEs of HBV reactivation had been reported in two participants participating in the CEGF816X2101 study. One case had a fatal outcome due to hepatic failure despite initiation of antiviral treatment after HBV reactivation, and the second case was HBV reactivation that was medically significant. The viral reactivation in these two participants was likely due to immunosuppression related to nazartinib. To ensure the safety of all participants participating in EGF816X2101 trial, changes were made to the protocol to implement the safety regarding the reactivation of HBV and HCV. Early preclinical and clinical findings suggested that nazartinib might have an immunomodulatory effect, related to its ability to inhibit the Tec family of kinases. Changes were made to the protocol to allow sample acquisition at time points at which the presence of such an effect could be evaluated.
    07 Apr 2017
    Amendment 6: As of 31-Mar-2017 in the Phase I part (dose-escalation) of the study, 180 participants were enrolled with 7 different dose levels at 10 sites in 8 countries. During a dose escalation meeting on 30-Aug-2016, the Investigators and Novartis agreed to declare the RP2D of EGF816 capsules & tablets at the dose level of 150 mg qd based on the available safety, PK, efficacy data & on the BLRM recommendation. The Phase II part (expansion phase) was originally planned to enroll participants in 6 different groups defined by the prior lines of treatment & the tumor molecular status of the participants. However, the rapid evolving landscape including ongoing trials in this disease setting led to the decision not to start the enrollment of participants who received more than 1 line of prior antineoplastic therapy in Groups 2 to 6. Indeed, approval was granted in different countries to osimertinib for the treatment of adult participants with locally advanced or metastatic EGFR T790M mutation-positive NSCLC who had progressed on or after prior systemic therapy, including an EGFR-TKI giving participants in this setting access to 3rd generation EGFR-TKI as per FDA & EMA information. Therefore, the Phase II part of the study continued as a single group of participants, all treated at 150 mg qd EGF816. An Investigator letter dated 07-Dec-2016 informed the investigators about the opening of the Phase II part of the study for enrollment in Group 1 only. This group now enrolled a minimum of 40 treatment naïve participants instead of 60 participants who had locally advanced or metastatic NSCLC with EGFR activating mutation, had not received any systemic antineoplastic therapy for advanced NSCLC, & were eligible to receive EGFR-TKI treatment. The main purpose of this amendment was to implement the above-mentioned decisions that were already communicated to all Investigators & submitted to all Ethics Committees and Health Authorities in participating countries.
    11 Mar 2020
    Amendment 7: The main purpose of this amendment is to implement the use of the capsules form again (25 mg / 50 mg / 100 mg) instead of tablets for the ongoing participants promptly upon availability. The decision to switch back from tablet to capsule is based on the following: The capsule formulation has a superior stability profile compared to the tablets, allowing the assignment of longer shelf lives; Statistical analysis showed that exposures between tablet and capsule are comparable with geometric mean ratios of 1.04 and 1.03 for AUCtau and Cmax, respectively, following single 150 mg dose, and 1.06 and 1.12 for AUCtau and Cmax, respectively, following 150 mg QD. Therefore, based on this rationale, capsules were used in a timely manner following approval of this amendment for the remainder of this study for all ongoing participants in Phase I and Phase II parts. Additionally, the guidelines for some selected toxicities (hepatitis B, skin rash, including maculo-papular rash and Interstitial Lung Disease (ILD)/pneumonitis) had been updated to optimize the participant’s safety. These changes were not due to new safety findings but reflect new internal/international clinical guidelines.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Due to EudraCT system limitations which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd. com/CtrdWeb/home.nov for complete trial results.
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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