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    Clinical Trial Results:
    A Phase II, multi-center, open-label, single-arm study of the efficacy and safety of oral LDE225 in patients with Hh-pathway activated relapsed medulloblastoma Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.novfor complete trial results.

    Summary
    EudraCT number
    		 2012-003066-40
    Trial protocol
    		 SE   IT   ES   DE   GB   FR   NL   BE   HU  
    Global end of trial date
    05 Oct 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Jul 2018
    First version publication date
    11 Jul 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CLDE225C2301
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01708174
    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
    05 Oct 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Oct 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of sonidegib with respect to Overall Response Rate (ORR) according to the independent central review (ICR).
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    13 Sep 2013
    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
    France: 3
    Country: Number of subjects enrolled
    Italy: 8
    Country: Number of subjects enrolled
    Netherlands: 2
    Country: Number of subjects enrolled
    Russian Federation: 1
    Country: Number of subjects enrolled
    Switzerland: 1
    Country: Number of subjects enrolled
    United States: 7
    Worldwide total number of subjects
    22
    EEA total number of subjects
    13
    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)
    1
    Adolescents (12-17 years)
    1
    Adults (18-64 years)
    20
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Analyses were performed by treatment and by age group.

    Period 1
    Period 1 title
    Treatment period
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Sonidegib (LDE225) Children
    Arm description
    		 500 mg/m2 orally
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sonidegib
    Investigational medicinal product code
    LDE225
    Other name
    Pharmaceutical forms
    Concentrate for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    500 mg/m2 orally

    Arm title
    		 Sonidegib (LDE225) Adults
    Arm description
    		 600 mg orally
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sonidegib
    Investigational medicinal product code
    LDE225
    Other name
    Pharmaceutical forms
    Concentrate for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    600 mg orally

    Arm title
    		 Temozolomide (TMZ)
    Arm description
    		 150 to 200 mg/m2 for 5 sequential days every 4 weeks according to prescribing information until the study was amended to a single arm study.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Temozolomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    150 to 200 mg/m2 for 5 sequential days every 4 weeks according to prescribing information until the study was amended to a single arm study.

    Number of subjects in period 1
    		Sonidegib (LDE225) Children Sonidegib (LDE225) Adults Temozolomide (TMZ)
    Started
    2
    16
    4
    Pharmacokinetic analysis set
    2
    13 [1]
    0 [2]
    Completed
    1
    14
    3
    Not completed
    1
    2
    1
         Adverse event, serious fatal
    -
    -
    1
         Consent withdrawn by subject
    1
    -
    -
         Adverse event, non-fatal
    -
    1
    -
         Progressive disease
    -
    1
    -
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The number of patients in the follow-up period 2 was less than the number of patients who started Period 1 Not all patients who completed the trial were available for the follow period of the trial.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: This arm was not analyzed in the follow-up period.
    Period 2
    Period 2 title
    Survival follow-up
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Sonidegib (LDE225) Children
    Arm description
    		 500 mg/m2 orally
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sonidegib
    Investigational medicinal product code
    LDE225
    Other name
    Pharmaceutical forms
    Concentrate for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    500 mg/m2 orally

    Arm title
    		 Sonidegib (LDE225) Adults
    Arm description
    		 600 mg orally
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sonidegib
    Investigational medicinal product code
    LDE225
    Other name
    Pharmaceutical forms
    Concentrate for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    600 mg orally

    Number of subjects in period 2 [3]
    		Sonidegib (LDE225) Children Sonidegib (LDE225) Adults
    Started
    1
    10
    Completed
    1
    10
    Notes
    [3] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: The number of patients in the follow-up period 2 was less than the number of patients who started Period 1. Not all patients who completed the trial were available for the follow period of the trial

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Sonidegib (LDE225) Children
    Reporting group description
    		 500 mg/m2 orally

    Reporting group title
    Sonidegib (LDE225) Adults
    Reporting group description
    		 600 mg orally

    Reporting group title
    Temozolomide (TMZ)
    Reporting group description
    		 150 to 200 mg/m2 for 5 sequential days every 4 weeks according to prescribing information until the study was amended to a single arm study.

