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    Clinical Trial Results:
    A Phase Ib/II, open-label, multi-center study of INC280 in combination with buparlisib in adult patients with recurrent glioblastoma

    Summary
    EudraCT number
    		 2013-000699-14
    Trial protocol
    		 NL   ES  
    Global end of trial date
    23 Dec 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 Dec 2017
    First version publication date
    24 Dec 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CINC280X2204
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01870726
    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, Novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    23 Dec 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 Dec 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Dec 2016
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of the Phase Ib part was to estimate the maximum tolerated dose (MTD) and/or to identify the recommended Phase II dose (RP2D) for the combination of INC280 and buparlisib. The primary objective of the Phase II part of the study w as to estimate the clinical efficacy and safety of INC280 as a single agent and in combination with buparlisib. The primary objective of the surgical arm was to determine the PK/PD profile of the study treatment.
    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
    09 Jan 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Switzerland: 2
    Country: Number of subjects enrolled
    Netherlands: 13
    Country: Number of subjects enrolled
    Germany: 8
    Country: Number of subjects enrolled
    Spain: 11
    Country: Number of subjects enrolled
    United States: 9
    Worldwide total number of subjects
    43
    EEA total number of subjects
    32
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    35
    From 65 to 84 years
    8
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 33 patients were enrolled into the Phase Ib part of the study. Patients were assigned to 6 dose combinations of INC280 with buparlisib. In the Phase II part of the study, 10 patients were enrolled.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 200 mg BID Cap+50 mg QD
    Arm description
    		 Phase Ib: The combination of 200mg INC280 (BID) capsule and 50 mg Buparlisib (QD) once daily for Phase Ib.
    Arm type
    		 Experimental

    Investigational medicinal product name
    INC280 and Buparlisib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    The combination of 200mg INC280 capsule and 50 mg Buparlisib once daily for Phase Ib.

    Arm title
    		 400 mg BID Cap+50 mg QD
    Arm description
    		 Phase Ib: The combination of 400 mg INC280 (BID) capsule and 50mg Buparlisib (QD) once daily for Phase Ib.
    Arm type
    		 Experimental

    Investigational medicinal product name
    INC280 and Buparlisib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    The combination of 400mg INC280 capsule and 50 mg Buparlisib once daily for Phase Ib.

    Arm title
    		 500 mg BID Cap+50 mg QD
    Arm description
    		 Phase Ib: The combination of 500 mg INC280 (BID) capsule and 50mg Buparlisib (QD) once daily for Phase Ib.
    Arm type
    		 Experimental

    Investigational medicinal product name
    INC280 and Buparlisib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    The combination of 500mg INC280 capsule and 50 mg Buparlisib once daily for Phase Ib.

    Arm title
    		 500 mg BID Cap+80 mg QD
    Arm description
    		 Phase Ib: The combination of 500 mg INC280 (BID) capsule and 80mg Buparlisib (QD) once daily for Phase Ib.
    Arm type
    		 Experimental

    Investigational medicinal product name
    INC280 and Buparlisib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    The combination of 500mg INC280 capsule and 80 mg Buparlisib once daily for Phase Ib.

    Arm title
    		 300 mg BID Tab +80 mg QD
    Arm description
    		 Phase Ib: The combination of 300 mg INC280 (BID) tablet and 80mg Buparlisib (QD) once daily for Phase Ib.
    Arm type
    		 Experimental

    Investigational medicinal product name
    INC280 and Buparlisib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The combination of 300mg INC280 tablet and 80 mg Buparlisib once daily for Phase Ib.

    Arm title
    		 400 mg BID Tab +80 mg QD
    Arm description
    		 Phase Ib: The combination of 400 mg INC280 (BID) tablet and 80mg Buparlisib (QD) once daily for Phase Ib.
    Arm type
    		 Experimental

    Investigational medicinal product name
    INC280 and Buparlisib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The combination of 400mg INC280 tablet and 80 mg Buparlisib once daily for Phase Ib.

    Arm title
    		 400 mg BID Tab
    Arm description
    		 Phase II: 400 mg INC280 (BID) tablet
    Arm type
    		 Experimental

    Investigational medicinal product name
    INC280
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    400mg INC280 tablet

    Number of subjects in period 1
    		200 mg BID Cap+50 mg QD 400 mg BID Cap+50 mg QD 500 mg BID Cap+50 mg QD 500 mg BID Cap+80 mg QD 300 mg BID Tab +80 mg QD 400 mg BID Tab +80 mg QD 400 mg BID Tab
    Started
    5
    6
    4
    6
    7
    5
    10
    Completed
    0
    0
    0
    0
    0
    0
    0
    Not completed
    5
    6
    4
    6
    7
    5
    10
         Consent withdrawn by subject
    -
    1
    -
    -
    -
    -
    -
         Adverse event, non-fatal
    -
    -
    -
    -
    1
    1
    -
         Progressive disease
    5
    5
    4
    5
    6
    4
    10
         Withdrawal of informed consent
    -
    -
    -
    1
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    200 mg BID Cap+50 mg QD
    Reporting group description
    		 Phase Ib: The combination of 200mg INC280 (BID) capsule and 50 mg Buparlisib (QD) once daily for Phase Ib.

    Reporting group title
    400 mg BID Cap+50 mg QD
    Reporting group description
    		 Phase Ib: The combination of 400 mg INC280 (BID) capsule and 50mg Buparlisib (QD) once daily for Phase Ib.

    Reporting group title
    500 mg BID Cap+50 mg QD
    Reporting group description
    		 Phase Ib: The combination of 500 mg INC280 (BID) capsule and 50mg Buparlisib (QD) once daily for Phase Ib.

    Reporting group title
    500 mg BID Cap+80 mg QD
    Reporting group description
    		 Phase Ib: The combination of 500 mg INC280 (BID) capsule and 80mg Buparlisib (QD) once daily for Phase Ib.

