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    Clinical Trial Results:
    A Phase I/II study of LDE225 in pediatric patients with recurrent or refractory medulloblastoma or other tumors potentially dependent on the Hedgehog-signaling pathway and adult patients with recurrent or refractory medulloblastoma

    Summary
    EudraCT number
    2010-019348-37
    Trial protocol
    FR   GB   IT  
    Global end of trial date
    03 Oct 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    13 Jul 2016
    First version publication date
    06 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CLDE225X2104
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01125800
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, +41 613241111,
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, +41 613241111,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-000880-PIP02-11
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    03 Oct 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Oct 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Determine the maximum tolerated dose (MTD) and/or recommended Phase II dose (RP2D) of sonidegib in children with advanced solid tumors (recurrent or refractory medulloblastoma, rhabdomyosarcoma, neuroblastoma, hepatoblastoma, high-grade glioma, or osteosarcoma) when administered on a continuous daily dosing schedule. (Phase I) Assess preliminary efficacy of sonidegib, as determined by objective response rate (ORR) in recurrent or refractory medulloblastoma (MB) patients (adult and pediatric combined) regardless of Hedgehog (Hh) pathway status (activated or non-activated) (Phase II)
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed. Rescue medication was not allowed during the course of the study. The investigator provided follow-up medical care for all subjects who were prematurely withdrawn from the study, or referred them for appropriate ongoing care.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    09 Feb 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 11
    Country: Number of subjects enrolled
    France: 16
    Country: Number of subjects enrolled
    Italy: 17
    Country: Number of subjects enrolled
    Australia: 4
    Country: Number of subjects enrolled
    Canada: 6
    Country: Number of subjects enrolled
    United States: 22
    Worldwide total number of subjects
    76
    EEA total number of subjects
    44
    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)
    29
    Adolescents (12-17 years)
    31
    Adults (18-64 years)
    15
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted at 14 centres in 6 countries.

    Pre-assignment
    Screening details
    A total of 60 pediatric subjects and 16 adult subjects were enrolled in this study, of which 59 pediatric subjects received sonidegib during the dose-escalation and expansion part (Phase I); 17 subjects (1 child and 16 adults) received sonidegib in the Phase II.

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded
    Blinding implementation details
    As the study was an open-label study, this section was not applicable.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Pediatric subjects, LDE225 233 mg/m^2
    Arm description
    Pediatric subjects received LDE225 233 mg/m^2 once daily through oral route.
    Arm type
    Experimental

    Investigational medicinal product name
    Sonidegib
    Investigational medicinal product code
    LDE225
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    LDE225 capsules were administered once daily through oral route in pediatric subjects to provide a dose of 233 mg/m^2.

    Arm title
    Pediatric subjects, LDE225 372 mg/m^2
    Arm description
    Pediatric subjects received LDE225 372 mg/m^2 once daily through oral route.
    Arm type
    Experimental

    Investigational medicinal product name
    Sonidegib
    Investigational medicinal product code
    LDE225
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    LDE225 capsules were administered once daily through oral route in pediatric subjects to provide a dose of 372 mg/m^2.

    Arm title
    Pediatric subjects, LDE225 425 mg/m^2
    Arm description
    Pediatric subjects received LDE225 425 mg/m^2 once daily through oral route.
    Arm type
    Experimental

    Investigational medicinal product name
    Sonidegib
    Investigational medicinal product code
    LDE225
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    LDE225 capsules were administered once daily through oral route in pediatric subjects to provide a dose of 425 mg/m^2.

    Arm title
    Pediatric subjects, LDE225 680 mg/m^2
    Arm description
    Pediatric subjects received LDE225 680 mg/m^2 once daily through oral route.
    Arm type
    Experimental

    Investigational medicinal product name
    Sonidegib
    Investigational medicinal product code
    LDE225
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    LDE225 capsules were administered once daily through oral route in pediatric subjects to provide a dose of 680 mg/m^2.

    Arm title
    Adult subjects, LDE225 800 mg
    Arm description
    Adult subjects were treated with LDE225 800 mg capsule once daily.
    Arm type
    Experimental

    Investigational medicinal product name
    Sonidegib
    Investigational medicinal product code
    LDE225
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    LDE225 capsules of 800 mg strength was administered once daily.

    Number of subjects in period 1
    Pediatric subjects, LDE225 233 mg/m^2 Pediatric subjects, LDE225 372 mg/m^2 Pediatric subjects, LDE225 425 mg/m^2 Pediatric subjects, LDE225 680 mg/m^2 Adult subjects, LDE225 800 mg
    Started
    11
    16
    11
    22
    16
    Completed
    0
    0
    0
    0
    0
    Not completed
    11
    16
    11
    22
    16
         Death
    -
    -
    -
    -
    2
         Disease Progression
    10
    15
    10
    21
    12
         Adverse event, non-fatal
    1
    1
    1
    1
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Pediatric subjects, LDE225 233 mg/m^2
    Reporting group description
    Pediatric subjects received LDE225 233 mg/m^2 once daily through oral route.

    Reporting group title
    Pediatric subjects, LDE225 372 mg/m^2
    Reporting group description
    Pediatric subjects received LDE225 372 mg/m^2 once daily through oral route.

    Reporting group title
    Pediatric subjects, LDE225 425 mg/m^2
    Reporting group description
    Pediatric subjects received LDE225 425 mg/m^2 once daily through oral route.

    Reporting group title
    Pediatric subjects, LDE225 680 mg/m^2
    Reporting group description
    Pediatric subjects received LDE225 680 mg/m^2 once daily through oral route.

    Reporting group title
    Adult subjects, LDE225 800 mg
    Reporting group description
    Adult subjects were treated with LDE225 800 mg capsule once daily.