    Reporting group values
    		 Sonidegib (LDE225) Children Sonidegib (LDE225) Adults Temozolomide (TMZ) Total
    Number of subjects
    		 2 16 4 22
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 1 0 0 1
        Adolescents (12-17 years)
    		 1 0 0 1
        Adults (18-64 years)
    		 0 16 4 20
        From 65-84 years
    		 0 0 0 0
        85 years and over
    		 0 0 0 0
    Age Continuous
    Units: Years
        median (full range (min-max))
    		 8.5 (4 to 13) 37 (24 to 51) 35.5 (31 to 38) -
    Gender, Male/Female
    Units: Subjects
        Female
    		 2 5 2 9
        Male
    		 0 11 2 13

    End points

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    End points reporting groups
    Reporting group title
    Sonidegib (LDE225) Children
    Reporting group description
    		 500 mg/m2 orally

    Reporting group title
    Sonidegib (LDE225) Adults
    Reporting group description
    		 600 mg orally

    Reporting group title
    Temozolomide (TMZ)
    Reporting group description
    		 150 to 200 mg/m2 for 5 sequential days every 4 weeks according to prescribing information until the study was amended to a single arm study.
    Reporting group title
    Sonidegib (LDE225) Children
    Reporting group description
    		 500 mg/m2 orally

    Reporting group title
    Sonidegib (LDE225) Adults
    Reporting group description
    		 600 mg orally

    Primary: Percentage of participants with Overall response rate (ORR) according to Independent Review Committee (IRC) from date first participant randomized, 13-Sep-2013 to date of data cut-off, 15-Nov-2016

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    End point title
    		 Percentage of participants with Overall response rate (ORR) according to Independent Review Committee (IRC) from date first participant randomized, 13-Sep-2013 to date of data cut-off, 15-Nov-2016 [1]
    End point description
    ORR was defined as the percentage of participants with best overall response of complete response (CR) or partial response (PR) (as per tumor response guidelines and criteria for Medulloblastoma). The IRC evaluated all radiological images and applicable clinical data (i.e., neurological examination, steroid use and cerebrospinal fluid (CSF) results as applicable). Assessments after crossover were not included for TMZ participants.
    End point type
    Primary
    End point timeframe
    from date first participant randomized, 13-Sep-2013 to date of data cut-off, 15-Nov-2016
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical analysis were not performed for this endpoint.
    End point values
    		 Sonidegib (LDE225) Children Sonidegib (LDE225) Adults Temozolomide (TMZ)
    Number of subjects analysed
    2
    16
    4
    Units: Percentage of participants
        number (not applicable)
    0
    18.8
    0
    No statistical analyses for this end point

    Secondary: Progression free survival (PFS) according to IRC from date first participant randomized, 13-Sep-2013 to date of data cut-off, 15-Nov-2016

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    End point title
    		 Progression free survival (PFS) according to IRC from date first participant randomized, 13-Sep-2013 to date of data cut-off, 15-Nov-2016
    End point description
    PFS was defined as the time from date of randomization to the date of event defined as the first documented progression or death due to any cause (as per tumor response guidelines and criteria for Medulloblastoma). The IRC evaluated all radiological images and applicable clinical data (i.e., neurological examination, steroid use and cerebrospinal fluid (CSF) results as applicable). TMZ participants without event prior to crossover were censored.
    End point type
    Secondary
    End point timeframe
    from date first participant randomized, 13-Sep-2013 to date of data cut-off, 15-Nov-2016
    End point values
    		 Sonidegib (LDE225) Children Sonidegib (LDE225) Adults Temozolomide (TMZ)
    Number of subjects analysed
    2
    16
    4
    Units: months
        median (confidence interval 95%)
    1.6 (-9999 to 9999)
    3.3 (1.7 to 17.1)
    2.9 (0.9 to 4)
    No statistical analyses for this end point

    Secondary: PFS according to local Investigator assessment from date first participant randomized, 13-Sep-2013 to date of data cut-off, 15-Nov-2016

