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    Clinical Trial Results:
    A Phase 1/2 Study of the Safety, Tolerability, Pharmacokinetics and Preliminary Anti-Tumor Activity of the Oral ALK/EGFR Inhibitor AP26113

    Summary
    EudraCT number
    2011-005718-12
    Trial protocol
    ES  
    Global end of trial date

    Results information
    Results version number
    v1(current)
    This version publication date
    29 Jun 2017
    First version publication date
    29 Jun 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AP26113-11-101
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01449461
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Takeda Development Center Americas, Inc.
    Sponsor organisation address
    One Takeda Parkway, Deerfield, IL, United States, 60015
    Public contact
    Medical Director, Clinical Science Organization: Takeda, +1 877-825-3327, clinicaltrialregistry@tpna.com
    Scientific contact
    Medical Director, Clinical Science Organization: Takeda, +1 877-825-3327, clinicaltrialregistry@tpna.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
    Interim
    Date of interim/final analysis
    16 Nov 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Nov 2015
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is 2-fold: initially, in the dose escalation phase, the goal is to determine the safety profile of orally administered AP26113, including: the maximum tolerated dose (MTD), dose limiting toxicities (DLTs), recommended phase 2 dose (RP2D), and pharmacokinetic (PK) profile. Then, once the RP2D is established, an expansion phase will assess the preliminary anti-tumor activity of AP26113, both in non-small cell lung cancer (NSCLC) with ALK gene rearrangement (including participants with active brain metastases) or mutated EGFR, and in other cancers with abnormal targets against which AP26113 is active.
    Protection of trial subjects
    All study participants were required to read and sign an Informed Consent Form.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    20 Sep 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Efficacy, Safety
    Long term follow-up duration
    2 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 7
    Country: Number of subjects enrolled
    United States: 130
    Worldwide total number of subjects
    137
    EEA total number of subjects
    7
    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)
    98
    From 65 to 84 years
    39
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Participants took part in the study at 9 investigative sites in the United States and Spain up to clinical cut-off date 16 November 2015. Study is ongoing.

    Pre-assignment
    Screening details
    Participants with advanced malignancies, all histologies other than leukemia were enrolled in dose-escalation and participants with non-small cell lung cancer (NSCLC) with anaplastic lymphoma kinase (ALK) rearrangements were enrolled in dose expansion phase. Participants received brigatinib 30 mg - 300 mg, tablets, orally once daily or twice daily.

    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
    Brigatinib 30 mg QD/60 mg QD
    Arm description
    Brigatinib 30 mg/60 mg, tablets, orally, once daily (QD) in each cycle of 28 days (approximately, up to 44.4 months).
    Arm type
    Experimental

    Investigational medicinal product name
    Brigatinib
    Investigational medicinal product code
    Other name
    AP26113
    Pharmaceutical forms
    Tablet, Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Brigatinib tablets and capsules

    Arm title
    Brigatinib 90 mg QD
    Arm description
    Brigatinib 90 mg, tablets, orally, once daily (QD) in each cycle of 28 days (approximately, up to 44.4 months).
    Arm type
    Experimental

    Investigational medicinal product name
    Brigatinib
    Investigational medicinal product code
    Other name
    AP26113
    Pharmaceutical forms
    Tablet, Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Brigatinib tablets and capsules

    Arm title
    Brigatinib 120 mg QD/60 mg BID
    Arm description
    Brigatinib 120 mg, once daily or 60 mg, twice daily (BID), tablets, orally, in each cycle of 28 days (approximately, up to 44.4 months).
    Arm type
    Experimental

    Investigational medicinal product name
    Brigatinib
    Investigational medicinal product code
    Other name
    AP26113
    Pharmaceutical forms
    Tablet, Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Brigatinib tablets and capsules

    Arm title
    Brigatinib 90 mg QD-180 mg QD
    Arm description
    Brigatinib 90 mg, tablets, orally, once daily for 7 days followed by brigatinib 180 mg, orally once daily in Cycle 1 of 28 days followed by brigatinib 180 mg, orally once daily in cycle 2 and onward cycles of 28 days.
    Arm type
    Experimental

    Investigational medicinal product name
    Brigatinib
    Investigational medicinal product code
    Other name
    AP26113
    Pharmaceutical forms
    Tablet, Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Brigatinib tablets and capsules

    Arm title
    Brigatinib 180 mg QD/90 mg BID
    Arm description
    Brigatinib 180 mg, once daily or 90 mg, twice daily (BID), tablets, orally in each cycle of 28 days (approximately, up to 44.4 months).
    Arm type
    Experimental

    Investigational medicinal product name
    Brigatinib
    Investigational medicinal product code
    Other name
    AP26113
    Pharmaceutical forms
    Tablet, Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Brigatinib tablets and capsules

    Arm title
    Brigatinib 240 mg QD/120 mg BID/300 mg QD
    Arm description
    Brigatinib 240 mg, once daily (QD) or 120 mg, twice daily (BID) or 300 mg once daily, tablets, orally, in each cycle of 28 days (approximately, up to 44.4 months).
    Arm type
    Experimental

    Investigational medicinal product name
    Brigatinib
    Investigational medicinal product code
    Other name
    AP26113
    Pharmaceutical forms
    Tablet, Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Brigatinib tablets and capsules

    Number of subjects in period 1
    Brigatinib 30 mg QD/60 mg QD Brigatinib 90 mg QD Brigatinib 120 mg QD/60 mg BID Brigatinib 90 mg QD-180 mg QD Brigatinib 180 mg QD/90 mg BID Brigatinib 240 mg QD/120 mg BID/300 mg QD
    Started
    6
    18
    18
    32
    48
    15
    Completed
    0
    0
    0
    0
    0
    0
    Not completed
    6
    18
    18
    32
    48
    15
         Adverse event, serious fatal
    -
    1
    -
    -
    4
    1
         Documented progressive disease
    4
    6
    14
    11
    21
    5
         Adverse event, non-fatal
    -
    3
    2
    3
    3
    3
         Clinical progressive disease
    2
    1
    -
    -
    3
    3
         Ongoing
    -
    6
    2
    15
    17
    2
         Reason not specified
    -
    1
    -
    3
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Brigatinib 30 mg QD/60 mg QD
    Reporting group description
    Brigatinib 30 mg/60 mg, tablets, orally, once daily (QD) in each cycle of 28 days (approximately, up to 44.4 months).

    Reporting group title
    Brigatinib 90 mg QD
    Reporting group description
    Brigatinib 90 mg, tablets, orally, once daily (QD) in each cycle of 28 days (approximately, up to 44.4 months).

    Reporting group title
    Brigatinib 120 mg QD/60 mg BID
    Reporting group description
    Brigatinib 120 mg, once daily or 60 mg, twice daily (BID), tablets, orally, in each cycle of 28 days (approximately, up to 44.4 months).

    Reporting group title
    Brigatinib 90 mg QD-180 mg QD
    Reporting group description
    Brigatinib 90 mg, tablets, orally, once daily for 7 days followed by brigatinib 180 mg, orally once daily in Cycle 1 of 28 days followed by brigatinib 180 mg, orally once daily in cycle 2 and onward cycles of 28 days.

    Reporting group title
    Brigatinib 180 mg QD/90 mg BID
    Reporting group description
    Brigatinib 180 mg, once daily or 90 mg, twice daily (BID), tablets, orally in each cycle of 28 days (approximately, up to 44.4 months).

    Reporting group title
    Brigatinib 240 mg QD/120 mg BID/300 mg QD
    Reporting group description
    Brigatinib 240 mg, once daily (QD) or 120 mg, twice daily (BID) or 300 mg once daily, tablets, orally, in each cycle of 28 days (approximately, up to 44.4 months).