    Reporting group values
    Pediatric subjects, LDE225 233 mg/m^2 Pediatric subjects, LDE225 372 mg/m^2 Pediatric subjects, LDE225 425 mg/m^2 Pediatric subjects, LDE225 680 mg/m^2 Adult subjects, LDE225 800 mg Total
    Number of subjects
    11 16 11 22 16 76
    Age categorical
    Units: Subjects
        ≤ 10 years
    4 3 5 11 0 23
        >10 years to 17 years
    7 13 6 11 0 37
        18-65 years
    0 0 0 0 16 16
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    12.36 ± 3.202 12.88 ± 3.519 10.27 ± 4.88 9.68 ± 4.932 35.13 ± 14.118 -
    Gender categorical
    Units: Subjects
        Female
    4 6 3 10 7 30
        Male
    7 10 8 12 9 46

    End points

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    End points reporting groups
    Reporting group title
    Pediatric subjects, LDE225 233 mg/m^2
    Reporting group description
    Pediatric subjects received LDE225 233 mg/m^2 once daily through oral route.

    Reporting group title
    Pediatric subjects, LDE225 372 mg/m^2
    Reporting group description
    Pediatric subjects received LDE225 372 mg/m^2 once daily through oral route.

    Reporting group title
    Pediatric subjects, LDE225 425 mg/m^2
    Reporting group description
    Pediatric subjects received LDE225 425 mg/m^2 once daily through oral route.

    Reporting group title
    Pediatric subjects, LDE225 680 mg/m^2
    Reporting group description
    Pediatric subjects received LDE225 680 mg/m^2 once daily through oral route.

    Reporting group title
    Adult subjects, LDE225 800 mg
    Reporting group description
    Adult subjects were treated with LDE225 800 mg capsule once daily.

    Subject analysis set title
    Pediatric subjects
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    All the pediatric subjects were treated with LDE225 dose determined in the Phase I (233, 372, 425 and 680 mg/m^2).

    Subject analysis set title
    Adult subjects
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    All adult subjects were treated with sonidegib 800 mg once daily in phase II portion of the study. Pediatric patients were also enrolled in phase II portion of the study at the recommended phase II pediatric dose - 680 mg/m^2

    Primary: Maximum tolerated dose (MTD) of sonidegib in Phase 1

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    End point title
    Maximum tolerated dose (MTD) of sonidegib in Phase 1 [1] [2]
    End point description
    MTD was defined as highest dose level for which for is unlikely to have more than 33% of patients experienced dose-limiting toxicity (DLT) during the first 6 weeks of treatment,no more than 1 subject in a dose cohort experienced dose-limiting toxicity (DLT), based on a Bayesian logistic regression model (BLRM) employing the escalation with overdose control (EWOC) principle. DLT was defined as an adverse event (AE) or abnormal laboratory value assessed as unrelated to disease, disease progression, intercurrent illness, or concomitant medications. MTD was not achieved since no more than 1 DLT was observed in any cohort. One DLT was observed at 372 mg/m^2 dose. The posterior probability of true DLT rate lies in excessive toxicity interval [0.33, 1] even at 680 mg/m2 was still very small (0.7%);The RP2D was established using the BLRM and joint clinical review of the safety data by the Investigators and Novartis personnel, including the Novartis medical monitor,at a dose escalation meeting
    End point type
    Primary
    End point timeframe
    Baseline, End of dose escalation part
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive summary statistics was planned for this primary outcome measure.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point summary statistics was planned only for treatment arms in Part 1 of the study.
    End point values
    Pediatric subjects, LDE225 233 mg/m^2 Pediatric subjects, LDE225 372 mg/m^2 Pediatric subjects, LDE225 425 mg/m^2 Pediatric subjects, LDE225 680 mg/m^2
    Number of subjects analysed
    11 [3]
    16 [4]
    11 [5]
    22 [6]
    Units: mg/m^2
        arithmetic mean (standard deviation)
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    Notes
    [3] - The MTD for the pediatric population was not established in this study.
    [4] - The MTD for the pediatric population was not established in this study.
    [5] - The MTD for the pediatric population was not established in this study.
    [6] - The MTD for the pediatric population was not established in this study.
    No statistical analyses for this end point

    Primary: Percentage of subjects with objective response rate (ORR) by treatment

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    End point title
    Percentage of subjects with objective response rate (ORR) by treatment [7]
    End point description
    The tumour response to the sonidegib treatment was measured by ORR. The ORR was defined as the proportion of subjects with partial response or complete response as their best overall response. Subjects with stable disease, progressive disease tumour assessment were considered as non-responders. The analysis was performed in full analysis set (FAS), defined as all the subjects who received at least one dose of sonidegib.
    End point type
    Primary
    End point timeframe
    Baseline to End of treatment
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive summary statistics was planned for this primary outcome measure.
    End point values
    Pediatric subjects Adult subjects
    Number of subjects analysed
    60
    16
    Units: percentage of tumor response
    number (not applicable)
        Complete response
    3.3
    13.5
        Partial response
    0
    6.3
        Stable disease
    8.3
    37.5
        Progressive disease
    76.7
    37.5
        Objective response rate
    3.3
    18.3
    No statistical analyses for this end point

    Secondary: Number of subjects with adverse events (AEs), serious adverse events (SAEs), treatment related AEs and death during the study