    Reporting group title
    300 mg BID Tab +80 mg QD
    Reporting group description
    		 Phase Ib: The combination of 300 mg INC280 (BID) tablet and 80mg Buparlisib (QD) once daily for Phase Ib.

    Reporting group title
    400 mg BID Tab +80 mg QD
    Reporting group description
    		 Phase Ib: The combination of 400 mg INC280 (BID) tablet and 80mg Buparlisib (QD) once daily for Phase Ib.

    Reporting group title
    400 mg BID Tab
    Reporting group description
    		 Phase II: 400 mg INC280 (BID) tablet

    Reporting group values
    		 200 mg BID Cap+50 mg QD 400 mg BID Cap+50 mg QD 500 mg BID Cap+50 mg QD 500 mg BID Cap+80 mg QD 300 mg BID Tab +80 mg QD 400 mg BID Tab +80 mg QD 400 mg BID Tab Total
    Number of subjects
    		 5 6 4 6 7 5 10 43
    Age Categorical
    Units: Subjects
        <=18 years
    		 0 0 0 0 0 0 0 0
        Between 18 and 65 years
    		 2 6 4 5 4 4 10 35
        >=65 years
    		 3 0 0 1 3 1 0 8
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 59.2 ( 10.03 ) 48.0 ( 12.43 ) 56.0 ( 3.56 ) 52.0 ( 13.48 ) 63.0 ( 10.08 ) 60.4 ( 5.50 ) 47.6 ( 11.06 ) -
    Gender, Male/Female
    Units: Subjects
        Female
    		 0 2 2 3 0 2 7 16
        Male
    		 5 4 2 3 7 3 3 27

    End points

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    End points reporting groups
    Reporting group title
    200 mg BID Cap+50 mg QD
    Reporting group description
    		 Phase Ib: The combination of 200mg INC280 (BID) capsule and 50 mg Buparlisib (QD) once daily for Phase Ib.

    Reporting group title
    400 mg BID Cap+50 mg QD
    Reporting group description
    		 Phase Ib: The combination of 400 mg INC280 (BID) capsule and 50mg Buparlisib (QD) once daily for Phase Ib.

    Reporting group title
    500 mg BID Cap+50 mg QD
    Reporting group description
    		 Phase Ib: The combination of 500 mg INC280 (BID) capsule and 50mg Buparlisib (QD) once daily for Phase Ib.

    Reporting group title
    500 mg BID Cap+80 mg QD
    Reporting group description
    		 Phase Ib: The combination of 500 mg INC280 (BID) capsule and 80mg Buparlisib (QD) once daily for Phase Ib.

    Reporting group title
    300 mg BID Tab +80 mg QD
    Reporting group description
    		 Phase Ib: The combination of 300 mg INC280 (BID) tablet and 80mg Buparlisib (QD) once daily for Phase Ib.

    Reporting group title
    400 mg BID Tab +80 mg QD
    Reporting group description
    		 Phase Ib: The combination of 400 mg INC280 (BID) tablet and 80mg Buparlisib (QD) once daily for Phase Ib.

    Reporting group title
    400 mg BID Tab
    Reporting group description
    		 Phase II: 400 mg INC280 (BID) tablet

    Subject analysis set title
    400 mg BID Tab+80 mg QD
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Phase Ib: The combination of 400 mg INC280 (BID) tablet and 80mg Buparlisib (QD) once daily for Phase Ib.

    Subject analysis set title
    BID Tab+Buparlisib
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Phase II: INC280 (BID) as a single agent and in combination with buparlisib

    Subject analysis set title
    BID + QD
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The combination of INC280 (BID) and Buparlisib (QD).

    Subject analysis set title
    300 mg BID Tab + 80 mg QD
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Phase Ib: The combination of 300 mg INC280 (BID) tablet and 80mg Buparlisib (QD) once daily for Phase Ib.

    Subject analysis set title
    400 mg BID Tab + 80 mg QD
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Phase Ib: the combination of 400 mg INC280 (BID) tablet and 80 mg Buparlisib (QD) once daily

    Subject analysis set title
    400 mg BID Tab+80 mg QD
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Phase Ib: The combination of 400 mg INC280 (BID) tablet and 80mg Buparlisib (QD) once daily for Phase Ib.

    Subject analysis set title
    400 mg BID Tab+80 mg QD
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Phase Ib: The combination of 400 mg INC280 (BID) capsule and 80mg Buparlisib (QD) once daily for Phase Ib.

    Subject analysis set title
    All Patients
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The combination of INC280 (BID) and Buparlisib (QD).

    Primary: Incidence of dose limiting toxicities (DLTs) in Cycle 1

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    End point title
    		 Incidence of dose limiting toxicities (DLTs) in Cycle 1 [1] [2]
    End point description
    A DLT is defined as an adverse event or abnormal laboratory value where the relationship to study treatment cannot be ruled out, and is not primarily related to disease, disease progression, inter-current illness, or concomitant medications that occurs within the first cycle of treatment (28 days) with INC280 in combination with buparlisib and meets any of the pre-defined criteria. Analysis was done in the dose-determining set (DDS). The DDS consisted of all patients from the SAS who either met the following minimum exposure criterion and had sufficient safety evaluations during cycle 1, or discontinued earlier due to DLT during Cycle 1: A patient was considered to have met the minimum exposure criterion if they had received at least 21 out of the 28 planned daily combo doses of INC280 and buparlisib (once daily) in the first 28 days of dosing.
    End point type
    Primary
    End point timeframe
    Cycle 1
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No comparative statistical analysis was conducted for this endpoint. The relationship between dose and the probability of DLT was modeled using adaptive Bayesian logistic regression model with overdose control principle. MTD was declared at INC280 300mg bid + BKM120 80mg qd. RP2D was not be declared.
    [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: Only treatment groups which are part of dose determining set are included.
    End point values
    		 200 mg BID Cap+50 mg QD 400 mg BID Cap+50 mg QD 500 mg BID Cap+50 mg QD 500 mg BID Cap+80 mg QD 300 mg BID Tab +80 mg QD 400 mg BID Tab +80 mg QD
    Number of subjects analysed
    4
    5
    3
    4
    7
    4
    Units: Number of Patients
        Personality Change
    0
    1
    0
    0
    0
    0
        Nausea
    0
    0
    0
    0
    1
    0
        Aspartate Aminotransferase Increased
    0
    0
    0
    0
    0
    2
    No statistical analyses for this end point