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    End point title
    		 PFS according to local Investigator assessment from date first participant randomized, 13-Sep-2013 to date of data cut-off, 15-Nov-2016
    End point description
    PFS was defined as the time from date of randomization to the date of event defined as the first documented progression or death due to any cause. PFS was evaluated by local Investigator assessment per tumor response guidelines and criteria for Medulloblastoma.
    End point type
    Secondary
    End point timeframe
    from date first participant randomized, 13-Sep-2013 to date of data cut-off, 15-Nov-2016
    End point values
    		 Sonidegib (LDE225) Children Sonidegib (LDE225) Adults Temozolomide (TMZ)
    Number of subjects analysed
    2
    16
    4
    Units: months
        median (confidence interval 95%)
    9999 (1.6 to 9999)
    3.3 (1.6 to 13)
    2.9 (0.9 to 4)
    No statistical analyses for this end point

    Secondary: Percentage of participants with ORR according to local Investigator assessment from date first participant randomized, 13-Sep-2013 to date of data cut-off, 15-Nov-2016

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    End point title
    		 Percentage of participants with ORR according to local Investigator assessment from date first participant randomized, 13-Sep-2013 to date of data cut-off, 15-Nov-2016
    End point description
    ORR was defined as the percentage of participants with best overall response of complete response (CR) or partial response (PR). ORR was evaluated by local Investigator assessment per tumor response guidelines and criteria for Medulloblastoma. Assessments after crossover were not included for TMZ patients.
    End point type
    Secondary
    End point timeframe
    from date first participant randomized, 13-Sep-2013 to date of data cut-off, 15-Nov-2016
    End point values
    		 Sonidegib (LDE225) Children Sonidegib (LDE225) Adults Temozolomide (TMZ)
    Number of subjects analysed
    2
    16
    4
    Units: Percentage of participants
        number (not applicable)
    0
    25
    0
    No statistical analyses for this end point

    Secondary: Duration of response (DoR) according to local Investigator assessment from date first participant randomized, 13-Sep-2013 to date of data cut-off, 15-Nov-2016

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    End point title
    		 Duration of response (DoR) according to local Investigator assessment from date first participant randomized, 13-Sep-2013 to date of data cut-off, 15-Nov-2016
    End point description
    DoR was defined as the time from the first documented onset of confirmed PR or CR to the date of PD/relapse or death due to medulloblastoma. DoR was evaluated by local Investigator assessment per tumor response guidelines and criteria for Medulloblastoma. TMZ participants without an event prior to crossover were censored.
    End point type
    Secondary
    End point timeframe
    from date first participant randomized, 13-Sep-2013 to date of data cut-off, 15-Nov-2016
    End point values
    		 Sonidegib (LDE225) Children Sonidegib (LDE225) Adults Temozolomide (TMZ)
    Number of subjects analysed
    2
    16
    4
    Units: months
        median (confidence interval 95%)
    9999 (-9999 to 9999)
    8.5 (4.1 to 16.6)
    9999 (-9999 to 9999)
    No statistical analyses for this end point

    Secondary: Overall survival (OS) from date first participant randomized, 13-Sep-2013 to date of data cut-off, 15-Nov-2016

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    End point title
    		 Overall survival (OS) from date first participant randomized, 13-Sep-2013 to date of data cut-off, 15-Nov-2016
    End point description
    OS was defined as the time from date of randomization to date of death due to any cause. All deaths are considered, including deaths occurred after crossover for TMZ participants.
    End point type
    Secondary
    End point timeframe
    from date first participant randomized, 13-Sep-2013 to date of data cut-off, 15-Nov-2016
    End point values
    		 Sonidegib (LDE225) Children Sonidegib (LDE225) Adults Temozolomide (TMZ)
    Number of subjects analysed
    2
    16
    4
    Units: months
        median (confidence interval 95%)
    9999 (4.5 to 9999)
    9.5 (4.9 to 15.6)
    9999 (1.2 to 9999)
    No statistical analyses for this end point

    Secondary: Pharmacokinetics (PK): Summary of plasma trough concentrations for Sonidegib (LDE225)