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    End point title
    Number of subjects with adverse events (AEs), serious adverse events (SAEs), treatment related AEs and death during the study
    End point description
    An AE was defined as any unfavorable and unintended sign, symptom, or disease temporally associated with the use of study drug, whether or not related to study drug. A SAE was defined as an event which was fatal or life threatening, required or prolonged hospitalization, was significantly or permanently disabling or incapacitating, constituted a congenital anomaly or a birth defect, or encompassed any other clinically significant event that could jeopardize the subject or require medical or surgical intervention to prevent one of the aforementioned outcomes. Treatment related AEs were defined as AEs that were suspected to be related to study treatment as per investigator. On-treatment deaths were deaths which occurred up to 30 days after last date of study treatment. The analysis was performed in safety set (SS), defined as all the subjects who received at least 1 dose of sonidegib.
    End point type
    Secondary
    End point timeframe
    Baseline (start of study treatment) up to End of treatment + 30 days
    End point values
    Pediatric subjects, LDE225 233 mg/m^2 Pediatric subjects, LDE225 372 mg/m^2 Pediatric subjects, LDE225 425 mg/m^2 Pediatric subjects, LDE225 680 mg/m^2 Adult subjects, LDE225 800 mg
    Number of subjects analysed
    11
    16
    11
    22
    16
    Units: Number of subjects
        AEs
    11
    16
    11
    22
    16
        AEs suspected to be drug related
    8
    13
    9
    14
    13
        AEs leading to discontinuation
    1
    1
    1
    1
    3
        On-treatment deaths
    2
    2
    1
    8
    2
        SAEs
    5
    8
    4
    14
    5
    No statistical analyses for this end point

    Secondary: Area under the drug concentration time curve from time zero to 24 hours after dosing (AUC0-24h) of sonidegib in Phase 1

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    End point title
    Area under the drug concentration time curve from time zero to 24 hours after dosing (AUC0-24h) of sonidegib in Phase 1 [8]
    End point description
    AUC(0-24h) was defined as the area under the drug concentration time curve calculated using linear trapezoidal summation from time zero to 24 hours after dosing. The analysis was performed in pharmacokinetic analysis set (PAS), defined as all the subjects who received at least one (full or partial) dose of sonidegib and provided at least one evaluable pharmacokinetic (PK) blood sample. The 'n' signifies those subjects evaluable for this measure at specified time points for each group, respectively.
    End point type
    Secondary
    End point timeframe
    Day 1 and Day 22 of Cycle 1
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point summary statistics was planned only for treatment arms in Part 1 of the study.
    End point values
    Pediatric subjects, LDE225 233 mg/m^2 Pediatric subjects, LDE225 372 mg/m^2 Pediatric subjects, LDE225 425 mg/m^2 Pediatric subjects, LDE225 680 mg/m^2
    Number of subjects analysed
    11
    16
    11
    22
    Units: nanograms*hours/millilitres (ng*hr/mL)
    arithmetic mean (standard deviation)
        Cycle 1/Day 1 (n=11, 15, 11, 19)
    1981.56 ± 736.928
    2194.29 ± 1592.396
    5309.44 ± 3247.088
    5117.61 ± 2658.133
        Cycle 1/Day 22 (n=9, 14, 9, 15)
    10589.53 ± 4163.192
    15431.43 ± 10433.35
    17753.32 ± 11551.57
    32622.67 ± 11670.63
    No statistical analyses for this end point

    Secondary: Time to reach maximum observed plasma concentration (Tmax) of sonidegib in Phase 1

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    End point title
    Time to reach maximum observed plasma concentration (Tmax) of sonidegib in Phase 1 [9]
    End point description
    Tmax was defined as the time required to reach maximum observed plasma concentration. Tmax was directly determined from the raw plasma concentration time data. The analysis was performed in PAS population. The 'n' signifies those subjects evaluable for this measure at specified time points for each group, respectively.
    End point type
    Secondary
    End point timeframe
    Day 1 and Day 22 of Cycle 1
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point summary statistics was planned only for treatment arms in Part 1 of the study.
    End point values
    Pediatric subjects, LDE225 233 mg/m^2 Pediatric subjects, LDE225 372 mg/m^2 Pediatric subjects, LDE225 425 mg/m^2 Pediatric subjects, LDE225 680 mg/m^2
    Number of subjects analysed
    11
    16
    11
    22
    Units: Hours
    median (full range (min-max))
        Cycle 1/Day 1 (n=11, 15, 10, 17)
    3.98 (1.07 to 6.75)
    2.03 (1 to 7)
    2.92 (0.5 to 7)
    2.08 (1 to 4.08)
        Cycle 1/Day 22 (n=9, 12, 9, 15)
    1.98 (1 to 7)
    2.06 (0.95 to 4.25)
    2 (0.67 to 7)
    2 (0 to 7.05)
    No statistical analyses for this end point

    Secondary: Maximum observed plasma concentration (Cmax) of sonidegib in Phase 1

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    End point title
    Maximum observed plasma concentration (Cmax) of sonidegib in Phase 1 [10]
    End point description
    Maximum observed plasma concentration following drug administration was calculated from the raw plasma concentration time data. The analysis was performed in PAS population. The 'n' signifies those subjects evaluable for this measure at specified time points for each group, respectively.
    End point type
    Secondary
    End point timeframe
    Day 1 and Day 22 of Cycle 1
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point summary statistics was planned only for treatment arms in Part 1 of the study.
    End point values
    Pediatric subjects, LDE225 233 mg/m^2 Pediatric subjects, LDE225 372 mg/m^2 Pediatric subjects, LDE225 425 mg/m^2 Pediatric subjects, LDE225 680 mg/m^2
    Number of subjects analysed
    11
    16
    11
    22
    Units: nanograms/millitres(ng/mL)
    arithmetic mean (standard deviation)
        Cycle 1/Day 1 (n=11, 15, 10, 17)
    191.18 ± 82.464
    246.39 ± 211.034
    642.5 ± 486.709
    618.88 ± 403.466
        Cycle 1/Day 22 (n=9, 12, 9, 15)
    769.22 ± 496.021
    944.17 ± 553.395
    1122 ± 736.862
    1930 ± 677.949
    No statistical analyses for this end point