    Primary: Phase II: Progression free survival rate (PFSR)

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    End point title
    		 Phase II: Progression free survival rate (PFSR) [3]
    End point description
    Estimated rate of patients treated during 6 months without experiencing disease progression.
    End point type
    Primary
    End point timeframe
    6 months
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Due to early termination, no statistical analysis was planned for this endpoint.
    End point values
    		 BID Tab+Buparlisib
    Number of subjects analysed
    0 [4]
    Units: Percentages of participants
    Notes
    [4] - PFS was not performed due to an insufficient number of patients enrolled.
    No statistical analyses for this end point

    Primary: Phase II Surgical arm: Concentrations of INC280 and buparlisib in tumor

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    End point title
    		 Phase II Surgical arm: Concentrations of INC280 and buparlisib in tumor [5]
    End point description
    Concentrations of INC280 and buparlisib in tumor tissue.
    End point type
    Primary
    End point timeframe
    7 days
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Due to early termination, no statistical analysis was planned for this endpoint.
    End point values
    		 BID + QD
    Number of subjects analysed
    0 [6]
    Units: mmol/L
    Notes
    [6] - A RP2D was not determined and phase II combination arms were not opened.
    No statistical analyses for this end point

    Secondary: Overview of Adverse Events

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    End point title
    		 Overview of Adverse Events
    End point description
    To characterize the safety of INC280 single agent and in combination with buparlisib including type, frequency, severity of adverse events, serious adverse events, and dose interruptions and adjustments. Analysis was done in the safety analysis set (SAS). The SAS comprised all patients who received at least one full or partial dose of study treatment. Patients were analyzed according to the treatment actually received. The SAS was used for all safety analyses.
    End point type
    Secondary
    End point timeframe
    Throughout the duration of the trial, approximately 3 years from FPFV to LPLV.
    End point values
    		 200 mg BID Cap+50 mg QD 400 mg BID Cap+50 mg QD 500 mg BID Cap+50 mg QD 500 mg BID Cap+80 mg QD 300 mg BID Tab +80 mg QD 400 mg BID Tab +80 mg QD 400 mg BID Tab
    Number of subjects analysed
    5
    6
    4
    6
    7
    5
    9
    Units: Participants
        Adverse events
    5
    6
    4
    6
    7
    5
    9
        Treatment-related AEs
    4
    4
    4
    4
    7
    5
    6
        AEs with grade ≥ 3
    5
    4
    4
    2
    5
    4
    8
        SAEs
    3
    2
    3
    3
    3
    4
    2
        AEs leading to discontinuation
    0
    0
    0
    0
    1
    1
    0
        AEs leading to dose adjustment/interruption
    2
    3
    2
    4
    4
    4
    5
        AEs requiring additional therapy
    4
    5
    3
    5
    7
    5
    7
    No statistical analyses for this end point

    Secondary: Pharmacokinetic profile of INC280 - AUCtau

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    End point title
    		 Pharmacokinetic profile of INC280 - AUCtau [7]
    End point description
    Plasma concentration profile of INC280 in combination with Buparlisib. AUCtau is the AUC from time zero to the end of dosing interval. Analysis was done in the pharmacokinetic analysis set (PAS). The PAS consisted of all patients who provided an evaluable PK profile. A profile was considered evaluable if all of the following conditions were satisfied: 1) Patient received one of the planned treatments of both study drugs 2) For PK samples taken on Cycle 1 Day 15 and Cycle 2 Day 1, patient took the same dose of INC280 for at least three consecutive days and the same dose of buparlisib for at least seven consecutive days prior to sampling 3) Patients provided at least one primary PK parameter of either INC280 or buparlisib 4) Patient did not vomit within four hours after the dosing of INC280 and/or buparlisib The respective PAS was used for the analysis and listings of the PK derived parameters.
    End point type
    Secondary
    End point timeframe
    Cycle 1 to cycle 6, approximately 6 months
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only treatment groups which are part of Pharmacokinetic analysis set are included.
    End point values
    		 200 mg BID Cap+50 mg QD 400 mg BID Cap+50 mg QD 500 mg BID Cap+50 mg QD 500 mg BID Cap+80 mg QD 300 mg BID Tab +80 mg QD 400 mg BID Tab +80 mg QD
    Number of subjects analysed
    5
    5
    4
    6
    4
    5
    Units: hr*ng/ml
    median (full range (min-max))
        Cycle 1 Day 1
    2435.6 (1870.1 to 4978.4)
    3005.9 (1010.1 to 5581.5)
    4789.7 (1716.5 to 8086.8)
    5071.7 (2463.8 to 8018.8)
    5732.2 (1657.2 to 8924.7)
    11127.7 (2978.35 to 13776.6)
        Cycle 1 Day 15
    5749.3 (4045.6 to 10405.8)
    11261.7 (3069.8 to 13946.9)
    10581.0 (6276.0 to 31532.5)
    2779.4 (1940.8 to 3618.0)
    12801.3 (8606.0 to 16381.0)
    16590.6 (11576.1 to 17422.8)
        Cycle 2 Day 1
    4894.6 (3880.4 to 7192.8)
    2655.6 (2655.6 to 2655.6)
    23498.3 (19903.7 to 27092.8)
    10554.3 (4793.3 to 14289.7)
    9593.5 (7002.3 to 12184.7)
    13051.1 (13051.1 to 13051.1)
    No statistical analyses for this end point