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    End point title
    		 Pharmacokinetics (PK): Summary of plasma trough concentrations for Sonidegib (LDE225) [2]
    End point description
    Blood samples were collected for assessment. The children's group was analyzed up until week 25 only.
    End point type
    Secondary
    End point timeframe
    Weeks 1, 3, 5, 7, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49 and 53
    Notes
    [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 Temozolomide arm was not analyzed at this milestone.
    End point values
    		 Sonidegib (LDE225) Children Sonidegib (LDE225) Adults
    Number of subjects analysed
    2
    13
    Units: ng/mL
    arithmetic mean (standard deviation)
        Week 1 (n=2,11)
    0 ± 0
    0 ± 0
        Week 3 (n=2,10)
    2890 ± 1240
    761 ± 519
        Week 5 (n=2,8)
    4930 ± 1380
    1090 ± 700
        Week 7 (n=1,8)
    2810 ± 9999
    1450 ± 842
        Week 9 (n=1,8)
    4670 ± 9999
    1530 ± 682
        Week 13 (n=1,4)
    3680 ± 9999
    2330 ± 1100
        Week 17 (n=1,6)
    3060 ± 9999
    1880 ± 730
        Week 21 (n=1,5)
    3770 ± 9999
    2270 ± 915
        Week 25 (n=1,4)
    1890 ± 9999
    2050 ± 625
        Week 29 (n=NA,4)
    9999 ± 9999
    2050 ± 906
        Week 33 (n=NA,4)
    9999 ± 9999
    2180 ± 512
        Week 37 (n=NA,3)
    9999 ± 9999
    2850 ± 306
        Week 41 (n=NA,4)
    9999 ± 9999
    2370 ± 916
        Week 45 (n=NA,2)
    9999 ± 9999
    2890 ± 290
        Week 49 (n=NA,2)
    9999 ± 9999
    2330 ± 990
        Week 53 (n=NA,2)
    9999 ± 9999
    2080 ± 764
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All adverse events reported in this record are from date of First Patient First Treatment until Last Patient Last Visit.
    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
    19.0
    Reporting groups
    Reporting group title
    Sonidegib (Children)
    Reporting group description
    		 Sonidegib (Children)

    Reporting group title
    Temozolomide
    Reporting group description
    		 Temozolomide

    Reporting group title
    Sonidegib (Total)
    Reporting group description
    		 Sonidegib (Total)

    Reporting group title
    Sonidegib (Adult)
    Reporting group description
    		 Sonidegib (Adult)