    Secondary: Percentage of pediatric subjects with objective response rate (ORR) by Hedgehog (Hh) signaling pathway status

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    End point title
    Percentage of pediatric subjects with objective response rate (ORR) by Hedgehog (Hh) signaling pathway status
    End point description
    ORR was determined in the subjects with mutations on Hh gene (Hh positive) and the subjects without mutations on Hh gene (Hh negative). The analysis was performed in full analysis set (FAS). 'n' signifies those subjects evaluable for this measure at specified time points for each group, respectively. 60 patients were screened, 10 were Hh positive, of the 10, 3 were pediatric.
    End point type
    Secondary
    End point timeframe
    Baseline to End of treatment
    End point values
    Pediatric subjects
    Number of subjects analysed
    3 [11]
    Units: Percentage of subjects
    number (not applicable)
        Objective response rate
    66.7
    Notes
    [11] - Number Hh positive pediatric subjects
    No statistical analyses for this end point

    Secondary: Duration of response by treatment

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    End point title
    Duration of response by treatment
    End point description
    Duration of overall response (complete response (CR) or partial response (PR)) was calculated for those subjects whose best overall response was CR or PR. The start date was the date of the first documented tumor response (CR or PR) and the end date was the date of the event defined as the first documented progression or death due to underlying cancer or after the same treatment line. If a subject did not have a progression or death, the duration of response was censored at the date of last adequate tumor assessment in that treatment line. The analysis was performed in FAS population.
    End point type
    Secondary
    End point timeframe
    Baseline to End of treatment
    End point values
    Pediatric subjects, LDE225 233 mg/m^2 Pediatric subjects, LDE225 372 mg/m^2 Pediatric subjects, LDE225 425 mg/m^2 Pediatric subjects, LDE225 680 mg/m^2 Adult subjects, LDE225 800 mg
    Number of subjects analysed
    0 [12]
    1 [13]
    1 [14]
    0 [15]
    3 [16]
    Units: Months
        median (full range (min-max))
    ( to )
    7.03 (7 to 7.03)
    8.08 (8 to 8.1)
    ( to )
    4.86 (1.6 to 8.7)
    Notes
    [12] - none of the subjects in this group acheived the endpoint
    [13] - only one responder in this group
    [14] - only one responder in this group
    [15] - none of the subjects in this group achieved the endpoint
    [16] - 3 responders in this group
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Serious Adverse Events are monitored from date of First Subject First Visit (FSFV) until Last Subject Last Visit (LSLV). All other adverse events are monitored from First Subject First Treatment (FSFT) until Last Subject Last Visit (LSLV).
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Pediatric subjects, LDE225 233 mg/m^2
    Reporting group description
    Pediatric subjects received LDE225 233 mg/m^2 once daily through oral route.

    Reporting group title
    Pediatric subjects, LDE225 372 mg/m^2
    Reporting group description
    Pediatric subjects received LDE225 372 mg/m^2 once daily through oral route.

    Reporting group title
    Pediatric subjects, LDE225 425 mg/m^2
    Reporting group description
    Pediatric subjects received LDE225 425 mg/m^2 once daily through oral route.

    Reporting group title
    Pediatric subjects, LDE225 680 mg/m^2
    Reporting group description
    Pediatric subjects received LDE225 680 mg/m^2 once daily through oral route.

    Reporting group title
    Adult subjects, LDE225 800 mg
    Reporting group description
    Adult subjects were treated with LDE225 800 mg capsule once daily.