    Secondary: Pharmacokinetic profile of INC280 - Cmax

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    End point title
    		 Pharmacokinetic profile of INC280 - Cmax [8]
    End point description
    Plasma concentration profile of INC280 in combination with Buparlisib. Cmax is the Maximum (peak) observed drug concentration after dose administration. Analysis was done in the pharmacokinetic analysis set (PAS).
    End point type
    Secondary
    End point timeframe
    Cycle 1 to cycle 6, approximately 6 months
    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: Only treatment groups which are part of Pharmacokinetic analysis set are included.
    End point values
    		 200 mg BID Cap+50 mg QD 400 mg BID Cap+50 mg QD 500 mg BID Cap+50 mg QD 500 mg BID Cap+80 mg QD 300 mg BID Tab +80 mg QD 400 mg BID Tab +80 mg QD
    Number of subjects analysed
    5
    5
    4
    6
    4
    5
    Units: ng/ml
    median (full range (min-max))
        Cycle 1 Day 1
    618.0 (406.0 to 1680.0)
    880.0 (219.0 to 1410.0)
    960.5 (434.0 to 2510.0)
    860.0 (195.0 to 2770.0)
    1990.0 (423.0 to 2510.0)
    3635.0 (1210.0 to 4640.0)
        Cycle 1 Day 15
    1560.0 (745.0 to 2610.0)
    2005.0 (763.0 to 3930.0)
    3480.0 (1350.0 to 8350.0)
    545.5 (315.0 to 776.0)
    3610.0 (2320.0 to 4940.0)
    4850.0 (1800.0 to 5350.0)
        Cycle 2 Day 1
    1200.0 (578.0 to 1540.0)
    2142.5 (675.0 to 3610.0)
    5010.0 (4230.0 to 5790.0)
    2254.5 (479.0 to 3740.0)
    3080.0 (2720.0 to 3440.0)
    3220.0 (3220.0 to 3220.0)
    No statistical analyses for this end point

    Secondary: Pharmacokinetic profile of INC280 - Tmax

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    End point title
    		 Pharmacokinetic profile of INC280 - Tmax [9]
    End point description
    Plasma concentration profile of INC280 in combination with Buparlisib. Tmax is the time to reach maximum (peak) observed concentration (Cmax) after dose administration. Analysis was done in the pharmacokinetic analysis set (PAS).
    End point type
    Secondary
    End point timeframe
    Cycle 1 to cycle 6, approximately 6 months
    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: Only treatment groups which are part of Pharmacokinetic analysis set are included.
    End point values
    		 200 mg BID Cap+50 mg QD 400 mg BID Cap+50 mg QD 500 mg BID Cap+50 mg QD 500 mg BID Cap+80 mg QD 300 mg BID Tab +80 mg QD 400 mg BID Tab +80 mg QD
    Number of subjects analysed
    5
    5
    4
    6
    4
    5
    Units: hr
    median (full range (min-max))
        Cycle 1 Day 1
    1.1 (1.0 to 2.0)
    2.0 (2.0 to 4.0)
    1.5 (1.0 to 2.2)
    1.3 (1.1 to 4.0)
    1.6 (1.0 to 2.2)
    2.0 (0.9 to 2.0)
        Cycle 1 Day 15
    1.9 (0.9 to 2.0)
    2.0 (1.0 to 2.1)
    2.0 (1.0 to 2.1)
    2.6 (1.2 to 4.0)
    1.0 (1.0 to 1.0)
    1.5 (1.0 to 2.1)
        Cycle 2 Day 1
    2.0 (1.0 to 4.0)
    2.0 (2.0 to 2.0)
    1.5 (1.0 to 2.1)
    2.1 (1.5 to 4.0)
    1.5 (1.0 to 2.0)
    1.0 (1.0 to 1.0)
    No statistical analyses for this end point

    Secondary: Pharmacokinetic profile of INC280 - T1/2

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    End point title
    		 Pharmacokinetic profile of INC280 - T1/2 [10]
    End point description
    Plasma concentration profile of INC280 in combination with Buparlisib. T1/2 is the terminal half life. Analysis was done in the pharmacokinetic analysis set (PAS).
    End point type
    Secondary
    End point timeframe
    Cycle 1 to cycle 6, approximately 6 months
    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: Only treatment groups which are part of Pharmacokinetic analysis set are included.
    End point values
    		 200 mg BID Cap+50 mg QD 400 mg BID Cap+50 mg QD 500 mg BID Cap+50 mg QD 500 mg BID Cap+80 mg QD 300 mg BID Tab +80 mg QD 400 mg BID Tab +80 mg QD
    Number of subjects analysed
    5
    5
    4
    6
    4
    5
    Units: hr
    median (full range (min-max))
        Cycle 1 Day 15
    13.4 (4.1 to 31.2)
    20.8 (16.3 to 28.6)
    26.0 (13.2 to 28.1)
    7.3 (7.3 to 7.3)
    13.1 (7.0 to 19.3)
    8.0 (4.2 to 28.0)
        Cycle 2 Day 1
    9.9 (3.8 to 20.1)
    17.4 (17.4 to 17.4)
    26.3 (23.5 to 29.1)
    8.7 (5.8 to 11.5)
    6.3 (6.3 to 6.3)
    4.3 (4.3 to 4.3)
    No statistical analyses for this end point