    Serious adverse events
    		 Sonidegib (Children) Temozolomide Sonidegib (Total) Sonidegib (Adult)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 2 (100.00%)
    1 / 4 (25.00%)
    11 / 18 (61.11%)
    9 / 16 (56.25%)
         number of deaths (all causes)
    1
    1
    12
    11
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Investigations
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BLOOD CREATINE PHOSPHOKINASE INCREASED
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    2 / 18 (11.11%)
    2 / 16 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    EMBOLISM
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    SEIZURE
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    GENERAL PHYSICAL HEALTH DETERIORATION
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PAIN
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    NAUSEA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    VOMITING
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    2 / 18 (11.11%)
    2 / 16 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    COUGH
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DYSPNOEA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    CONFUSIONAL STATE
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DRUG DEPENDENCE
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    HALLUCINATION
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    BACK PAIN
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    NECK PAIN
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Infections and infestations
    BACTERIAL SEPSIS
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CLOSTRIDIAL INFECTION
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LUNG INFECTION
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    SEPSIS
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Product issues
    THROMBOSIS IN DEVICE
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    DEHYDRATION
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HYPERNATRAEMIA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HYPONATRAEMIA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Sonidegib (Children) Temozolomide Sonidegib (Total) Sonidegib (Adult)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 2 (100.00%)
    4 / 4 (100.00%)
    18 / 18 (100.00%)
    16 / 16 (100.00%)
    Vascular disorders
    HAEMATOMA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    HYPERTENSION
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    HYPOTENSION
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    2 / 18 (11.11%)
    2 / 16 (12.50%)
         occurrences all number
    0
    0
    2
    2
    THROMBOSIS
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    1
    0
    General disorders and administration site conditions
    ASTHENIA
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    2 / 18 (11.11%)
    2 / 16 (12.50%)
         occurrences all number
    0
    1
    2
    2
    FATIGUE
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 4 (50.00%)
    7 / 18 (38.89%)
    7 / 16 (43.75%)
         occurrences all number
    0
    2
    9
    9
    GAIT DISTURBANCE
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    OEDEMA PERIPHERAL
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    2 / 18 (11.11%)
    2 / 16 (12.50%)
         occurrences all number
    0
    1
    2
    2
    NON-CARDIAC CHEST PAIN
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    PAIN
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    2 / 18 (11.11%)
    2 / 16 (12.50%)
         occurrences all number
    0
    0
    2
    2
    PYREXIA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    2 / 18 (11.11%)
    2 / 16 (12.50%)
         occurrences all number
    0
    0
    3
    3
    Immune system disorders
    ALLERGY TO ARTHROPOD BITE
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    Respiratory, thoracic and mediastinal disorders
    APNOEA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    ATELECTASIS
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    COUGH
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    2 / 18 (11.11%)
    2 / 16 (12.50%)
         occurrences all number
    0
    0
    2
    2
    DYSPNOEA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    EPISTAXIS
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    PRODUCTIVE COUGH
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    PNEUMONITIS
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    Psychiatric disorders
    DELIRIUM
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    2 / 18 (11.11%)
    2 / 16 (12.50%)
         occurrences all number
    0
    0
    2
    2
    CONFUSIONAL STATE
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    2 / 18 (11.11%)
    2 / 16 (12.50%)
         occurrences all number
    0
    0
    2
    2
    DEPRESSION
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    2 / 18 (11.11%)
    2 / 16 (12.50%)
         occurrences all number
    0
    0
    2
    2
    INSOMNIA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    3 / 18 (16.67%)
    3 / 16 (18.75%)
         occurrences all number
    0
    0
    3
    3
    IRRITABILITY
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    Investigations
    ACTIVATED PARTIAL THROMBOPLASTIN TIME PROLONGED
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    3 / 18 (16.67%)
    3 / 16 (18.75%)
         occurrences all number
    0
    0
    3
    3
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    2 / 18 (11.11%)
    2 / 16 (12.50%)
         occurrences all number
    0
    0
    2
    2
    BLOOD ALKALINE PHOSPHATASE INCREASED
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    BLOOD CREATINE PHOSPHOKINASE INCREASED
         subjects affected / exposed
    1 / 2 (50.00%)
    1 / 4 (25.00%)
    8 / 18 (44.44%)
    7 / 16 (43.75%)
         occurrences all number
    1
    1
    9
    8
    BLOOD CREATINE PHOSPHOKINASE MB INCREASED
         subjects affected / exposed
    1 / 2 (50.00%)
    1 / 4 (25.00%)
    2 / 18 (11.11%)
    1 / 16 (6.25%)
         occurrences all number
    1
    1
    2
    1
    BLOOD CREATININE INCREASED
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    3 / 18 (16.67%)
    3 / 16 (18.75%)
         occurrences all number
    0
    0
    4
    4
    BLOOD PHOSPHORUS INCREASED
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    BODY TEMPERATURE INCREASED
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    C-REACTIVE PROTEIN INCREASED
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    GRANULOCYTE COUNT INCREASED