    Serious adverse events
    Pediatric subjects, LDE225 233 mg/m^2 Pediatric subjects, LDE225 372 mg/m^2 Pediatric subjects, LDE225 425 mg/m^2 Pediatric subjects, LDE225 680 mg/m^2 Adult subjects, LDE225 800 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 11 (45.45%)
    8 / 16 (50.00%)
    4 / 11 (36.36%)
    14 / 22 (63.64%)
    5 / 16 (31.25%)
         number of deaths (all causes)
    2
    2
    1
    8
    2
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Vascular disorders
    Venous Insufficiency
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    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
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour Haemorrhage
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    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
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    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
    General disorders and administration site conditions
    Chest Pain
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    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
    General Physical Health Deterioration
         subjects affected / exposed
    1 / 11 (9.09%)
    2 / 16 (12.50%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    2 / 22 (9.09%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    1 / 11 (9.09%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    1 / 22 (4.55%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    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
    Confusional State
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    2 / 22 (9.09%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Disorientation
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    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
    Suicidal Ideation
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    1 / 11 (9.09%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    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
    Injury, poisoning and procedural complications
    Femur Fracture
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    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
    Procedural Complication
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    1 / 11 (9.09%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    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
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    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
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    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
    Blood Creatine Phosphokinase Increased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    2 / 16 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myoglobin Blood Increased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    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
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    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
    Pneumonia Aspiration
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    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
    Pleural Effusion
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    1 / 22 (4.55%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    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
    Respiratory Distress
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    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 / 1
    Nervous system disorders
    Altered State Of Consciousness
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    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
    Amnesia
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    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
    Aphasia
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    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
    Coma
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    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
    Convulsion
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    3 / 22 (13.64%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depressed Level Of Consciousness
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    2 / 22 (9.09%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysaesthesia
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    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
    Dystonia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    1 / 11 (9.09%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    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
    Encephalopathy
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    1 / 11 (9.09%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 11 (9.09%)
    2 / 16 (12.50%)
    1 / 11 (9.09%)
    4 / 22 (18.18%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 1
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    1 / 22 (4.55%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intracranial Pressure Increased
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    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
    Neuralgia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    1 / 22 (4.55%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neurological Decompensation
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    1 / 11 (9.09%)
    1 / 22 (4.55%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Quadriparesis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    1 / 22 (4.55%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    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
    Somnolence
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    1 / 22 (4.55%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    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
    Tremor
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    1 / 11 (9.09%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    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
    VIIth nerve paralysis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    1 / 11 (9.09%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    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
    Eye disorders
    Vision Blurred
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    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
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    1 / 22 (4.55%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    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
    Dysphagia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    1 / 11 (9.09%)
    0 / 22 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    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
    Vomiting
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 16 (0.00%)
    1 / 11 (9.09%)
    4 / 22 (18.18%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary Incontinence
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    1 / 22 (4.55%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    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
    Musculoskeletal and connective tissue disorders
    Muscular Weakness
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    1 / 11 (9.09%)
    0 / 22 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    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
    Pain In Extremity
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    1 / 22 (4.55%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    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
    Rhabdomyolysis
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    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
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 16 (6.25%)
    1 / 11 (9.09%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    1 / 11 (9.09%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Cystitis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    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
    Cellulitis
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    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
    Mucosal Infection
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    1 / 11 (9.09%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    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
    Wound Infection
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    1 / 22 (4.55%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    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
    Urinary Tract Infection
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    1 / 11 (9.09%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Pediatric subjects, LDE225 233 mg/m^2 Pediatric subjects, LDE225 372 mg/m^2 Pediatric subjects, LDE225 425 mg/m^2 Pediatric subjects, LDE225 680 mg/m^2 Adult subjects, LDE225 800 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    11 / 11 (100.00%)
    16 / 16 (100.00%)
    11 / 11 (100.00%)
    21 / 22 (95.45%)
    16 / 16 (100.00%)
    Vascular disorders
    Haematoma
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Hypotension
         subjects affected / exposed
    1 / 11 (9.09%)
    2 / 16 (12.50%)
    0 / 11 (0.00%)
    1 / 22 (4.55%)
    1 / 16 (6.25%)
         occurrences all number
    1
    2
    0
    1
    1
    Pallor
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    1 / 11 (9.09%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin Papilloma