    Secondary: Pharmacokinetic profile of Buparlisib - AUCtau

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    End point title
    		 Pharmacokinetic profile of Buparlisib - AUCtau [11]
    End point description
    Plasma concentration profile of INC280 in combination with Buparlisib. AUCtau is the AUC from time zero to the end of dosing interval. Analysis was done in the pharmacokinetic analysis set (PAS).
    End point type
    Secondary
    End point timeframe
    Cycle 1 to cycle 6, approximately 6 months
    Notes
    [11] - 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: Only treatment groups which are part of Pharmacokinetic analysis set are included.
    End point values
    		 200 mg BID Cap+50 mg QD 400 mg BID Cap+50 mg QD 500 mg BID Cap+50 mg QD 500 mg BID Cap+80 mg QD 300 mg BID Tab +80 mg QD 400 mg BID Tab +80 mg QD
    Number of subjects analysed
    5
    5
    4
    6
    4
    5
    Units: hr*ng/ml
    median (full range (min-max))
        Cycle 1 Day 1
    3072.0 (2119.7 to 3448.0)
    1865.0 (1383.2 to 3840.8)
    3328.2 (2830.2 to 4104.1)
    3825.8 (2784.0 to 5201.4)
    4425.3 (3109.8 to 5238.2)
    3658.8 (3347.7 to 5509.4)
        Cycle 1 Day 15
    8728.5 (4874.3 to 10962.7)
    4591.9 (3167.1 to 10562.3)
    6108.4 (5300.5 to 7605.5)
    10844.6 (6761.7 to 14927.4)
    10366.5 (8257.8 to 11052.6)
    8535.1 (4102.2 to 8908.3)
        Cycle 2 Day 1
    7930.8 (3563.5 to 9712.2)
    3776.7 (3477.6 to 4075.7)
    6976.0 (3436.1 to 10515.9)
    5903.0 (4850.4 to 12072.9)
    7857.2 (7757.7 to 9361.9)
    7344.3 (7344.3 to 7344.3)
    No statistical analyses for this end point

    Secondary: Pharmacokinetic profile of Buparlisib - Cmax

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    End point title
    		 Pharmacokinetic profile of Buparlisib - Cmax [12]
    End point description
    Plasma concentration profile of INC280 in combination with Buparlisib. Cmax is the Maximum (peak) observed drug concentration after dose administration. Analysis was done in the pharmacokinetic analysis set (PAS).
    End point type
    Secondary
    End point timeframe
    Cycle 1 to cycle 6, approximately 6 months
    Notes
    [12] - 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: Only treatment groups which are part of Pharmacokinetic analysis set are included.
    End point values
    		 200 mg BID Cap+50 mg QD 400 mg BID Cap+50 mg QD 500 mg BID Cap+50 mg QD 500 mg BID Cap+80 mg QD 300 mg BID Tab +80 mg QD 400 mg BID Tab +80 mg QD
    Number of subjects analysed
    5
    5
    4
    6
    4
    5
    Units: ng/ml
    median (full range (min-max))
        Cycle 1 Day 1
    484.0 (234.0 to 590.0)
    351.0 (162.0 to 488.0)
    399.0 (347.0 to 469.0)
    522.0 (333.0 to 776.0)
    508.0 (373.0 to 711.0)
    475.0 (361.0 to 542.0)
        Cycle 1 Day 15
    664.0 (568.0 to 791.0)
    459.0 (294.0 to 623.0)
    542.0 (456.0 to 791.0)
    785.0 (684.0 to 886.0)
    814.0 (628.0 to 1330.0)
    788.5 (390.0 to 1700.0)
        Cycle 2 Day 1
    560.0 (290.0 to 813.0)
    377.5 (285.0 to 470.0)
    611.0 (409.0 to 813.0)
    529.5 (383.0 to 865.0)
    735.0 (558.0 to 890.0)
    600.0 (600.0 to 600.0)
    No statistical analyses for this end point

    Secondary: Pharmacokinetic profile of Buparlisib - Tmax

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    End point title
    		 Pharmacokinetic profile of Buparlisib - Tmax [13]
    End point description
    Plasma concentration profile of INC280 in combination with Buparlisib. Tmax is the time to reach maximum (peak) observed concentration (Cmax) after dose administration. Analysis was done in the pharmacokinetic analysis set (PAS).
    End point type
    Secondary
    End point timeframe
    Cycle 1 to cycle 6, approximately 6 months
    Notes
    [13] - 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: Only treatment groups which are part of Pharmacokinetic analysis set are included.
    End point values
    		 200 mg BID Cap+50 mg QD 400 mg BID Cap+50 mg QD 500 mg BID Cap+50 mg QD 500 mg BID Cap+80 mg QD 300 mg BID Tab +80 mg QD 400 mg BID Tab +80 mg QD
    Number of subjects analysed
    5
    5
    4
    6
    4
    5
    Units: hr
    median (full range (min-max))
        Cycle 1 Day 1
    1.0 (0.6 to 1.2)
    1.0 (0.6 to 2.0)
    1.0 (0.5 to 1.2)
    0.6 (0.5 to 2.0)
    1.2 (0.5 to 2.0)
    1.0 (0.9 to 2.0)
        Cycle 1 Day 15
    0.9 (0.9 to 1.0)
    2.0 (1.0 to 2.1)
    1.0 (1.0 to 2.0)
    1.6 (1.2 to 2.0)
    1.0 (0.5 to 1.0)
    1.3 (0.5 to 2.1)
        Cycle 2 Day 1
    1.0 (0.5 to 2.0)
    1.5 (1.0 to 2.0)
    1.0 (1.0 to 1.0)
    1.8 (1.0 to 2.1)
    1.0 (1.0 to 1.0)
    1.0 (1.0 to 1.0)
    No statistical analyses for this end point