    Reporting group values
    Brigatinib 30 mg QD/60 mg QD Brigatinib 90 mg QD Brigatinib 120 mg QD/60 mg BID Brigatinib 90 mg QD-180 mg QD Brigatinib 180 mg QD/90 mg BID Brigatinib 240 mg QD/120 mg BID/300 mg QD Total
    Number of subjects
    6 18 18 32 48 15 137
    Age Categorical
    Units: Subjects
        18 – 64 years
    2 11 12 25 39 9 98
        ≥65 years
    4 7 6 7 9 6 39
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    66.8 ± 9.3 57.9 ± 12.93 57.8 ± 10.91 55.7 ± 11.41 53.9 ± 11.1 58.5 ± 15.6 -
    Gender, Male/Female
    Units: Subjects
        Female
    3 6 5 18 19 7 58
        Male
    3 12 13 14 29 8 79
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian or Alaska Native
    0 0 0 1 1 0 2
        Asian
    0 4 3 3 5 2 17
        Black or African American
    0 1 2 0 1 1 5
        Native Hawaiian or Other Pacific Islander
    0 0 0 0 1 0 1
        White
    6 13 13 27 39 12 110
        Unknown
    0 0 0 0 1 0 1
        Other
    0 0 0 1 0 0 1
    Race/Ethnicity, Customized
    Units: Subjects
        Hispanic or Latino
    1 0 0 1 1 0 3
        Not Hispanic or Latino
    5 18 18 31 47 15 134
    Eastern Cooperative Oncology Group (ECOG) Performance Score
    ECOG assessed participant's performance status on a 5 point scale: 0 equals (=) fully active/able to carry on all pre-disease activities without restriction; 1=restricted in physically strenuous activity, but ambulatory/able to carry out light or sedentary work; 2=ambulatory (greater than [>] 50 percentage [%] of waking hours [h]), capable of all self care, but unable to carry out any work activities; 3=capable of only limited self care, confined to bed/chair >50% of waking hours; 4= completely disabled, cannot carry on any selfcare, totally confined to bed or chair and 5=Dead.
    Units: Subjects
        ECOG Score=0
    0 3 3 13 13 2 34
        ECOG Score=1
    6 15 15 19 33 13 101
        ECOG Score=3
    0 0 0 0 2 0 2
    Participants with Diagnosis of Cancer Type
    Units: Subjects
        NSCLC
    3 16 18 31 45 15 128
        Other
    3 2 0 1 3 0 9
    Number of Participants with Mutation Types
    Units: Subjects
        Anaplastic lymphoma kinase (ALK+)
    1 16 6 29 27 5 84
        Epidermal Growth Factor Receptor (EGFRm)
    2 1 10 3 18 9 43
        ROS proto-oncogene 1 (ROS1+)
    0 0 0 0 3 1 4
        Other
    3 1 2 0 0 0 6
    Participants with Prior Chemotherapy Regimen
    Units: Subjects
        Prior Therapy=0
    0 2 7 12 12 3 36
        Prior Therapy=1
    3 4 3 6 17 2 35
        Prior Therapy=2
    0 9 4 8 10 5 36
        Prior Therapy >2
    3 3 4 6 9 5 30
    Participants with Prior Radiotherapy to Brain
    Units: Subjects
        No Prior Radiotherapy
    6 13 17 24 36 14 110
        Prior Radiotherapy
    0 5 1 8 12 1 27
    Region of Enrollment
    Units: Subjects
        United States
    6 18 18 32 41 15 130
        Spain
    0 0 0 0 7 0 7
    Study Specific Characteristic | Time Since Diagnosis of Cancer
    Units: years
        arithmetic mean (standard deviation)
    2.48 ± 3.303 3.33 ± 2.184 2.41 ± 1.346 3.19 ± 2.726 2.77 ± 2.053 3.27 ± 1.913 -

    End points

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    End points reporting groups
    Reporting group title
    Brigatinib 30 mg QD/60 mg QD
    Reporting group description
    Brigatinib 30 mg/60 mg, tablets, orally, once daily (QD) in each cycle of 28 days (approximately, up to 44.4 months).

    Reporting group title
    Brigatinib 90 mg QD
    Reporting group description
    Brigatinib 90 mg, tablets, orally, once daily (QD) in each cycle of 28 days (approximately, up to 44.4 months).

    Reporting group title
    Brigatinib 120 mg QD/60 mg BID
    Reporting group description
    Brigatinib 120 mg, once daily or 60 mg, twice daily (BID), tablets, orally, in each cycle of 28 days (approximately, up to 44.4 months).

    Reporting group title
    Brigatinib 90 mg QD-180 mg QD
    Reporting group description
    Brigatinib 90 mg, tablets, orally, once daily for 7 days followed by brigatinib 180 mg, orally once daily in Cycle 1 of 28 days followed by brigatinib 180 mg, orally once daily in cycle 2 and onward cycles of 28 days.

    Reporting group title
    Brigatinib 180 mg QD/90 mg BID
    Reporting group description
    Brigatinib 180 mg, once daily or 90 mg, twice daily (BID), tablets, orally in each cycle of 28 days (approximately, up to 44.4 months).

    Reporting group title
    Brigatinib 240 mg QD/120 mg BID/300 mg QD
    Reporting group description
    Brigatinib 240 mg, once daily (QD) or 120 mg, twice daily (BID) or 300 mg once daily, tablets, orally, in each cycle of 28 days (approximately, up to 44.4 months).

    Subject analysis set title
    Brigatinib
    Subject analysis set type
    Full analysis
    Subject analysis set description
    All participants who received Brigatinib, tablets, orally, once daily in each cycle of 28 days.

    Subject analysis set title
    Brigatinib 30 mg
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Brigatinib 30 mg, tablets, orally, once daily (QD) in each cycle of 28 days (approximately, up to 44.4 months).

    Subject analysis set title
    Brigatinib 60 mg
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Brigatinib 60 mg, tablets, orally, once daily (QD) in each cycle of 28 days (approximately, up to 44.4 months).

    Subject analysis set title
    Brigatinib 90 mg
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Brigatinib 90 mg, tablets, orally, once daily or twice daily in each cycle of 28 days (approximately, up to 44.4 months).

    Subject analysis set title
    Brigatinib 120 mg
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Brigatinib 120 mg, tablets, orally, once daily in each cycle of 28 days (approximately, up to 44.4 months).

    Subject analysis set title
    Brigatinib 180 mg
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Brigatinib 180 mg, tablets, orally once daily in each cycle of 28 days (approximately, up to 44.4 months).

    Subject analysis set title
    Brigatinib 240 mg
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Brigatinib 240 mg, tablets, orally, once daily in each cycle of 28 days (approximately, up to 44.4 months).

    Subject analysis set title
    Brigatinib 300 mg
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Brigatinib 300 mg, tablets, orally, once daily in each cycle of 28 days (approximately, up to 44.4 months).

    Subject analysis set title
    Brigatinib 90 mg
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Brigatinib 90 mg, tablets, orally, once daily or twice daily in each cycle of 28 days (approximately, up to 44.4 months).

    Subject analysis set title
    Brigatinib 120 mg
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Brigatinib 120 mg, tablets, orally, once daily in each cycle of 28 days (approximately, up to 44.4 months).

    Subject analysis set title
    Brigatinib 180 mg
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Brigatinib 180 mg, tablets, orally once daily in each cycle of 28 days (approximately, up to 44.4 months).

    Subject analysis set title
    Brigatinib 240 mg
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Brigatinib 240 mg, tablets, orally, once daily in each cycle of 28 days (approximately, up to 44.4 months).

    Subject analysis set title
    Brigatinib 300 mg
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Brigatinib 300 mg, tablets, orally, once daily in each cycle of 28 days (approximately, up to 44.4 months).

    Subject analysis set title
    Brigatinib 180 mg
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Brigatinib 180 mg, tablets, orally once daily in each cycle of 28 days (approximately, up to 44.4 months).

    Subject analysis set title
    Brigatinib 90 mg
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Brigatinib 90 mg, tablets, orally, once daily or twice daily in each cycle of 28 days (approximately, up to 44.4 months).

    Subject analysis set title
    Brigatinib 240 mg
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Brigatinib 240 mg, tablets, orally, once daily in each cycle of 28 days (approximately, up to 44.4 months).

    Subject analysis set title
    Brigatinib 30 mg
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Brigatinib 30 mg, tablets, orally, once daily (QD) in each cycle of 28 days (approximately, up to 44.4 months).

    Subject analysis set title
    Brigatinib 120 mg
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Brigatinib 120 mg, tablets, orally, once daily in each cycle of 28 days (approximately, up to 44.4 months).

    Subject analysis set title
    Dose Escalation Phase
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Participants received brigatinib tablets, orally, once daily (QD) starting at 30 mg in each cycle of 28 days (approximately, up to 44.4 months).

    Subject analysis set title
    Brigatinib 30 mg
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Brigatinib 30 mg, tablets, orally, once daily (QD) in each cycle of 28 days (approximately, up to 44.4 months).

    Subject analysis set title
    Brigatinib 60 mg
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Brigatinib 60 mg, tablets, orally, once daily (QD) in each cycle of 28 days (approximately, up to 44.4 months).

    Subject analysis set title
    Brigatinib 90 mg
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Brigatinib 90 mg, tablets, orally, once daily or twice daily in each cycle of 28 days (approximately, up to 44.4 months).

    Subject analysis set title
    Brigatinib 120 mg
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Brigatinib 120 mg, tablets, orally, once daily in each cycle of 28 days (approximately, up to 44.4 months).

    Subject analysis set title
    Brigatinib 180 mg
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Brigatinib 180 mg, tablets, orally once daily in each cycle of 28 days (approximately, up to 44.4 months).

    Subject analysis set title
    Brigatinib 240 mg
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Brigatinib 240 mg, tablets, orally, once daily in each cycle of 28 days (approximately, up to 44.4 months).