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    CRYSTAL URINE PRESENT
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    OXYGEN SATURATION DECREASED
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    LYMPHOCYTE COUNT DECREASED
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    5 / 18 (27.78%)
    5 / 16 (31.25%)
         occurrences all number
    0
    1
    6
    6
    PLATELET COUNT DECREASED
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    2
    2
    RED BLOOD CELL COUNT DECREASED
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    PROTHROMBIN TIME PROLONGED
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    RED BLOOD CELL SEDIMENTATION RATE INCREASED
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    WEIGHT DECREASED
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    2 / 18 (11.11%)
    2 / 16 (12.50%)
         occurrences all number
    0
    1
    4
    4
    WHITE BLOOD CELL COUNT DECREASED
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    Cardiac disorders
    ATRIOVENTRICULAR BLOCK FIRST DEGREE
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    SINUS TACHYCARDIA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    2 / 18 (11.11%)
    2 / 16 (12.50%)
         occurrences all number
    0
    0
    2
    2
    Nervous system disorders
    APHASIA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    2 / 18 (11.11%)
    2 / 16 (12.50%)
         occurrences all number
    0
    0
    3
    3
    DEPRESSED LEVEL OF CONSCIOUSNESS
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    CEREBROSPINAL FLUID LEAKAGE
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    ATAXIA
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    1
    1
    DIZZINESS
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    3 / 18 (16.67%)
    3 / 16 (18.75%)
         occurrences all number
    0
    1
    3
    3
    DROOLING
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    DYSARTHRIA
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    1
    1
    DYSGEUSIA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    5 / 18 (27.78%)
    5 / 16 (31.25%)
         occurrences all number
    0
    0
    6
    6
    FACIAL NERVE DISORDER
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    HEADACHE
         subjects affected / exposed
    2 / 2 (100.00%)
    1 / 4 (25.00%)
    5 / 18 (27.78%)
    3 / 16 (18.75%)
         occurrences all number
    2
    1
    6
    4
    HEMIPARESIS
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    IIIRD NERVE DISORDER
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    LETHARGY
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    MUSCLE SPASTICITY
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 4 (0.00%)
    2 / 18 (11.11%)
    1 / 16 (6.25%)
         occurrences all number
    1
    0
    2
    1
    MYOCLONUS
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    NEUROPATHY PERIPHERAL
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    2 / 18 (11.11%)
    2 / 16 (12.50%)
         occurrences all number
    0
    0
    2
    2
    NYSTAGMUS
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    PARAESTHESIA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    PERIPHERAL MOTOR NEUROPATHY
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    PYRAMIDAL TRACT SYNDROME
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    SCIATICA
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    SYNCOPE
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    SOMNOLENCE
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    3 / 18 (16.67%)
    3 / 16 (18.75%)
         occurrences all number
    0
    0
    4
    4
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    2 / 18 (11.11%)
    2 / 16 (12.50%)
         occurrences all number
    0
    0
    3
    3
    THROMBOCYTOPENIA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    Ear and labyrinth disorders
    EAR CONGESTION
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    VERTIGO
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    Eye disorders
    DIPLOPIA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    PHOTOPHOBIA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    VISION BLURRED
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    Gastrointestinal disorders
    ABDOMINAL DISTENSION
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    ABDOMINAL PAIN
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    2 / 18 (11.11%)
    2 / 16 (12.50%)
         occurrences all number
    0
    2
    2
    2
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    AEROPHAGIA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    ANAL INCONTINENCE
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    CONSTIPATION
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    6 / 18 (33.33%)
    6 / 16 (37.50%)
         occurrences all number
    0
    1
    7
    7
    DYSPHAGIA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    DIARRHOEA
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 4 (0.00%)
    4 / 18 (22.22%)
    3 / 16 (18.75%)
         occurrences all number
    1
    0
    5
    4
    PARAESTHESIA ORAL
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    NAUSEA
         subjects affected / exposed
    0 / 2 (0.00%)
    3 / 4 (75.00%)
    5 / 18 (27.78%)
    5 / 16 (31.25%)
         occurrences all number
    0
    4
    9
    9
    HAEMATOCHEZIA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    TOOTH LOSS
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    TOOTH DISCOLOURATION
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    REGURGITATION
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    VOMITING
         subjects affected / exposed
    2 / 2 (100.00%)
    1 / 4 (25.00%)
    9 / 18 (50.00%)
    7 / 16 (43.75%)
         occurrences all number
    4
    1
    15
    11
    Skin and subcutaneous tissue disorders
    DERMATITIS ACNEIFORM
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    1
    1
    ALOPECIA
         subjects affected / exposed
    2 / 2 (100.00%)
    0 / 4 (0.00%)
    8 / 18 (44.44%)
    6 / 16 (37.50%)
         occurrences all number
    2
    0
    8
    6
    DRY SKIN
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    HYPERHIDROSIS
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    ERYTHEMA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    PRURITUS
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    RASH
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    RASH MACULO-PAPULAR