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    2
    1
    0
    0
    0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 11 (18.18%)
    4 / 16 (25.00%)
    1 / 11 (9.09%)
    1 / 22 (4.55%)
    3 / 16 (18.75%)
         occurrences all number
    2
    5
    2
    1
    3
    Chest Pain
         subjects affected / exposed
    0 / 11 (0.00%)
    2 / 16 (12.50%)
    0 / 11 (0.00%)
    1 / 22 (4.55%)
    0 / 16 (0.00%)
         occurrences all number
    0
    2
    0
    1
    0
    Chills
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Face Oedema
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Facial Pain
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    0
    0
    1
    Fatigue
         subjects affected / exposed
    5 / 11 (45.45%)
    7 / 16 (43.75%)
    3 / 11 (27.27%)
    6 / 22 (27.27%)
    1 / 16 (6.25%)
         occurrences all number
    7
    10
    3
    6
    1
    Gait Disturbance
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 16 (6.25%)
    1 / 11 (9.09%)
    1 / 22 (4.55%)
    2 / 16 (12.50%)
         occurrences all number
    1
    1
    1
    1
    2
    General Physical Health Deterioration
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    1
    Influenza Like Illness
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    1
    Non-Cardiac Chest Pain
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    1 / 11 (9.09%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Oedema Peripheral
         subjects affected / exposed
    0 / 11 (0.00%)
    2 / 16 (12.50%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    2
    0
    0
    1
    Pain
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    1 / 11 (9.09%)
    1 / 22 (4.55%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Pyrexia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    3 / 22 (13.64%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    3
    0
    Performance Status Decreased
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    1 / 22 (4.55%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Anxiety
         subjects affected / exposed
    0 / 11 (0.00%)
    2 / 16 (12.50%)
    1 / 11 (9.09%)
    1 / 22 (4.55%)
    0 / 16 (0.00%)
         occurrences all number
    0
    2
    1
    1
    0
    Bruxism
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    1 / 11 (9.09%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Disorientation
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Confusional State
         subjects affected / exposed
    1 / 11 (9.09%)
    2 / 16 (12.50%)
    1 / 11 (9.09%)
    0 / 22 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    1
    3
    1
    0
    2
    Euphoric Mood
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    1 / 11 (9.09%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Insomnia
         subjects affected / exposed
    2 / 11 (18.18%)
    2 / 16 (12.50%)
    1 / 11 (9.09%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    2
    2
    1
    0
    0
    Irritability
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    1 / 11 (9.09%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    Paranoia
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Mood Altered
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    1 / 11 (9.09%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Reproductive system and breast disorders
    Vaginal Discharge
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Penile Pain
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    1
    Femur Fracture
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Procedural Pain
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Thermal Burn
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Vascular Procedure Complication
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Investigations
    Activated Partial Thromboplastin Time Prolonged
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    0 / 11 (0.00%)
    2 / 16 (12.50%)
    2 / 11 (18.18%)
    2 / 22 (9.09%)
    1 / 16 (6.25%)
         occurrences all number
    0
    2
    2
    3
    1
    Alanine Aminotransferase Increased
         subjects affected / exposed
    1 / 11 (9.09%)
    2 / 16 (12.50%)
    0 / 11 (0.00%)
    2 / 22 (9.09%)
    4 / 16 (25.00%)
         occurrences all number
    2
    2
    0
    2
    4
    Blood Bilirubin Increased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    1 / 22 (4.55%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    1
    1
    Blood Alkaline Phosphatase Increased
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 16 (6.25%)
    1 / 11 (9.09%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    1
    1
    0
    0
    Blood Creatine Phosphokinase Increased
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 16 (6.25%)
    2 / 11 (18.18%)
    6 / 22 (27.27%)
    8 / 16 (50.00%)
         occurrences all number
    1
    3
    4
    6
    15
    Blood Creatinine Increased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    1 / 11 (9.09%)
    1 / 22 (4.55%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    2
    1
    0
    Blood Fibrinogen Decreased
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Blood Lactate Dehydrogenase Increased
         subjects affected / exposed
    2 / 11 (18.18%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    Blood Magnesium Decreased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    1 / 11 (9.09%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Cardiac Murmur
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Blood Urea Increased
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Haemoglobin Decreased
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Lymphocyte Count Decreased
         subjects affected / exposed
    2 / 11 (18.18%)
    1 / 16 (6.25%)
    3 / 11 (27.27%)
    3 / 22 (13.64%)
    1 / 16 (6.25%)
         occurrences all number
    2
    2
    4
    3
    1
    Platelet Count Decreased
         subjects affected / exposed
    0 / 11 (0.00%)
    2 / 16 (12.50%)
    1 / 11 (9.09%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    2
    2
    0
    0
    Neutrophil Count Decreased
         subjects affected / exposed
    0 / 11 (0.00%)
    2 / 16 (12.50%)
    2 / 11 (18.18%)
    2 / 22 (9.09%)
    0 / 16 (0.00%)
         occurrences all number
    0
    2
    2
    5
    0
    Weight Decreased
         subjects affected / exposed
    1 / 11 (9.09%)
    2 / 16 (12.50%)
    0 / 11 (0.00%)
    2 / 22 (9.09%)
    3 / 16 (18.75%)
         occurrences all number
    1
    2
    0
    2
    3
    White Blood Cell Count Decreased
         subjects affected / exposed
    2 / 11 (18.18%)
    2 / 16 (12.50%)
    3 / 11 (27.27%)
    3 / 22 (13.64%)
    1 / 16 (6.25%)
         occurrences all number
    3
    4
    4
    5
    3
    Cardiac disorders
    Sinus Bradycardia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    1
    Left Ventricular Hypertrophy
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 11 (27.27%)
    1 / 16 (6.25%)
    5 / 11 (45.45%)
    1 / 22 (4.55%)
    3 / 16 (18.75%)
         occurrences all number
    3
    1
    5
    1
    3
    Apnoea
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    1 / 11 (9.09%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Dyspnoea
         subjects affected / exposed
    2 / 11 (18.18%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    3
    0
    0
    0
    0
    Epistaxis
         subjects affected / exposed
    1 / 11 (9.09%)
    2 / 16 (12.50%)
    0 / 11 (0.00%)
    1 / 22 (4.55%)
    0 / 16 (0.00%)
         occurrences all number
    1
    2
    0
    1
    0
    Hiccups
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    3 / 16 (18.75%)
         occurrences all number
    1
    0
    0
    0
    3
    Laryngeal Inflammation
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Nasal Congestion
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Pleural Effusion
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Stridor
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    1 / 11 (9.09%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    1
    Anaemia
         subjects affected / exposed
    0 / 11 (0.00%)
    2 / 16 (12.50%)
    4 / 11 (36.36%)
    2 / 22 (9.09%)
    0 / 16 (0.00%)
         occurrences all number
    0
    2
    4
    2
    0
    Lymphadenopathy
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    1 / 11 (9.09%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Lymphopenia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    2 / 22 (9.09%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    0
    2
    2
    Thrombocytopenia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    1 / 11 (9.09%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Nervous system disorders
    Amnesia
         subjects affected / exposed
    0 / 11 (0.00%)
    2 / 16 (12.50%)
    0 / 11 (0.00%)
    1 / 22 (4.55%)
    0 / 16 (0.00%)
         occurrences all number
    0
    3
    0
    1
    0
    Aphasia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    1 / 11 (9.09%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Balance Disorder
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 16 (0.00%)
    1 / 11 (9.09%)
    0 / 22 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    1
    0
    2
    0
    1
    Ataxia
         subjects affected / exposed
    2 / 11 (18.18%)
    2 / 16 (12.50%)
    2 / 11 (18.18%)