    Primary: Recommended Phase 2 Dose of AP26113

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    End point title
    Recommended Phase 2 Dose of AP26113 [1]
    End point description
    The RP2D is the maximum tolerated dose (MTD) or less. The MTD is defined as the dose range at which ≤ 1 of 6 evaluable participants experience dose limiting toxicities (DLT) within the first 28 days of treatment (end of cycle 1). Safety population included all enrolled participants who received at least one dose of study drug. Here, 99.999 indicates R2PD for this study is a dose range.
    End point type
    Primary
    End point timeframe
    28 days
    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: Statistical Analysis not reported for this endpoint.
    End point values
    Brigatinib
    Number of subjects analysed
    137
    Units: mg
        arithmetic mean (full range (min-max))
    99.999 (90 to 180)
    No statistical analyses for this end point

    Primary: Objective Response Rate (ORR)

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    End point title
    Objective Response Rate (ORR) [2]
    End point description
    ORR is defined as the proportion of participants with complete response (CR) or partial response (PR) according to RECIST v1.1 after the initiation of study treatment. CR for target lesion: disappearance of all extranodal lesions and all pathological lymph nodes must have decreased to <10 mm in short axis. CR for non-target lesion: Disappearance of all extranodal non-target lesions, all lymph nodes must be non-pathological in size (<10mm short axis) and normalization of tumor marker level. PR: at least a 30% decrease in the sum of the longest diameters (SLD) of target lesions, taking as reference the baseline sum diameters. Full analysis set (FAS) included all participants who received at least one dose of study drug. Participants with ALK and NSCLC were evaluated for this outcome measure. Here, n is the number of participants who were evaluable for specific category. 99999 indicates that no participant was analyzed in this arm. Crzb=Crizotinib.
    End point type
    Primary
    End point timeframe
    Screening and at 8-week intervals thereafter up to data cut-off date: 16 November 2015 (approximately up to 50 months)
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical Analysis not reported for this endpoint.
    End point values
    Brigatinib 30 mg QD/60 mg QD Brigatinib 90 mg QD Brigatinib 120 mg QD/60 mg BID Brigatinib 90 mg QD-180 mg QD Brigatinib 180 mg QD/90 mg BID Brigatinib 240 mg QD/120 mg BID/300 mg QD
    Number of subjects analysed
    1
    14
    6
    28
    25
    5
    Units: percentage of participants
    number (confidence interval 95%)
        With Prior Treatment with Crzb (n=1,13,5,25,23,4)
    100 (2.5 to 100)
    76.9 (46.2 to 95)
    60 (14.7 to 94.7)
    80 (59.3 to 93.2)
    65.2 (42.7 to 83.6)
    50 (6.8 to 93.2)
        Without Prior Treatment with Crzb (n=0,1,1,3,2,1)
    99999 (99999 to 99999)
    100 (2.5 to 100)
    100 (2.5 to 100)
    100 (29.2 to 100)
    100 (15.8 to 100)
    100 (2.5 to 100)
    No statistical analyses for this end point

    Secondary: Intracranial Objective Response Rate

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    End point title
    Intracranial Objective Response Rate
    End point description
    Intracranial objective response rate is defined as the proportion of the participants with CR or PR in the intracranial CNS per modification of RECIST v1.1 after the initiation of study drug. CR for target lesion: disappearance of all extranodal lesions. CR for non-target lesion: disappearance of all extranodal non-target lesions and normalization of tumor marker level. PR: at least a 30% decrease in the sum of the longest diameters (SLD) of target lesions, taking as reference the baseline sum diameters. Full analysis set. ALK+ NSCLC participants with measurable and only non-measurable brain metastases at baseline were evaluated for this outcome measure. Here, n is the number of participants who were evaluable for specific category. 99999 indicates No participant was evaluated for this arm. Meta.=Metastases.
    End point type
    Secondary
    End point timeframe
    Screening and at 8-week intervals thereafter up to data cut-off date: 16 November 2015 (approximately up to 50 months)
    End point values
    Brigatinib 30 mg QD/60 mg QD Brigatinib 90 mg QD Brigatinib 120 mg QD/60 mg BID Brigatinib 90 mg QD-180 mg QD Brigatinib 180 mg QD/90 mg BID Brigatinib 240 mg QD/120 mg BID/300 mg QD
    Number of subjects analysed
    0 [3]
    8
    1
    18
    16
    3
    Units: percentage of participants
    number (confidence interval 95%)
        With Measurable Brain Metastases (n=0,2,0,5,7,1)
    ( to )
    100 (15.8 to 100)
    99999 (99999 to 99999)
    80 (28.4 to 99.5)
    42.9 (9.9 to 81.6)
    100 (2.5 to 100)
        With Non-Measurable Brain Meta. (n=0,6,1,13,9,2)
    ( to )
    16.7 (0.4 to 64.1)
    100 (2.5 to 100)
    46.2 (19.2 to 74.9)
    44.4 (13.7 to 78.8)
    50 (1.3 to 98.7)
    Notes
    [3] - No participant was evaluated for this arm.
    No statistical analyses for this end point

    Secondary: Number of Participants Who Had at Least One Treatment-Emergent Adverse Event (TEAE)

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    End point title
    Number of Participants Who Had at Least One Treatment-Emergent Adverse Event (TEAE)
    End point description
    An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug. Safety population included all enrolled participants who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    Any adverse event reported on or after the day of first dose of study drug (approximately up to 50 months)
    End point values
    Brigatinib 30 mg QD/60 mg QD Brigatinib 90 mg QD Brigatinib 120 mg QD/60 mg BID Brigatinib 90 mg QD-180 mg QD Brigatinib 180 mg QD/90 mg BID Brigatinib 240 mg QD/120 mg BID/300 mg QD
    Number of subjects analysed
    6
    18
    18
    32
    48
    15
    Units: participants
    6
    18
    18
    31
    48
    15
    No statistical analyses for this end point

    Secondary: Maximum Tolerated Dose (MTD) Assessed in Dose Escalation Phase of the Study

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    End point title
    Maximum Tolerated Dose (MTD) Assessed in Dose Escalation Phase of the Study
    End point description
    The MTD is defined as the highest dose at which ≤ 1 of 6 evaluable participants experience a DLT within the first 28 days of treatment (end of cycle 1). Evaluable participants must complete at least 75% of their planned doses, unless missed doses are due to AEs. The cohort may be expanded to better define the safety profile for confirmation of the MTD. The maximum administered dose in the trial will likely exceed the MTD. Safety population included all enrolled participants who received at least one dose of study drug. MTD was not formally determined. Here 99999 indicates that MTD criteria was not met.
    End point type
    Secondary
    End point timeframe
    Up to Cycle 1 (28 days)
    End point values
    Dose Escalation Phase
    Number of subjects analysed
    66
    Units: mg
        number (not applicable)
    99999
    No statistical analyses for this end point

    Secondary: Number of Participants with Dose Limiting Toxicities (DLTs) Assessed in Dose Escalation Phase of the Study

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    End point title
    Number of Participants with Dose Limiting Toxicities (DLTs) Assessed in Dose Escalation Phase of the Study
    End point description
    DLT include any toxicity that is possibly, probably, or definitely drug-related. Toxicity grades will be defined by the NCI CTCAE v 4.0. DLTs are defined by the following: A) Non-hematologic toxicities: Any grade ≥3 non-hematologic toxicity, with the exception of self-limiting or medically controllable toxicities (eg, nausea, vomiting, fatigue, electrolyte disturbances, hypersensitivity reactions) lasting < 3 days, and excluding alopecia. B) Hematologic toxicities: Febrile neutropenia not related to underlying disease (fever, > 101°F; ANC<500); Prolonged grade 4 neutropenia (> 7 days); Neutropenic infection: ≥ grade 3 neutropenia with ≥ grade 3 infection; Thrombocytopenia ≥ grade 3 with bleeding or grade 4 lasting ≥ 7 days. C) Missed ≥ 25% of planned doses of brigatinib over 28 days due to treatment-related AEs in the first cycle. Safety population included all enrolled participants who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    Up to Cycle 1 (28 days)
    End point values
    Brigatinib 30 mg Brigatinib 60 mg Brigatinib 90 mg Brigatinib 120 mg Brigatinib 180 mg Brigatinib 240 mg Brigatinib 300 mg
    Number of subjects analysed
    3
    3
    5
    3
    3
    6
    2
    Units: participants
    0
    0
    0
    0
    0
    1
    1
    No statistical analyses for this end point

    Secondary: Cmax: Maximum Observed Plasma Concentration for Brigatinib

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    End point title
    Cmax: Maximum Observed Plasma Concentration for Brigatinib
    End point description
    Analysis was performed on all enrolled participants in the study who received at least one dose of brigatinib. Here number of participant analyzed is the participants who were evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1
    End point values
    Brigatinib 30 mg Brigatinib 60 mg Brigatinib 90 mg Brigatinib 120 mg Brigatinib 180 mg Brigatinib 240 mg Brigatinib 300 mg
    Number of subjects analysed
    3
    3
    50
    11
    44
    10
    2
    Units: ng/mL
    arithmetic mean (standard deviation)
        Cmax
    125.6 ± 41.07
    406.3 ± 102
    493 ± 289.5
    793.7 ± 828.7
    1185 ± 607.6
    1515 ± 637.9
    895 ± 99999
    No statistical analyses for this end point