    Secondary: Pharmacokinetic profile of Buparlisib - T1/2

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    End point title
    		 Pharmacokinetic profile of Buparlisib - T1/2 [14]
    End point description
    Plasma concentration profile of INC280 in combination with Buparlisib. T1/2 is the terminal half life. Analysis was done in the pharmacokinetic analysis set (PAS).
    End point type
    Secondary
    End point timeframe
    Cycle 1 to cycle 6, approximately 6 months
    Notes
    [14] - 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: Only treatment groups which are part of Pharmacokinetic analysis set are included.
    End point values
    		 200 mg BID Cap+50 mg QD 400 mg BID Cap+50 mg QD 500 mg BID Cap+50 mg QD 500 mg BID Cap+80 mg QD 300 mg BID Tab +80 mg QD 400 mg BID Tab +80 mg QD
    Number of subjects analysed
    5
    5
    4
    6
    4
    5
    Units: hr
    median (full range (min-max))
        Cycle 1 Day 15
    37.3 (29.1 to 52.4)
    31.1 (18.7 to 46.4)
    21.8 (20.8 to 29.4)
    30.9 (19.9 to 41.8)
    38.0 (21.3 to 44.9)
    22.8 (5.8 to 31.5)
        Cycle 2 Day 1
    34.0 (10.4 to 37.9)
    21.3 (16.4 to 26.1)
    27.0 (9.6 to 44.3)
    17.2 (16.8 to 31.9)
    20.1 (19.4 to 41.2)
    12.0 (12.0 to 12.0)
    No statistical analyses for this end point

    Secondary: Best Overall Response (BOR)

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    End point title
    		 Best Overall Response (BOR)
    End point description
    Best Overall Response (BOR) observed in the study population of INC280 Single Agent and in Combination with Buparlisib
    End point type
    Secondary
    End point timeframe
    throughout the duration of the trial - approximately 3 years (from FPFV to LPLV)
    End point values
    		 200 mg BID Cap+50 mg QD 400 mg BID Cap+50 mg QD 500 mg BID Cap+50 mg QD 500 mg BID Cap+80 mg QD 300 mg BID Tab +80 mg QD 400 mg BID Tab +80 mg QD 400 mg BID Tab
    Number of subjects analysed
    5
    6
    4
    6
    7
    5
    10
    Units: Percentages of participants
        Complete Response (CR)
    0
    0
    0
    0
    0
    0
    0
        Partial Response (PR)
    0
    0
    0
    0
    0
    0
    0
        Stable Disease (SD)
    0
    0
    0
    1
    0
    0
    3
        Progressive Disease (PD)
    5
    5
    4
    4
    7
    4
    6
        Unknown (UNK)
    0
    0
    0
    0
    0
    0
    0
        Not Assessed
    0
    1
    0
    1
    0
    1
    1
    No statistical analyses for this end point

    Secondary: Overall survival (OS)

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    End point title
    		 Overall survival (OS)
    End point description
    Survival rate of patients from start of treatment to date of death due to any cause
    End point type
    Secondary
    End point timeframe
    throughout the duration of the trial - approximately 3 years (FPFV to LPLV)
    End point values
    		 All Patients
    Number of subjects analysed
    0 [15]
    Units: Percentages of participants
    Notes
    [15] - OS was not performed as there were an insufficient number of patients enrolled for the analysis.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment Emergent Adverse Events (AEs) are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All AEs 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
    19.1
    Reporting groups
    Reporting group title
    INC280 200 mg BID Tab
    Reporting group description
    		 INC280 200 mg BID Tab

    Reporting group title
    INC280 200 mg BID Cap + Buparlisib 50 mg QD
    Reporting group description
    		 INC280 200 mg BID Cap + Buparlisib 50 mg QD

    Reporting group title
    INC280 400 mg BID Cap + Buparlisib 50 mg QD
    Reporting group description
    		 INC280 400 mg BID Cap + Buparlisib 50 mg QD

    Reporting group title
    INC280 500 mg BID Cap + Buparlisib 50 mg QD
    Reporting group description
    		 INC280 500 mg BID Cap + Buparlisib 50 mg QD

    Reporting group title
    INC280 500 mg BID Cap + Buparlisib 80 mg QD
    Reporting group description
    		 INC280 500 mg BID Cap + Buparlisib 80 mg QD

    Reporting group title
    INC280 300 mg BID Tab + Buparlisib 80 mg QD
    Reporting group description
    		 INC280 300 mg BID Tab + Buparlisib 80 mg QD

    Reporting group title
    INC280 400 mg BID Tab + Buparlisib 80 mg QD
    Reporting group description
    		 INC280 400 mg BID Tab + Buparlisib 80 mg QD

    Reporting group title
    Phase Ib All@Patients
    Reporting group description
    		 Phase Ib All@Patients

    Reporting group title
    INC280 400 mg BID Tab
    Reporting group description
    		 INC280 400 mg BID Tab

    Reporting group title
    Phase II All Patients
    Reporting group description
    		 Phase II All@Patients