    4 / 22 (18.18%)
    0 / 16 (0.00%)
         occurrences all number
    2
    2
    2
    4
    0
    Cerebellar Syndrome
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    1 / 22 (4.55%)
    1 / 16 (6.25%)
         occurrences all number
    0
    2
    0
    1
    1
    Brain Oedema
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Coma
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Convulsion
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    2 / 11 (18.18%)
    2 / 22 (9.09%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    7
    2
    1
    Coordination Abnormal
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    1 / 11 (9.09%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Depressed Level Of Consciousness
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Dizziness
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 16 (6.25%)
    1 / 11 (9.09%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    2
    1
    0
    0
    Dysarthria
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    1 / 11 (9.09%)
    1 / 22 (4.55%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Dysaesthesia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    2
    Facial Nerve Disorder
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Dysgeusia
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    1 / 22 (4.55%)
    0 / 16 (0.00%)
         occurrences all number
    2
    0
    0
    1
    0
    Facial Paresis
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    Headache
         subjects affected / exposed
    6 / 11 (54.55%)
    7 / 16 (43.75%)
    4 / 11 (36.36%)
    9 / 22 (40.91%)
    2 / 16 (12.50%)
         occurrences all number
    7
    17
    13
    10
    2
    Hemiplegia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Hemiparesis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    1 / 11 (9.09%)
    3 / 22 (13.64%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    3
    0
    Hyperaesthesia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Hypoaesthesia
         subjects affected / exposed
    0 / 11 (0.00%)
    2 / 16 (12.50%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    IIIrd nerve paresis
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Intracranial Pressure Increased
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Lethargy
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 16 (0.00%)
    3 / 11 (27.27%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    3
    0
    0
    Meningism
         subjects affected / exposed
    2 / 11 (18.18%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    Neuralgia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    1 / 22 (4.55%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    Neuropathy Peripheral
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    0
    0
    1
    Neurological Decompensation
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    1 / 11 (9.09%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Paraparesis
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Paraesthesia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    2 / 16 (12.50%)
         occurrences all number
    0
    1
    0
    0
    3
    Peripheral Sensory Neuropathy
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Peroneal Nerve Palsy
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    1
    Presyncope
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Somnolence
         subjects affected / exposed
    0 / 11 (0.00%)
    3 / 16 (18.75%)
    1 / 11 (9.09%)
    1 / 22 (4.55%)
    0 / 16 (0.00%)
         occurrences all number
    0
    3
    3
    2
    0
    Pyramidal Tract Syndrome
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Speech Disorder
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    1 / 11 (9.09%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Tremor
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    1 / 11 (9.09%)
    1 / 22 (4.55%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    2
    1
    0
    VIIth nerve paralysis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    1 / 11 (9.09%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    VIth nerve disorder
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Eye disorders
    Conjunctivitis Allergic
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    1 / 11 (9.09%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Blindness Unilateral
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Dry Eye
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    1 / 11 (9.09%)
    1 / 22 (4.55%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Diplopia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Eye Irritation
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    1 / 11 (9.09%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Eyelid Ptosis
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Lacrimation Increased
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    1 / 22 (4.55%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    Ocular Hyperaemia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Strabismus
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    1 / 11 (9.09%)
    1 / 22 (4.55%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    2
    1
    0
    Vision Blurred
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    2 / 11 (18.18%)
    1 / 22 (4.55%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    2
    1
    0
    Visual Acuity Reduced
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    1 / 11 (9.09%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Visual Impairment
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 16 (0.00%)
    1 / 11 (9.09%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    Ear and labyrinth disorders
    Cerumen Impaction
         subjects affected / exposed
    2 / 11 (18.18%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    Deafness
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Ear Pain
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Ear Canal Stenosis
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Hypoacusis
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Vertigo
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    1
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    1 / 11 (9.09%)
    3 / 16 (18.75%)
    2 / 11 (18.18%)
    5 / 22 (22.73%)
    1 / 16 (6.25%)
         occurrences all number
    1
    4
    4
    5
    1
    Abdominal Pain Lower
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Anal Pruritus
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Constipation
         subjects affected / exposed
    1 / 11 (9.09%)
    6 / 16 (37.50%)
    4 / 11 (36.36%)
    3 / 22 (13.64%)
    2 / 16 (12.50%)
         occurrences all number
    1
    10
    5
    5
    3
    Dental Caries
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Dysphagia
         subjects affected / exposed
    0 / 11 (0.00%)
    2 / 16 (12.50%)
    1 / 11 (9.09%)
    0 / 22 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    2
    1
    0
    1
    Diarrhoea
         subjects affected / exposed
    2 / 11 (18.18%)
    5 / 16 (31.25%)
    2 / 11 (18.18%)
    1 / 22 (4.55%)
    4 / 16 (25.00%)
         occurrences all number
    2
    7
    2
    1
    5
    Faecal Incontinence
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    1 / 11 (9.09%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Faeces Hard
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    1 / 11 (9.09%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Gastritis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    1
    Gastrointestinal Pain
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Gingival Pain
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    2 / 11 (18.18%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Nausea
         subjects affected / exposed
    5 / 11 (45.45%)
    4 / 16 (25.00%)
    3 / 11 (27.27%)
    8 / 22 (36.36%)
    4 / 16 (25.00%)
         occurrences all number
    5
    5
    8
    10
    5
    Mouth Ulceration
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    1 / 11 (9.09%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Odynophagia
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Oesophagitis
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Oral Dysaesthesia
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Oral Pain
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Stomatitis
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 16 (6.25%)
    1 / 11 (9.09%)
    0 / 22 (0.00%)
    3 / 16 (18.75%)
         occurrences all number
    1
    1
    2
    0
    3
    Tooth Disorder
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Toothache
         subjects affected / exposed
    2 / 11 (18.18%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    2
    1
    0
    0
    0
    Vomiting
         subjects affected / exposed
    5 / 11 (45.45%)
    9 / 16 (56.25%)
    7 / 11 (63.64%)
    15 / 22 (68.18%)
    2 / 16 (12.50%)
         occurrences all number
    5
    12
    13
    21
    3
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 11 (0.00%)
    2 / 16 (12.50%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Micturition Disorder
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Micturition Urgency
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Neurogenic Bladder
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Polyuria