    Secondary: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Brigatinib

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    End point title
    Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Brigatinib
    End point description
    Analysis was performed on all enrolled participants in the study who received at least one dose of brigatinib. Participants of brigatinib 90 mg QD-180 mg QD arm were included as per treatment received at each time point. Here 99999 indicates that standard deviation was not calculated.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1
    End point values
    Brigatinib 30 mg Brigatinib 60 mg Brigatinib 300 mg Brigatinib 90 mg Brigatinib 120 mg Brigatinib 240 mg Brigatinib 180 mg
    Number of subjects analysed
    3
    3
    2
    50
    11
    10
    44
    Units: hours
    arithmetic mean (standard deviation)
        Tmax
    3.9 ± 99999
    1.83 ± 1.9
    4.05 ± 99999
    3.26 ± 4.53
    2.78 ± 1.7
    2.22 ± 1.02
    2.99 ± 3.77
    No statistical analyses for this end point

    Secondary: AUC(0-24): Area Under the Plasma Concentration-Time Curve From Time 0 to 24 hours post-dose for AP26113

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    End point title
    AUC(0-24): Area Under the Plasma Concentration-Time Curve From Time 0 to 24 hours post-dose for AP26113
    End point description
    Analysis was performed on all enrolled participants in the study who received at least one dose of brigatinib. Participants of brigatinib 90 mg QD-180 mg QD arm were included as per treatment received at each time point.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1, 8, 15 and 22 pre-dose and Day 1 multiple timepoints (up to 48 hours) post-dose; Cycle 2 Day 1 and 3 pre-dose and Day 1 multiple time points (up to 48 hours) post-dose
    End point values
    Brigatinib 30 mg Brigatinib 60 mg Brigatinib 300 mg Brigatinib 120 mg Brigatinib 180 mg Brigatinib 90 mg Brigatinib 240 mg
    Number of subjects analysed
    3
    3
    2
    11
    44
    15
    7
    Units: h*ng/mL
        arithmetic mean (standard deviation)
    1320.9 ± 576.29
    3900 ± 430.31
    7571.1 ± 99999
    9895.5 ± 11772
    13204 ± 6306.9
    5710.1 ± 3268.4
    16800 ± 7571.1
    No statistical analyses for this end point

    Secondary: Terminal Phase Elimination Half-life (T1/2) for Brigatinib

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    End point title
    Terminal Phase Elimination Half-life (T1/2) for Brigatinib
    End point description
    Analysis was performed on all enrolled participants in the study who received at least one dose of brigatinib. Participants of brigatinib 90 mg QD-180 mg QD arm were included as per treatment received at each time point. Here, 99999 indicates that standard deviation was not calculated.
    End point type
    Secondary
    End point timeframe
    Cycle 2 Day 1
    End point values
    Brigatinib 60 mg Brigatinib 180 mg Brigatinib 90 mg Brigatinib 240 mg Brigatinib 30 mg Brigatinib 120 mg
    Number of subjects analysed
    3
    63
    15
    7
    2
    10
    Units: hours
        arithmetic mean (standard deviation)
    30.93 ± 5.873
    24.9 ± 7.437
    28.69 ± 10.06
    21.77 ± 4.007
    31.55 ± 99999
    25.52 ± 7.958
    No statistical analyses for this end point

    Secondary: Best Overall Response

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    End point title
    Best Overall Response
    End point description
    Best overall response is defined as proportion of participants with CR, PR, stable disease (SD) or progressive disease (PD) as per of RECIST v1.1 as evaluated by investigator. Disease progression for target lesion: SLD increased by at least 20% from smallest value on study and SLD must also demonstrate an absolute increase of at least 5 mm or development of any new lesion. PD for non-target lesion: unequivocal progression of existing non-target lesions. SD for neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Full analysis set. Participants with ALK and NSCLC were evaluated for this outcome measure. Here 99999 indicates 95% CI was not estimable due to low number of participants with events.
    End point type
    Secondary
    End point timeframe
    Screening and at 8-week intervals thereafter up to data cut-off date: 16 November 2015 (approximately up to 50 months)
    End point values
    Brigatinib 30 mg QD/60 mg QD Brigatinib 90 mg QD Brigatinib 120 mg QD/60 mg BID Brigatinib 90 mg QD-180 mg QD Brigatinib 180 mg QD/90 mg BID Brigatinib 240 mg QD/120 mg BID/300 mg QD
    Number of subjects analysed
    1
    13
    5
    25
    23
    4
    Units: percentage of participants
    number (confidence interval 95%)
        Complete Response
    0 (-99999 to 99999)
    0 (-99999 to 99999)
    0 (-99999 to 99999)
    8 (1 to 26)
    8.7 (1.1 to 28)
    0 (-99999 to 99999)
        Partial Response
    100 (2.5 to 100)
    76.9 (46.2 to 95)
    60 (14.7 to 94.7)
    72 (50.6 to 87.9)
    56.5 (34.5 to 76.8)
    50 (6.8 to 93.2)
        Stable Disease
    0 (-99999 to 99999)
    0 (-99999 to 99999)
    0 (-99999 to 99999)
    8 (1 to 26)
    13 (2.8 to 33.6)
    50 (6.8 to 93.2)
        Progressive Disease
    0 (-99999 to 99999)
    0 (-99999 to 99999)
    0 (-99999 to 99999)
    8 (1 to 26)
    21.7 (7.5 to 43.7)
    0 (-99999 to 99999)
    No statistical analyses for this end point

    Secondary: Duration of Response

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    End point title
    Duration of Response
    End point description
    Duration of response is defined as time interval from the time that measurement criteria are first met for CR/PR (whichever is first recorded) until first date that progressive disease is objectively documented or death due to any cause. Participants who did not progress nor die were censored at last valid response assessment. FAS. Participants who were responders among those who were had anaplastic lymphoma kinase (ALK) and non-small cell lung cancer (NSCLC) were evaluated for this outcome measure. Here 'n' is participants analysed for each category. Duration of response was calculated by Kaplan-Meier estimation. Here 99999 indicates that Median/Upper/lower limits of CI were not reached due to low number of participants with events.
    End point type
    Secondary
    End point timeframe
    Screening and at 8-week intervals thereafter up to data cut-off date: 16 November 2015 (approximately up to 50 months)
    End point values
    Brigatinib 30 mg QD/60 mg QD Brigatinib 90 mg QD Brigatinib 120 mg QD/60 mg BID Brigatinib 90 mg QD-180 mg QD Brigatinib 180 mg QD/90 mg BID Brigatinib 240 mg QD/120 mg BID/300 mg QD
    Number of subjects analysed
    1
    13
    5
    25
    23
    4
    Units: months
    median (confidence interval 95%)
        With Prior Treatment with Crzb (n=1,10,3,20,15,2)
    1.9 (-99999 to 99999)
    8.3 (1.1 to 11.2)
    4 (3.7 to 99999)
    14.8 (7.4 to 99999)
    9.9 (3.6 to 99999)
    29.7 (-99999 to 99999)
        Without Prior Treatment with Crzb (n=0,1,1,3,2,1)
    99999 (-99999 to 99999)
    99999 (-99999 to 99999)
    99999 (-99999 to 99999)
    99999 (5.6 to 99999)
    99999 (9.2 to 99999)
    99999 (-99999 to 99999)
    No statistical analyses for this end point

    Secondary: Progression Free Survival (PFS)

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    End point title
    Progression Free Survival (PFS)
    End point description
    PFS is defined as the time interval from the date of the first dose of the study treatment until the first date at which disease progression is objectively documented, or death due to any cause, whichever occurs first. Disease progression for target lesion: SLD increased by at least 20% from the smallest value on study (including baseline, if that is the smallest) and SLD must also demonstrate an absolute increase of at least 5 mm or development of any new lesion. Disease progression for non-target lesion: Unequivocal progression of existing non-target lesions. (Subjective judgment by experienced reader). PFS was calculated by Kaplan-Meier estimation. Full analysis set. Participants with anaplastic lymphoma kinase (ALK) and non-small cell lung cancer (NSCLC) were evaluated for this outcome measure. Here 'n' is participants analysed for each category. Here 99999 indicates that Median/Upper/lower limits of CI were not reached due to low number of participants with events.
    End point type
    Secondary
    End point timeframe
    Screening and at 8-week intervals thereafter up to data cut-off date: 16 November 2015 (approximately up to 50 months)
    End point values
    Brigatinib 30 mg QD/60 mg QD Brigatinib 90 mg QD Brigatinib 120 mg QD/60 mg BID Brigatinib 90 mg QD-180 mg QD Brigatinib 180 mg QD/90 mg BID Brigatinib 240 mg QD/120 mg BID/300 mg QD
    Number of subjects analysed
    1
    13
    5
    25
    23
    4
    Units: months
    median (confidence interval 95%)
        With Prior Treatment with Crzb (n=1,9,4,13,14,3)
    3.5 (-99999 to 99999)
    11.9 (3.5 to 18.7)
    5.7 (0.5 to 99999)
    16.3 (9.2 to 99999)
    10.8 (4.5 to 99999)
    7.3 (1.9 to 31.5)
        Without Prior Treatment with Crzb (n=0,0,0,1,1,0)
    99999 (-99999 to 99999)
    99999 (-99999 to 99999)
    99999 (-99999 to 99999)
    99999 (7.4 to 99999)
    99999 (11.1 to 99999)
    99999 (-99999 to 99999)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    Overall Survival (OS)
    End point description
    OS is defined as the time interval from the date of the first dose of the study treatment until death due to any cause. Full analysis set. Participants with anaplastic lymphoma kinase (ALK) and non-small cell lung cancer (NSCLC) were evaluated for this outcome measure. Here, 99999 indicates that median overall survival was not reached due to low number of participants with events.
    End point type
    Secondary
    End point timeframe
    Screening and at 8-week intervals thereafter up to data cut-off date: 16 November 2015 (approximately up to 50 months)
    End point values
    Brigatinib 30 mg QD/60 mg QD Brigatinib 90 mg QD Brigatinib 120 mg QD/60 mg BID Brigatinib 90 mg QD-180 mg QD Brigatinib 180 mg QD/90 mg BID Brigatinib 240 mg QD/120 mg BID/300 mg QD
    Number of subjects analysed
    1
    14
    6
    28
    25
    5
    Units: months
        median (confidence interval 95%)
    99999 (-99999 to 99999)
    9.9999 (8 to 18.7)
    99999 (-99999 to 99999)
    9.9999 (1.4 to 22.5)
    9.9999 (0.2 to 17.6)
    9.9999 (-99999 to 99999)
    No statistical analyses for this end point