    Serious adverse events
    		 INC280 200 mg BID Tab INC280 200 mg BID Cap + Buparlisib 50 mg QD INC280 400 mg BID Cap + Buparlisib 50 mg QD INC280 500 mg BID Cap + Buparlisib 50 mg QD INC280 500 mg BID Cap + Buparlisib 80 mg QD INC280 300 mg BID Tab + Buparlisib 80 mg QD INC280 400 mg BID Tab + Buparlisib 80 mg QD Phase Ib All@Patients INC280 400 mg BID Tab Phase II All Patients
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 1 (100.00%)
    3 / 5 (60.00%)
    2 / 6 (33.33%)
    3 / 4 (75.00%)
    3 / 6 (50.00%)
    3 / 7 (42.86%)
    4 / 5 (80.00%)
    18 / 33 (54.55%)
    2 / 9 (22.22%)
    3 / 10 (30.00%)
         number of deaths (all causes)
    0
    0
    1
    0
    0
    0
    0
    1
    1
    1
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    3 / 5 (60.00%)
    4 / 33 (12.12%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    3 / 3
    4 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    3 / 5 (60.00%)
    3 / 33 (9.09%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    3 / 3
    3 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    FALL
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    EMBOLISM
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HYPERTENSION
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    APHASIA
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ATAXIA
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    3 / 33 (9.09%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BRAIN OEDEMA
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HAEMORRHAGE INTRACRANIAL
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 5 (40.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    3 / 33 (9.09%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HEMIPARESIS
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LETHARGY
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    NEUROLOGICAL DECOMPENSATION
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PARAPARESIS
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PARTIAL SEIZURES
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SEIZURE
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    2 / 4 (50.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    3 / 33 (9.09%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    PYREXIA
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    ABDOMINAL PAIN
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DIARRHOEA
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GASTRIC ULCER
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    NAUSEA
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    1 / 9 (11.11%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    DERMATITIS ALLERGIC
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    RASH
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    APATHY
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    FEBRILE INFECTION
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INFLUENZA
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PERITONITIS
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
    1 / 9 (11.11%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PNEUMOCYSTIS JIROVECII PNEUMONIA
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PNEUMONIA
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    URINARY TRACT INFECTION
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    HYPONATRAEMIA
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 INC280 200 mg BID Tab INC280 200 mg BID Cap + Buparlisib 50 mg QD INC280 400 mg BID Cap + Buparlisib 50 mg QD INC280 500 mg BID Cap + Buparlisib 50 mg QD INC280 500 mg BID Cap + Buparlisib 80 mg QD INC280 300 mg BID Tab + Buparlisib 80 mg QD INC280 400 mg BID Tab + Buparlisib 80 mg QD Phase Ib All@Patients INC280 400 mg BID Tab Phase II All Patients
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 1 (0.00%)
    5 / 5 (100.00%)
    6 / 6 (100.00%)
    4 / 4 (100.00%)
    6 / 6 (100.00%)
    7 / 7 (100.00%)
    5 / 5 (100.00%)
    33 / 33 (100.00%)
    9 / 9 (100.00%)
    9 / 10 (90.00%)
    Vascular disorders
    EMBOLISM
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    1
    0
    0
    HAEMATOMA
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    1
    0
    0
    HOT FLUSH
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
    1 / 9 (11.11%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    1
    HYPERTENSION
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 5 (20.00%)
    2 / 33 (6.06%)
    1 / 9 (11.11%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    2
    1
    1
    HYPOTENSION
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    0
    0
    General disorders and administration site conditions
    ASTHENIA
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    2 / 33 (6.06%)
    1 / 9 (11.11%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    2
    1
    1
    CHILLS
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    0
    0
    FATIGUE
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 5 (40.00%)
    3 / 6 (50.00%)
    1 / 4 (25.00%)
    2 / 6 (33.33%)
    2 / 7 (28.57%)
    2 / 5 (40.00%)
    12 / 33 (36.36%)
    3 / 9 (33.33%)
    3 / 10 (30.00%)
         occurrences all number
    0
    2
    3
    1
    2
    3
    2
    13
    5
    5
    GAIT DISTURBANCE
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    0
    0
    GENERAL PHYSICAL HEALTH DETERIORATION
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
    1 / 9 (11.11%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    1
    OEDEMA PERIPHERAL
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    2 / 5 (40.00%)
    4 / 33 (12.12%)
    1 / 9 (11.11%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    2
    0
    2
    5
    3
    3
    PYREXIA
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    0
    0
    Reproductive system and breast disorders
    TESTICULAR PAIN
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    BRONCHOSPASM
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
    1 / 9 (11.11%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    1
    COUGH
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 5 (20.00%)
    3 / 33 (9.09%)
    2 / 9 (22.22%)
    2 / 10 (20.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    1
    3
    2
    2
    HICCUPS
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    2 / 33 (6.06%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    1
    3
    0
    0
    OROPHARYNGEAL PAIN
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    1 / 9 (11.11%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    1
    1
    PRODUCTIVE COUGH
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    1
    0
    0
    RHINORRHOEA
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    0
    0
    Psychiatric disorders
    AGITATION
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    2 / 33 (6.06%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    2
    0
    0
    ANXIETY
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 5 (40.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    2 / 7 (28.57%)
    1 / 5 (20.00%)
    6 / 33 (18.18%)
    1 / 9 (11.11%)
    1 / 10 (10.00%)
         occurrences all number
    0
    2
    0
    0
    1
    2
    1
    6
    1
    1
    APATHY
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    1
    0
    0
    BRADYPHRENIA
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    1
    0
    0
    CONFUSIONAL STATE
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    0
    0
    DEPRESSED MOOD
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
    1 / 9 (11.11%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    1
    DEPRESSION
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 5 (40.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    3 / 7 (42.86%)
    2 / 5 (40.00%)
    8 / 33 (24.24%)
    1 / 9 (11.11%)
    1 / 10 (10.00%)
         occurrences all number
    0
    2
    0
    1
    0
    3
    2
    8
    1
    1
    DISORIENTATION
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    3 / 33 (9.09%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    2
    1
    0
    1
    0
    0
    4
    0
    0
    INSOMNIA
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    3 / 33 (9.09%)
    1 / 9 (11.11%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    0
    0
    1
    1
    0
    3
    1
    1
    IRRITABILITY
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    0
    0
    MOOD ALTERED
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    2 / 33 (6.06%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    2
    0
    0
    0
    0
    3
    0
    0
    PERSONALITY CHANGE
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    0
    0
    SLEEP DISORDER
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    0
    0
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    1 / 6 (16.67%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    2 / 7 (28.57%)
    4 / 5 (80.00%)
    9 / 33 (27.27%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    2