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Pollakiuria
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    1 / 11 (9.09%)
    1 / 22 (4.55%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    1
    1
    1
    Urinary Incontinence
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    2 / 11 (18.18%)
    0 / 22 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    2
    0
    1
    Urinary Retention
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    1 / 11 (9.09%)
    1 / 22 (4.55%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Urinary Tract Disorder
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    1 / 11 (9.09%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Hepatobiliary disorders
    Hepatotoxicity
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    3 / 11 (27.27%)
    1 / 22 (4.55%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    3
    1
    0
    Dermatitis Acneiform
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Dermatitis
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Dry Skin
         subjects affected / exposed
    0 / 11 (0.00%)
    2 / 16 (12.50%)
    3 / 11 (27.27%)
    1 / 22 (4.55%)
    1 / 16 (6.25%)
         occurrences all number
    0
    2
    3
    1
    1
    Erythema
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Hyperhidrosis
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Fungating Wound
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    1 / 11 (9.09%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Madarosis
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 16 (6.25%)
    2 / 11 (18.18%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    5
    3
    2
    0
    0
    Pain Of Skin
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    1
    Nail Disorder
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 16 (0.00%)
    1 / 11 (9.09%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    Pruritus
         subjects affected / exposed
    2 / 11 (18.18%)
    3 / 16 (18.75%)
    1 / 11 (9.09%)
    2 / 22 (9.09%)
    0 / 16 (0.00%)
         occurrences all number
    2
    4
    1
    3
    0
    Rash
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    1
    0
    0
    0
    1
    Rash Maculo-Papular
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    1 / 11 (9.09%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Rash Papular
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Solar Dermatitis
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Skin Exfoliation
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    0 / 11 (0.00%)
    4 / 16 (25.00%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    4
    0
    0
    1
    Arthralgia
         subjects affected / exposed
    2 / 11 (18.18%)
    3 / 16 (18.75%)
    3 / 11 (27.27%)
    1 / 22 (4.55%)
    0 / 16 (0.00%)
         occurrences all number
    3
    5
    5
    2
    0
    Epiphyseal Disorder
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    1 / 11 (9.09%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Chondropathy
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Muscle Spasms
         subjects affected / exposed
    2 / 11 (18.18%)
    4 / 16 (25.00%)
    5 / 11 (45.45%)
    2 / 22 (9.09%)
    4 / 16 (25.00%)
         occurrences all number
    5
    9
    9
    2
    5
    Muscular Weakness
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    1 / 11 (9.09%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    2
    1
    0
    0
    Musculoskeletal Stiffness
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Musculoskeletal Pain
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    2 / 11 (18.18%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    2
    0
    0
    Neck Pain
         subjects affected / exposed
    0 / 11 (0.00%)
    3 / 16 (18.75%)
    2 / 11 (18.18%)
    1 / 22 (4.55%)
    2 / 16 (12.50%)
         occurrences all number
    0
    5
    2
    1
    2
    Myalgia
         subjects affected / exposed
    1 / 11 (9.09%)
    2 / 16 (12.50%)
    4 / 11 (36.36%)
    5 / 22 (22.73%)
    5 / 16 (31.25%)
         occurrences all number
    2
    2
    10
    5
    5
    Pain In Extremity
         subjects affected / exposed
    2 / 11 (18.18%)
    6 / 16 (37.50%)
    4 / 11 (36.36%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    2
    11
    6
    0
    0
    Pain In Jaw
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 16 (0.00%)
    2 / 11 (18.18%)
    0 / 22 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    1
    0
    3
    0
    1
    Posture Abnormal
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    1 / 11 (9.09%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Rhabdomyolysis
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Sensation Of Heaviness
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Temporomandibular Joint Syndrome
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    1 / 11 (9.09%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Endocrine disorders
    Cushingoid
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 16 (6.25%)
    3 / 11 (27.27%)
    4 / 22 (18.18%)
    3 / 16 (18.75%)
         occurrences all number
    1
    1
    5
    4
    3
    Dehydration
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    3 / 22 (13.64%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    3
    0
    Hyperglycaemia
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    1
    1
    0
    0
    2
    Hypermagnesaemia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    1 / 11 (9.09%)
    2 / 22 (9.09%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    2
    0
    Hyperkalaemia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    2 / 11 (18.18%)
    2 / 22 (9.09%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    4
    2
    1
    Hypernatraemia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    1
    Hyperphagia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Hyperphosphataemia
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Hypoglycaemia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    1
    Hypocalcaemia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    1 / 11 (9.09%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    Hypokalaemia
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    1 / 22 (4.55%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Hypomagnesaemia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    1 / 11 (9.09%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Hypophosphataemia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    1 / 11 (9.09%)
    1 / 22 (4.55%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    1
    2
    0
    Hyponatraemia
         subjects affected / exposed
    1 / 11 (9.09%)
    3 / 16 (18.75%)
    1 / 11 (9.09%)
    3 / 22 (13.64%)
    0 / 16 (0.00%)
         occurrences all number
    1
    4
    4
    4
    0
    Vitamin D Deficiency
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    1 / 11 (9.09%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Infections and infestations
    Catheter Site Cellulitis
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Cellulitis
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Conjunctivitis
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    1 / 22 (4.55%)
    1 / 16 (6.25%)
         occurrences all number
    1
    1
    0
    1
    1
    Ear Infection
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    2
    Influenza
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    1
    0
    0
    0
    1
    Pharyngitis
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 16 (0.00%)
    1 / 11 (9.09%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Skin Infection
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    1
    0
    0
    0
    1
    Tooth Abscess
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Urinary Tract Infection
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    1 / 11 (9.09%)
    1 / 22 (4.55%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    1
    1
    1
    Upper Respiratory Tract Infection
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 16 (6.25%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    2 / 16 (12.50%)
         occurrences all number
    0
    1
    0
    0
    2
    Vulvovaginal Mycotic Infection
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 16 (0.00%)
    0 / 11 (0.00%)
    0 / 22 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Jul 2011
    List of breast cancer resistance protein (BCRP) substrates was added as non-authorized drugs in the study to avoid potential adverse drug-drug interactions.
    11 Nov 2011
    1. The second part of the study (Phase II) was incorporated to enroll approximately 55 adults and children with recurrent or refractory MB. 2. The plasma PK parameters to be analyzed was updated based on the emerging PK data. 3. The definition of MTD and RP2D was added and, clarified the BLRM considerations for specific DLTs with potentially more serious medical implications. 4. Hypersensitivity or signs of allergic reaction were not considered a DLT.
    23 Jul 2014
    Inclusion criteria for female subjects was modified. The language states that woman of child bearing potential must not become pregnant during the study and for 20 months after taking the last dose of study drug. This was changed from 6 to 20 months.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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