    Secondary: Duration of Intracranial Response

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    End point title
    Duration of Intracranial Response
    End point description
    Intracranial duration of response is defined as the time interval from the time that the measurement criteria are first met for CR/PR in brain metastases (whichever is first recorded) until the first date that progressive disease is objectively documented or death due to any cause. Participants who did not progress nor die were censored at the last valid response assessment. Duration intracranial of response was calculated by Kaplan-Meier estimation. Full analysis set. ALK+ NSCLC participants with measurable and only non-measurable brain metastases at baseline were evaluated for this outcome measure. Here 99999 indicates that median/upper/lower limits of CI were not reached due to low number of participants with events.
    End point type
    Secondary
    End point timeframe
    Screening and at 8-week intervals thereafter up to data cut-off date: 16 November 2015 (approximately up to 50 months)
    End point values
    Brigatinib 30 mg QD/60 mg QD Brigatinib 90 mg QD Brigatinib 120 mg QD/60 mg BID Brigatinib 90 mg QD-180 mg QD Brigatinib 180 mg QD/90 mg BID Brigatinib 240 mg QD/120 mg BID/300 mg QD
    Number of subjects analysed
    0 [4]
    8
    1
    18
    16
    3
    Units: months
        median (confidence interval 95%)
    ( to )
    12.9 (-99999 to 99999)
    5 (-99999 to 99999)
    11.4 (7.5 to 11.4)
    29.2 (5.5 to 29.2)
    11.3 (3.6 to 18.9)
    Notes
    [4] - No participant was analysed in this arm
    No statistical analyses for this end point

    Secondary: Intracranial Progression Free Survival (PFS)

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    End point title
    Intracranial Progression Free Survival (PFS)
    End point description
    PFS is defined as the time interval from the date of the first dose of the study treatment until the first date at which disease progression in brain, or death due to any cause, whichever occurs first. Intracranial PFS was calculated by Kaplan-Meier estimation. Full analysis set. ALK+ NSCLC participants with measurable and only non-measurable brain metastases at baseline were evaluated for this outcome measure. Here 99999 indicates that medan/upper limit of CI was not reached due to low number of participants with events.
    End point type
    Secondary
    End point timeframe
    Screening and at 8-week intervals thereafter up to data cut-off date: 16 November 2015 (approximately up to 50 months)
    End point values
    Brigatinib 30 mg QD/60 mg QD Brigatinib 90 mg QD Brigatinib 120 mg QD/60 mg BID Brigatinib 90 mg QD-180 mg QD Brigatinib 180 mg QD/90 mg BID Brigatinib 240 mg QD/120 mg BID/300 mg QD
    Number of subjects analysed
    0 [5]
    8
    1
    18
    16
    3
    Units: months
        median (confidence interval 95%)
    ( to )
    36.8 (5.5 to 36.8)
    6.7 (-99999 to 99999)
    99999 (9.4 to 99999)
    14.4 (7.3 to 31.1)
    7.3 (3.1 to 22.3)
    Notes
    [5] - No participant was analysed in this arm.
    No statistical analyses for this end point

    Secondary: Cmax: Maximum Observed Plasma Concentration for Brigatinib

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    End point title
    Cmax: Maximum Observed Plasma Concentration for Brigatinib
    End point description
    Analysis was performed on all enrolled participants in the study who received at least one dose of brigatinib. Here number of participants analyzed is the participants who were evaluable for this outcome measure. Here 99999 indicates that standard deviation was not calculated.
    End point type
    Secondary
    End point timeframe
    Cycle 2 Day 2
    End point values
    Brigatinib 30 mg Brigatinib 60 mg Brigatinib 90 mg Brigatinib 120 mg Brigatinib 180 mg Brigatinib 240 mg
    Number of subjects analysed
    2
    3
    15
    10
    63
    7
    Units: ng/mL
        arithmetic mean (standard deviation)
    249.5 ± 99999
    491.67 ± 223.95
    634.07 ± 310.05
    942.3 ± 472.33
    1694.3 ± 1014.3
    1694.3 ± 1014.3
    No statistical analyses for this end point

    Secondary: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Brigatinib

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    End point title
    Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Brigatinib
    End point description
    Analysis was performed on all enrolled participants in the study who received at least one dose of brigatinib. Here, 99999 indicates that standard deviation was not calculated.
    End point type
    Secondary
    End point timeframe
    Cycle 2 Day 1
    End point values
    Brigatinib 30 mg Brigatinib 60 mg Brigatinib 90 mg Brigatinib 120 mg Brigatinib 180 mg Brigatinib 240 mg
    Number of subjects analysed
    2
    3
    15
    10
    63
    7
    Units: hour
        arithmetic mean (standard deviation)
    2.49 ± 99999
    1.1 ± 0.656
    2.56 ± 1.98
    2.79 ± 1.88
    2.66 ± 1.46
    2.44 ± 1.13
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Any adverse event reported on or after the day of first dose of study drug (approximately up to 50 months)
    Adverse event reporting additional description
    At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    AP26113 30 mg QD/60 mg QD
    Reporting group description
    AP26113 30 mg/60 mg (lower doses than RP2Ds), tablets, orally, once daily (QD) in each cycle of 28 days (approximately, up to 44.4 months).

    Reporting group title
    AP26113 90 mg QD
    Reporting group description
    AP26113 90 mg (lower dose than RP2Ds), tablets, orally, once daily (QD) in each cycle of 28 days (approximately, up to 44.4 months).

    Reporting group title
    AP26113 120 mg QD/60 mg BID
    Reporting group description
    AP26113 120 mg, once daily or 60 mg, twice daily (BID) (doses between the two RP2Ds), tablets, orally, in each cycle of 28 days (approximately, up to 44.4 months).

    Reporting group title
    AP26113 90 mg QD-180 mg QD
    Reporting group description
    AP26113 90 mg, tablets, orally, once daily for up to 7 days followed by 180 mg (higher RP2D), tablets, orally, once daily in each cycle of 28 days (approximately, up to 44.4 months).

    Reporting group title
    AP26113 180 mg QD/90 mg BID
    Reporting group description
    AP26113 180 mg, once daily or 90 mg, twice daily (BID), tablets, orally in each cycle of 28 days (approximately, up to 44.4 months).

    Reporting group title
    AP26113 240 mg QD/120 mg BID/300 mg QD
    Reporting group description
    AP26113 240 mg, once daily (QD) or 120 mg, twice daily (BID) or 300 mg once daily (doses higher than 180 mg QD), tablets, orally, in each cycle of 28 days (approximately, up to 44.4 months).