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    Renal and urinary disorders
    HAEMATURIA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    MICTURITION URGENCY
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    PROTEINURIA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    URINARY RETENTION
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    Endocrine disorders
    DIABETES INSIPIDUS
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    BACK PAIN
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    4 / 18 (22.22%)
    4 / 16 (25.00%)
         occurrences all number
    0
    0
    4
    4
    MUSCLE SPASMS
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    4 / 18 (22.22%)
    4 / 16 (25.00%)
         occurrences all number
    0
    0
    4
    4
    MYALGIA
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 4 (0.00%)
    6 / 18 (33.33%)
    5 / 16 (31.25%)
         occurrences all number
    1
    0
    8
    7
    NECK PAIN
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    3 / 18 (16.67%)
    3 / 16 (18.75%)
         occurrences all number
    0
    1
    3
    3
    PAIN IN EXTREMITY
         subjects affected / exposed
    1 / 2 (50.00%)
    1 / 4 (25.00%)
    3 / 18 (16.67%)
    2 / 16 (12.50%)
         occurrences all number
    1
    1
    3
    2
    Infections and infestations
    ACINETOBACTER INFECTION
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    FOLLICULITIS
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    2 / 18 (11.11%)
    2 / 16 (12.50%)
         occurrences all number
    0
    0
    2
    2
    ORAL HERPES
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    1
    0
    RHINITIS
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    URINARY TRACT INFECTION
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    4 / 18 (22.22%)
    4 / 16 (25.00%)
         occurrences all number
    0
    0
    5
    5
    Metabolism and nutrition disorders
    DECREASED APPETITE
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    4 / 18 (22.22%)
    4 / 16 (25.00%)
         occurrences all number
    0
    0
    5
    5
    FAILURE TO THRIVE
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    HYPERCALCAEMIA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    HYPERGLYCAEMIA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    2
    2
    HYPERURICAEMIA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    HYPOALBUMINAEMIA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    HYPOCALCAEMIA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    3 / 18 (16.67%)
    3 / 16 (18.75%)
         occurrences all number
    0
    0
    3
    3
    HYPOMAGNESAEMIA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    2 / 18 (11.11%)
    2 / 16 (12.50%)
         occurrences all number
    0
    0
    2
    2
    HYPONATRAEMIA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    3 / 18 (16.67%)
    3 / 16 (18.75%)
         occurrences all number
    0
    0
    5
    5
    HYPOKALAEMIA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    4 / 18 (22.22%)
    4 / 16 (25.00%)
         occurrences all number
    0
    0
    4
    4
    HYPOPHOSPHATAEMIA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    2 / 18 (11.11%)
    2 / 16 (12.50%)
         occurrences all number
    0
    0
    2
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Sep 2013
    Protocol Version 1/Amendment 1 was issued before an eligible patient was identified. Key changes included: • Specifying a minimum number of pediatric patients • Addition of an exploratory objective to assess effects on bone and cartilage markers for pediatric patients • Collection of additional data (Tanner staging and age at menarche) to support interpretation of bone growth plate assessments in pediatric patients
    17 Apr 2014
    Protocol Version 2/Amendment 2 was issued after 11 patients (ten adults and one pediatric patient) had been enrolled and treated. Protocol Version 2 reduced the scope of the study to a single-arm Phase II study and decreased the total number of patients to be enrolled to 20. While the original estimation of Hh pathway mutation rate in patients with MB was approximately 20% – 30%, of 79 pediatric patients screened for Hh activation to date, approximately 5% were Hh-activated. In addition, many potential patients had a prior history of treatment with temozolomide, which led to an imbalance in patients eligible for the randomized arms. Other key changes included • All patients who had been assigned to the temozolomide arm were switched to sonidegib treatment • The time period for which women of child-bearing potential were required to use highly effective contraception after the final dose of study treatment was increased to 20 months • Guidance on management of suspected sonidegib-related toxicity was updated with respect to musculoskeletal toxicities.
    22 Jun 2015
    Protocol Version 3/Amendment 3 (22-Jun-2015) was issued when enrollment in the study was completed (total enrollment 22 patients) and five patients remained on study treatment. The purpose was to allow patients who were deriving clinical benefit according to the Investigator, to continue to receive sonidegib until discontinuation criteria were met or until other alternatives became available. The timing of the final analysis was changed to the point when all patients have discontinued the study treatment and completed the 30-day Safety Follow-up Period. Other key changes follow: • Several assessments that were collected and evaluated (tumor assessment, neurological assessment, lumbar puncture assessment, steroid use information, ECG) by ICR were to be reviewed locally after study Week 105 • The frequency of study visits and evaluations after Week 105 was changed to every 12 weeks • The schedule of assessments was modified for visits after Week 105 so that physical exam, weight, vital signs, ECG, and performance status assessments were performed per local standard of care • The dose modification table for CK was replaced with the program level updates (urine myoglobin and muscle biopsy were no longer applicable) These amendments affected the interpretation of study results per the initial design, as only four patients had been enrolled in the comparator arm (temozolomide) before the study was changed from a two-arm comparative study to a single-arm study.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

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

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