    Serious adverse events
    AP26113 30 mg QD/60 mg QD AP26113 90 mg QD AP26113 120 mg QD/60 mg BID AP26113 90 mg QD-180 mg QD AP26113 180 mg QD/90 mg BID AP26113 240 mg QD/120 mg BID/300 mg QD
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 6 (16.67%)
    9 / 18 (50.00%)
    10 / 18 (55.56%)
    9 / 32 (28.13%)
    25 / 48 (52.08%)
    10 / 15 (66.67%)
         number of deaths (all causes)
    0
    3
    2
    3
    8
    1
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Vascular disorders
    Haematoma
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    1 / 48 (2.08%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasm progression
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 18 (11.11%)
    1 / 18 (5.56%)
    1 / 32 (3.13%)
    4 / 48 (8.33%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 1
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 1
    0 / 4
    0 / 0
    Pericardial effusion malignant
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    3 / 32 (9.38%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    1 / 48 (2.08%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cancer pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    1 / 48 (2.08%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intracranial tumour haemorrhage
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    1 / 48 (2.08%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant ascites
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    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
    Metastatic malignant melanoma
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    1 / 48 (2.08%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastatic pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    1 / 48 (2.08%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Food allergy
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    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
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    1 / 48 (2.08%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    Pyrexia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 32 (3.13%)
    0 / 48 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 32 (3.13%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    1 / 48 (2.08%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza like illness
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 32 (3.13%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    1 / 48 (2.08%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 32 (3.13%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    1 / 48 (2.08%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    1 / 48 (2.08%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    1 / 48 (2.08%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radiation necrosis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    1 / 48 (2.08%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radiation pneumonitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    2 / 32 (6.25%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 32 (3.13%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Computerised tomogram thorax abnormal
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 32 (3.13%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    1 / 32 (3.13%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    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
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    2 / 48 (4.17%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    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
    Cardiac tamponade
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 32 (3.13%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 32 (3.13%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    1 / 18 (5.56%)
    1 / 32 (3.13%)
    2 / 48 (4.17%)
    4 / 15 (26.67%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 2
    3 / 3
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Hypoxia
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 18 (11.11%)
    0 / 18 (0.00%)
    1 / 32 (3.13%)
    2 / 48 (4.17%)
    2 / 15 (13.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    1 / 1
    2 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    1 / 18 (5.56%)
    1 / 32 (3.13%)
    1 / 48 (2.08%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 32 (3.13%)
    1 / 48 (2.08%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    2 / 15 (13.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    2 / 48 (4.17%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    1 / 48 (2.08%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    1 / 48 (2.08%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Seizure
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 32 (3.13%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    1 / 32 (3.13%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    Central nervous system haemorrhage
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    1 / 48 (2.08%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    1 / 48 (2.08%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cognitive disorder
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 32 (3.13%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Embolic stroke
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    1 / 48 (2.08%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    1 / 48 (2.08%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    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
    Headache
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    1 / 48 (2.08%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorder
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 32 (3.13%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    1 / 48 (2.08%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Pancreatitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 32 (3.13%)
    0 / 48 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal wall haematoma
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    1 / 48 (2.08%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bezoar
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 32 (3.13%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer haemorrhage
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophageal compression
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal ulcer
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    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
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    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
    Skin and subcutaneous tissue disorders
    Eczema
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    1 / 48 (2.08%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    1 / 48 (2.08%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    1 / 48 (2.08%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 32 (3.13%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    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
    Metabolism and nutrition disorders
    Failure to thrive
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    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
    Hyperglycaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    1 / 48 (2.08%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    1 / 48 (2.08%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Insulin resistance
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    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
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 18 (11.11%)
    3 / 18 (16.67%)
    1 / 32 (3.13%)
    3 / 48 (6.25%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 3
    0 / 2
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    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
    Sepsis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 32 (3.13%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection bacterial
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    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
    Pneumonia pseudomonal
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    1 / 48 (2.08%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    1 / 48 (2.08%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    AP26113 30 mg QD/60 mg QD AP26113 90 mg QD AP26113 120 mg QD/60 mg BID AP26113 90 mg QD-180 mg QD AP26113 180 mg QD/90 mg BID AP26113 240 mg QD/120 mg BID/300 mg QD
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 6 (100.00%)
    18 / 18 (100.00%)
    18 / 18 (100.00%)
    31 / 32 (96.88%)
    44 / 48 (91.67%)
    15 / 15 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    5 / 18 (27.78%)
    7 / 32 (21.88%)
    6 / 48 (12.50%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    6
    14
    10
    1
    Hypotension
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    2 / 32 (6.25%)
    0 / 48 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    0
    2
    0
    1
    Deep vein thrombosis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Vascular pain
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Pericardial effusion malignant
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 32 (3.13%)
    0 / 48 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Melanocytic naevus
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Skin papilloma
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Tumour pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    3 / 48 (6.25%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    0
    3
    0
    Contrast media allergy
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    2 / 6 (33.33%)
    9 / 18 (50.00%)
    6 / 18 (33.33%)
    13 / 32 (40.63%)
    16 / 48 (33.33%)
    12 / 15 (80.00%)
         occurrences all number
    2
    14
    7
    16
    25
    15
    Oedema peripheral
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 18 (5.56%)
    3 / 18 (16.67%)
    6 / 32 (18.75%)
    3 / 48 (6.25%)
    5 / 15 (33.33%)
         occurrences all number
    1
    1
    3
    6
    5
    6
    Pyrexia
         subjects affected / exposed
    0 / 6 (0.00%)
    3 / 18 (16.67%)
    2 / 18 (11.11%)
    5 / 32 (15.63%)
    6 / 48 (12.50%)
    2 / 15 (13.33%)
         occurrences all number
    0
    3
    2
    5
    7
    2
    Pain
         subjects affected / exposed
    0 / 6 (0.00%)
    3 / 18 (16.67%)
    2 / 18 (11.11%)
    3 / 32 (9.38%)
    3 / 48 (6.25%)
    1 / 15 (6.67%)
         occurrences all number
    0
    4
    2
    3
    3
    1
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    2 / 18 (11.11%)
    1 / 32 (3.13%)
    3 / 48 (6.25%)
    3 / 15 (20.00%)
         occurrences all number
    0
    1
    3
    1
    3
    3
    Chest discomfort
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    3 / 32 (9.38%)
    5 / 48 (10.42%)
    2 / 15 (13.33%)
         occurrences all number
    0
    1
    0
    3
    6
    3
    Influenza like illness
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    1 / 18 (5.56%)
    3 / 32 (9.38%)
    3 / 48 (6.25%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    1
    5
    3
    1
    Asthenia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 32 (3.13%)
    5 / 48 (10.42%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    1
    6
    1
    Chills
         subjects affected / exposed
    0 / 6 (0.00%)
    3 / 18 (16.67%)
    0 / 18 (0.00%)
    1 / 32 (3.13%)
    1 / 48 (2.08%)
    2 / 15 (13.33%)
         occurrences all number
    0
    3
    0
    1
    1
    5
    Gait disturbance
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    2 / 32 (6.25%)
    3 / 48 (6.25%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    2
    3
    0
    Peripheral swelling
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 18 (11.11%)
    0 / 18 (0.00%)
    2 / 32 (6.25%)
    2 / 48 (4.17%)
    0 / 15 (0.00%)
         occurrences all number
    0
    2
    0
    2
    2
    0
    Chest pain
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    2 / 32 (6.25%)
    1 / 48 (2.08%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    2
    1
    0
    Thirst
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    1 / 48 (2.08%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    Axillary pain
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Exercise tolerance decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Feeling abnormal
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Feeling jittery
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    1 / 18 (5.56%)
    6 / 32 (18.75%)
    3 / 48 (6.25%)
    3 / 15 (20.00%)
         occurrences all number
    0
    1
    1
    6
    3
    3
    Anxiety
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    4 / 32 (12.50%)
    1 / 48 (2.08%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    0
    4
    1
    1
    Depression
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    3 / 32 (9.38%)
    3 / 48 (6.25%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    3
    3
    0
    Bruxism
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    1 / 32 (3.13%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Anticipatory anxiety
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Confusional state
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Disorientation
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    Nervousness
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Stress
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Reproductive system and breast disorders
    Vulvovaginal dryness
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    1 / 32 (3.13%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Nipple pain
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Laceration
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    1 / 32 (3.13%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Rib fracture
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    1 / 32 (3.13%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Procedural pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Radiation neuropathy
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Radiation pneumonitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Investigations
    Amylase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    4 / 18 (22.22%)
    5 / 18 (27.78%)
    9 / 32 (28.13%)
    8 / 48 (16.67%)
    3 / 15 (20.00%)
         occurrences all number
    0
    10
    12
    22
    14
    6
    Lipase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    3 / 18 (16.67%)
    4 / 18 (22.22%)
    10 / 32 (31.25%)
    6 / 48 (12.50%)
    2 / 15 (13.33%)
         occurrences all number
    0
    6
    6
    21
    24
    5
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 18 (11.11%)
    6 / 18 (33.33%)
    7 / 32 (21.88%)
    7 / 48 (14.58%)
    2 / 15 (13.33%)
         occurrences all number
    0
    4
    8
    10
    12
    4
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    3 / 18 (16.67%)
    3 / 18 (16.67%)
    4 / 32 (12.50%)
    4 / 48 (8.33%)
    1 / 15 (6.67%)
         occurrences all number
    0
    4
    3
    10
    4
    4
    Blood insulin increased
         subjects affected / exposed
    0 / 6 (0.00%)
    3 / 18 (16.67%)
    2 / 18 (11.11%)
    3 / 32 (9.38%)
    5 / 48 (10.42%)
    0 / 15 (0.00%)
         occurrences all number
    0
    4
    5
    5
    9
    0
    Weight decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    3 / 32 (9.38%)
    3 / 48 (6.25%)
    2 / 15 (13.33%)
         occurrences all number
    0
    1
    0
    3
    4
    3
    Blood creatinine increased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    2 / 18 (11.11%)
    3 / 32 (9.38%)
    1 / 48 (2.08%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    2
    3
    1
    1
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    3 / 32 (9.38%)
    2 / 48 (4.17%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    0
    4
    2
    1
    Weight increased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    2 / 18 (11.11%)
    0 / 32 (0.00%)
    3 / 48 (6.25%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    3
    0
    4
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 18 (11.11%)
    1 / 18 (5.56%)
    1 / 32 (3.13%)
    1 / 48 (2.08%)
    1 / 15 (6.67%)
         occurrences all number
    0
    2
    1
    1
    1
    1
    Blood testosterone decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    2 / 32 (6.25%)
    2 / 48 (4.17%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    2
    2
    1
    Blood thyroid stimulating hormone decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 18 (11.11%)
    1 / 18 (5.56%)
    0 / 32 (0.00%)
    1 / 48 (2.08%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    2 / 32 (6.25%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    2
    0
    0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    2 / 32 (6.25%)
    0 / 48 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    2
    0
    1
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 32 (3.13%)
    1 / 48 (2.08%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    2
    1
    1
    0
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    1 / 32 (3.13%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    Bacterial test positive
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Ejection fraction decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Heart rate increased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Urinary sediment present
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Urine leukocyte esterase positive
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    White blood cells urine
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    White blood cells urine positive
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    2 / 32 (6.25%)
    1 / 48 (2.08%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    2
    1
    0
    Palpitations
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    1 / 18 (5.56%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    Sinus bradycardia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    2 / 32 (6.25%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    Atrial fibrillation
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Atrial flutter
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 6 (16.67%)
    6 / 18 (33.33%)
    6 / 18 (33.33%)
    11 / 32 (34.38%)
    13 / 48 (27.08%)
    8 / 15 (53.33%)
         occurrences all number
    1
    7
    10
    17
    17
    10
    Dyspnoea
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 18 (11.11%)
    5 / 18 (27.78%)
    7 / 32 (21.88%)
    7 / 48 (14.58%)
    3 / 15 (20.00%)
         occurrences all number
    0
    3
    6
    8
    9
    4
    Dyspnoea exertional
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 18 (11.11%)
    2 / 18 (11.11%)
    1 / 32 (3.13%)
    4 / 48 (8.33%)
    1 / 15 (6.67%)
         occurrences all number
    0
    2
    2
    1
    4
    2
    Oropharyngeal pain
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 18 (11.11%)
    1 / 18 (5.56%)
    2 / 32 (6.25%)
    4 / 48 (8.33%)
    1 / 15 (6.67%)
         occurrences all number
    0
    2
    1
    2
    4
    1
    Epistaxis
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 18 (11.11%)
    0 / 18 (0.00%)
    1 / 32 (3.13%)
    4 / 48 (8.33%)
    2 / 15 (13.33%)
         occurrences all number
    0
    2
    0
    1
    4
    2
    Productive cough
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    1 / 18 (5.56%)
    3 / 32 (9.38%)
    2 / 48 (4.17%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    1
    3
    3
    0
    Nasal congestion
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 18 (11.11%)
    2 / 18 (11.11%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    2
    2
    0
    0
    2
    Haemoptysis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    1 / 32 (3.13%)
    2 / 48 (4.17%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    0
    3
    3
    2
    Hypoxia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 32 (3.13%)
    1 / 48 (2.08%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    1
    1
    2
    3
    Rhinorrhoea
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 32 (3.13%)
    2 / 48 (4.17%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    1
    2
    0
    Sinus congestion
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    3 / 32 (9.38%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    3
    0
    0
    Dysphonia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    2 / 48 (4.17%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    2
    1
    Rhinitis allergic
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    1 / 18 (5.56%)
    1 / 32 (3.13%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    2
    1
    0
    0
    Sputum discoloured
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 32 (3.13%)
    1 / 48 (2.08%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    1
    1
    0
    Dry throat
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    1 / 48 (2.08%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Hiccups
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Laryngeal inflammation
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    2 / 32 (6.25%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    Pleural effusion
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    1 / 48 (2.08%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Pleuritic pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 32 (3.13%)
    0 / 48 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Throat irritation
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    1 / 48 (2.08%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    Wheezing
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    Nasal dryness
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Pleurisy
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Pneumothorax
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Pulmonary hypertension
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Respiratory tract irritation
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Sneezing
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    Upper-airway cough syndrome
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    4 / 18 (22.22%)
    4 / 32 (12.50%)
    2 / 48 (4.17%)
    3 / 15 (20.00%)
         occurrences all number
    0
    0
    5
    6
    4
    4
    Increased tendency to bruise
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    2 / 48 (4.17%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    2
    1
    Leukocytosis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    1 / 32 (3.13%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 6 (0.00%)
    7 / 18 (38.89%)
    7 / 18 (38.89%)
    12 / 32 (37.50%)
    14 / 48 (29.17%)
    6 / 15 (40.00%)
         occurrences all number
    0
    12
    8
    13
    18
    8
    Dizziness
         subjects affected / exposed
    0 / 6 (0.00%)
    4 / 18 (22.22%)
    1 / 18 (5.56%)
    4 / 32 (12.50%)
    3 / 48 (6.25%)
    1 / 15 (6.67%)
         occurrences all number
    0
    7
    2
    4
    3
    1
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    2 / 18 (11.11%)
    5 / 32 (15.63%)
    3 / 48 (6.25%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    3
    5
    3
    0
    Paraesthesia
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    2 / 32 (6.25%)
    3 / 48 (6.25%)
    1 / 15 (6.67%)
         occurrences all number
    1
    1
    0
    2
    4
    1
    Dysgeusia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    1 / 18 (5.56%)
    1 / 32 (3.13%)
    3 / 48 (6.25%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    1
    1
    4
    2
    Tremor
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    1 / 18 (5.56%)
    2 / 32 (6.25%)
    2 / 48 (4.17%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    1
    2
    2
    1
    Amnesia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    1 / 32 (3.13%)
    3 / 48 (6.25%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    1
    5
    0
    Balance disorder
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 18 (11.11%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    3 / 48 (6.25%)
    0 / 15 (0.00%)
         occurrences all number
    0
    2
    0
    0
    3
    0
    Hypoaesthesia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    3 / 48 (6.25%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    0
    0
    8
    1
    Visual field defect
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    4 / 48 (8.33%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    5
    1
    Seizure
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    1 / 18 (5.56%)
    0 / 32 (0.00%)
    1 / 48 (2.08%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    1
    0
    3
    1
    Aphasia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    2 / 48 (4.17%)
    0 / 15 (0.00%)
         occurrences all number
    0
    2
    0
    0
    2
    0
    Disturbance in attention
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    1 / 32 (3.13%)
    1 / 48 (2.08%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    1
    1
    0
    Dysarthria
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 18 (11.11%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    1 / 48 (2.08%)
    0 / 15 (0.00%)
         occurrences all number
    0
    2
    0
    0
    2
    0
    Memory impairment
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    1 / 32 (3.13%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    1
    0
    1
    0
    0
    Sinus headache
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    2 / 32 (6.25%)
    1 / 48 (2.08%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    2
    1
    0
    Somnolence
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    1 / 18 (5.56%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    Syncope
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 32 (3.13%)
    0 / 48 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Burning sensation
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Cognitive disorder
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    Neuralgia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Parosmia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Peripheral motor neuropathy
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Eye disorders
    Vision blurred
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    2 / 18 (11.11%)
    4 / 32 (12.50%)
    4 / 48 (8.33%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    2
    4
    4
    0
    Dry eye
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    1 / 32 (3.13%)
    1 / 48 (2.08%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    1
    1
    0
    Visual impairment
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    1 / 32 (3.13%)
    0 / 48 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    0
    1
    0
    2
    Blepharospasm
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Lacrimation increased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    1 / 32 (3.13%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Photopsia
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Vitreous floaters
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    1 / 32 (3.13%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Asthenopia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Cataract cortical
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Colour blindness acquired
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Eye pain
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    Eyelid margin crusting
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 18 (11.11%)
    0 / 18 (0.00%)
    1 / 32 (3.13%)
    1 / 48 (2.08%)
    1 / 15 (6.67%)
         occurrences all number
    0
    2
    0
    1
    1
    1
    Deafness unilateral
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Vertigo
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    3
    0
    0
    0
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    3 / 6 (50.00%)
    6 / 18 (33.33%)
    8 / 18 (44.44%)
    14 / 32 (43.75%)
    31 / 48 (64.58%)
    8 / 15 (53.33%)
         occurrences all number
    3
    7
    9
    15
    42
    11
    Diarrhoea
         subjects affected / exposed
    1 / 6 (16.67%)
    7 / 18 (38.89%)
    7 / 18 (38.89%)
    15 / 32 (46.88%)
    18 / 48 (37.50%)
    8 / 15 (53.33%)
         occurrences all number
    1
    11
    10
    17
    32
    28
    Constipation
         subjects affected / exposed
    1 / 6 (16.67%)
    6 / 18 (33.33%)
    5 / 18 (27.78%)
    9 / 32 (28.13%)
    7 / 48 (14.58%)
    5 / 15 (33.33%)
         occurrences all number
    1
    6
    8
    10
    7
    5
    Vomiting
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 18 (5.56%)
    5 / 18 (27.78%)
    5 / 32 (15.63%)
    15 / 48 (31.25%)
    5 / 15 (33.33%)
         occurrences all number
    2
    2
    6
    8
    24
    5
    Abdominal pain
         subjects affected / exposed
    3 / 6 (50.00%)
    2 / 18 (11.11%)
    3 / 18 (16.67%)
    7 / 32 (21.88%)
    9 / 48 (18.75%)
    2 / 15 (13.33%)
         occurrences all number
    3
    2
    3
    8
    12
    5
    Dry mouth
         subjects affected / exposed
    0 / 6 (0.00%)
    3 / 18 (16.67%)
    0 / 18 (0.00%)
    4 / 32 (12.50%)
    1 / 48 (2.08%)
    2 / 15 (13.33%)
         occurrences all number
    0
    5
    0
    4
    1
    2
    Abdominal distension
         subjects affected / exposed
    0 / 6 (0.00%)
    3 / 18 (16.67%)
    1 / 18 (5.56%)
    1 / 32 (3.13%)
    4 / 48 (8.33%)
    0 / 15 (0.00%)
         occurrences all number
    0
    3
    1
    1
    4
    0
    Abdominal discomfort
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    1 / 18 (5.56%)
    2 / 32 (6.25%)
    4 / 48 (8.33%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    1
    2
    4
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 32 (3.13%)
    2 / 48 (4.17%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    1
    1
    2
    2
    Dyspepsia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    1 / 18 (5.56%)
    1 / 32 (3.13%)
    1 / 48 (2.08%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    1
    1
    1
    1
    Dysphagia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 32 (0.00%)
    2 / 48 (4.17%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    1
    0
    2
    4
    Aphthous stomatitis
         subjects affected / exposed
    0 / 6 (0.00%)
    3 / 18 (16.67%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    1 / 48 (2.08%)
    0 / 15 (0.00%)
         occurrences all number
    0
    3
    0
    0
    1
    0
    Flatulence
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 32 (3.13%)
    1 / 48 (2.08%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    1
    1
    Sensitivity of teeth
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    1 / 32 (3.13%)
    0 / 48 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    0
    1
    0
    1
    Stomatitis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    2 / 18 (11.11%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    3
    0
    0
    0
    Cheilitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 32 (0.00%)
    1 / 48 (2.08%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    Mouth ulceration
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 32 (0.00%)
    1 / 48 (2.08%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    Abdominal rigidity
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Abnormal faeces
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Lip dry
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Lip swelling
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Oesophageal irritation
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    Oesophageal pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Toothache
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Hypoaesthesia oral
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    1 / 48 (2.08%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Renal and urinary disorders
    Pollakiuria
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    1 / 18 (5.56%)
    2 / 32 (6.25%)
    4 / 48 (8.33%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    1
    2
    4
    0
    Proteinuria
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 32 (3.13%)
    1 / 48 (2.08%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    0
    1
    1
    2
    Haematuria
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 32 (3.13%)
    1 / 48 (2.08%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    1
    1
    0
    Dysuria
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    1 / 48 (2.08%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Renal failure
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Urinary retention
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 6 (0.00%)
    3 / 18 (16.67%)
    2 / 18 (11.11%)
    4 / 32 (12.50%)
    7 / 48 (14.58%)
    1 / 15 (6.67%)
         occurrences all number
    0
    4
    2
    6
    12
    1
    Photosensitivity reaction
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    4 / 18 (22.22%)
    3 / 32 (9.38%)
    5 / 48 (10.42%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    7
    4
    6
    0
    Pruritus
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 18 (11.11%)
    1 / 18 (5.56%)
    6 / 32 (18.75%)
    3 / 48 (6.25%)
    0 / 15 (0.00%)
         occurrences all number
    0
    2
    2
    6
    3
    0
    Dry skin
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    2 / 18 (11.11%)
    4 / 32 (12.50%)
    3 / 48 (6.25%)
    0 / 15 (0.00%)
         occurrences all number
    0
    3
    2
    5
    3
    0
    Night sweats
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 18 (11.11%)
    1 / 18 (5.56%)
    0 / 32 (0.00%)
    4 / 48 (8.33%)
    0 / 15 (0.00%)
         occurrences all number
    0
    2
    1
    0
    4
    0
    Dermatitis acneiform
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    1 / 18 (5.56%)
    3 / 32 (9.38%)
    1 / 48 (2.08%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    1
    3
    1
    0
    Alopecia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    3 / 48 (6.25%)
    1 / 15 (6.67%)
         occurrences all number
    0
    2
    0
    0
    3
    1
    Hyperhidrosis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    1 / 32 (3.13%)
    1 / 48 (2.08%)
    1 / 15 (6.67%)
         occurrences all number
    0
    2
    0
    1
    1
    2
    Onychoclasis
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 18 (11.11%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    2 / 48 (4.17%)
    0 / 15 (0.00%)
         occurrences all number
    0
    2
    0
    0
    2
    0
    Rash pruritic
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    2 / 32 (6.25%)
    1 / 48 (2.08%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    4
    2
    0
    Dermatitis contact
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 32 (0.00%)
    2 / 48 (4.17%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    2
    0
    Eczema
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    1 / 48 (2.08%)
    1 / 15 (6.67%)
         occurrences all number
    0
    3
    0
    0
    1
    1
    Pain of skin
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    1 / 32 (3.13%)
    1 / 48 (2.08%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    1
    1
    0
    Erythema
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    2 / 32 (6.25%)
    1 / 48 (2.08%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    2
    1
    0
    Skin disorder
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 32 (3.13%)
    1 / 48 (2.08%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    1
    1
    0
    Dermal cyst
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 32 (3.13%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    Dermatitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    1 / 48 (2.08%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Dermatitis atopic
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    1 / 48 (2.08%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Nail disorder
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 32 (3.13%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    Petechiae
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    1 / 32 (3.13%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Skin hyperpigmentation
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Urticaria
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    1 / 48 (2.08%)
    0 / 15 (0.00%)
         occurrences all number
    0
    2
    0
    0
    1
    0
    Nail growth abnormal
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 18 (5.56%)
    3 / 18 (16.67%)
    7 / 32 (21.88%)
    11 / 48 (22.92%)
    3 / 15 (20.00%)
         occurrences all number
    1
    8
    3
    9
    16
    6
    Back pain
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 18 (0.00%)
    5 / 18 (27.78%)
    7 / 32 (21.88%)
    7 / 48 (14.58%)
    1 / 15 (6.67%)
         occurrences all number
    1
    0
    6
    7
    8
    1
    Musculoskeletal pain
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 18 (11.11%)
    0 / 18 (0.00%)
    2 / 32 (6.25%)
    4 / 48 (8.33%)
    3 / 15 (20.00%)
         occurrences all number
    0
    2
    0
    2
    5
    3
    Arthralgia
         subjects affected / exposed
    1 / 6 (16.67%)
    3 / 18 (16.67%)
    0 / 18 (0.00%)
    10 / 32 (31.25%)
    6 / 48 (12.50%)
    0 / 15 (0.00%)
         occurrences all number
    1
    5
    0
    15
    9
    0
    Pain in extremity
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 18 (11.11%)
    2 / 18 (11.11%)
    2 / 32 (6.25%)
    2 / 48 (4.17%)
    2 / 15 (13.33%)
         occurrences all number
    1
    5
    3
    3
    3
    3
    Musculoskeletal chest pain
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    3 / 32 (9.38%)
    3 / 48 (6.25%)
    1 / 15 (6.67%)
         occurrences all number
    2
    1
    0
    4
    3
    1
    Joint swelling
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    5 / 32 (15.63%)
    2 / 48 (4.17%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    5
    2
    0
    Myalgia
         subjects affected / exposed
    0 / 6 (0.00%)
    3 / 18 (16.67%)
    0 / 18 (0.00%)
    1 / 32 (3.13%)
    1 / 48 (2.08%)
    2 / 15 (13.33%)
         occurrences all number
    0
    5
    0
    1
    1
    2
    Bone pain
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    5 / 48 (10.42%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    0
    0
    5
    0
    Musculoskeletal discomfort
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    2 / 18 (11.11%)
    2 / 32 (6.25%)
    2 / 48 (4.17%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    2
    2
    2
    0
    Flank pain
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 18 (11.11%)
    1 / 18 (5.56%)
    2 / 32 (6.25%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    2
    1
    2
    0
    0
    Muscular weakness
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 32 (3.13%)
    1 / 48 (2.08%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    1
    1
    0
    Pain in jaw
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    1
    0
    0
    0
    2
    Arthritis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    1 / 48 (2.08%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    Fracture pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    2 / 32 (6.25%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    Limb discomfort
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    1 / 32 (3.13%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Groin pain
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Musculoskeletal stiffness
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 18 (5.56%)
    1 / 18 (5.56%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    2
    1
    0
    0
    0
    Neck pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 32 (0.00%)
    0 / 48 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1