    4
    9
    0
    0
    AMYLASE INCREASED
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    2 / 33 (6.06%)
    2 / 9 (22.22%)
    2 / 10 (20.00%)
         occurrences all number
    0
    2
    0
    1
    0
    0
    0
    3
    2
    2
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    1 / 6 (16.67%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    2 / 7 (28.57%)
    3 / 5 (60.00%)
    8 / 33 (24.24%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    3
    3
    9
    0
    0
    BLOOD ALBUMIN DECREASED
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    1
    0
    0
    BLOOD BILIRUBIN INCREASED
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    2 / 4 (50.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 5 (20.00%)
    5 / 33 (15.15%)
    1 / 9 (11.11%)
    1 / 10 (10.00%)
         occurrences all number
    0
    2
    0
    2
    0
    1
    2
    7
    2
    2
    BLOOD CREATININE INCREASED
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 5 (40.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    2 / 5 (40.00%)
    5 / 33 (15.15%)
    1 / 9 (11.11%)
    1 / 10 (10.00%)
         occurrences all number
    0
    2
    0
    1
    0
    0
    2
    5
    1
    1
    BLOOD GLUCOSE INCREASED
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    0
    0
    BLOOD POTASSIUM INCREASED
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    1
    0
    0
    BLOOD TRIGLYCERIDES INCREASED
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    0
    0
    GLOMERULAR FILTRATION RATE DECREASED
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 5 (40.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    4 / 33 (12.12%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    5
    0
    1
    0
    1
    0
    7
    0
    0
    INSULIN C-PEPTIDE INCREASED
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 5 (40.00%)
    1 / 6 (16.67%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    2 / 7 (28.57%)
    0 / 5 (0.00%)
    6 / 33 (18.18%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    2
    1
    1
    0
    2
    0
    6
    0
    0
    LIPASE INCREASED
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    4 / 33 (12.12%)
    3 / 9 (33.33%)
    3 / 10 (30.00%)
         occurrences all number
    0
    1
    0
    1
    1
    0
    2
    5
    3
    3
    LYMPHOCYTE COUNT DECREASED
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    2 / 7 (28.57%)
    0 / 5 (0.00%)
    3 / 33 (9.09%)
    1 / 9 (11.11%)
    1 / 10 (10.00%)
         occurrences all number
    0
    2
    0
    0
    0
    3
    0
    5
    3
    3
    NEUTROPHIL COUNT DECREASED
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    2
    0
    0
    PLATELET COUNT DECREASED
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    2 / 5 (40.00%)
    3 / 33 (9.09%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    2
    4
    0
    0
    PROTEIN TOTAL DECREASED
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    1
    0
    0
    PROTHROMBIN TIME PROLONGED
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    1
    0
    0
    WEIGHT DECREASED
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    1 / 9 (11.11%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    1
    1
    1
    WEIGHT INCREASED
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
    1 / 9 (11.11%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    1
    Injury, poisoning and procedural complications
    CONTUSION
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    0
    0
    FALL
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    2 / 5 (40.00%)
    3 / 33 (9.09%)
    2 / 9 (22.22%)
    2 / 10 (20.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    2
    3
    2
    2
    LACERATION
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
    1 / 9 (11.11%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    1
    Cardiac disorders
    LEFT VENTRICULAR DYSFUNCTION
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    0
    0
    SINUS BRADYCARDIA
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    1
    0
    0
    Nervous system disorders
    AMNESIA
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    1
    0
    0
    APHASIA
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    2 / 7 (28.57%)
    1 / 5 (20.00%)
    4 / 33 (12.12%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    2
    1
    4
    0
    0
    ATAXIA
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 5 (40.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    3 / 33 (9.09%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    1
    3
    0
    0
    BRAIN OEDEMA
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    2 / 33 (6.06%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    2
    0
    0
    COGNITIVE DISORDER
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    2 / 33 (6.06%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    2
    0
    0
    DISTURBANCE IN ATTENTION
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    1 / 6 (16.67%)
    1 / 4 (25.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    2 / 5 (40.00%)
    7 / 33 (21.21%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    1
    1
    1
    1
    2
    7
    0
    0
    DIZZINESS
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    2 / 33 (6.06%)
    1 / 9 (11.11%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    0
    2
    1
    1
    DYSARTHRIA
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    3 / 33 (9.09%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    1
    3
    0
    0
    DYSKINESIA
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    0
    0
    DYSMETRIA
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    1
    0
    0
    EPILEPSY
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
    1 / 9 (11.11%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    1
    FACIAL PARALYSIS
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    1
    0
    0
    FACIAL PARESIS
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    1
    0
    0
    HEADACHE
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 5 (40.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    2 / 6 (33.33%)
    2 / 7 (28.57%)
    2 / 5 (40.00%)
    9 / 33 (27.27%)
    4 / 9 (44.44%)
    4 / 10 (40.00%)
         occurrences all number
    0
    3
    0
    1
    2
    2
    2
    10
    5
    5
    HEMIANOPIA
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    2 / 33 (6.06%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    2
    0
    0
    HEMIANOPIA HOMONYMOUS
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    2 / 33 (6.06%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    0
    2
    0
    0
    HEMIPARESIS
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    2 / 4 (50.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    1 / 5 (20.00%)
    5 / 33 (15.15%)
    1 / 9 (11.11%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    2
    1
    1
    1
    5
    1
    1
    HEMIPLEGIA
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
    1 / 9 (11.11%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    1
    LETHARGY
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    2 / 33 (6.06%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    0
    2
    0
    0
    MEMORY IMPAIRMENT
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    2 / 6 (33.33%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    2 / 7 (28.57%)
    2 / 5 (40.00%)
    7 / 33 (21.21%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    2
    1
    0
    2
    2
    7
    0
    0
    NEUROLOGIC NEGLECT SYNDROME
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    1
    0
    0
    NEUROLOGICAL SYMPTOM
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
    1 / 9 (11.11%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    1
    PARAESTHESIA
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    1
    0
    0
    PARALYSIS
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    1
    0
    0
    PARAPARESIS
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    1
    0
    0
    PARESIS
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    1 / 9 (11.11%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    1
    1
    1
    PERIPHERAL MOTOR NEUROPATHY
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    1 / 9 (11.11%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    1
    1
    1
    PERIPHERAL SENSORY NEUROPATHY
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    2 / 33 (6.06%)
    1 / 9 (11.11%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    2
    1
    1
    PYRAMIDAL TRACT SYNDROME
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    2 / 33 (6.06%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    1
    2
    0
    0
    RESTLESS LEGS SYNDROME
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    0
    0
    SEIZURE
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    3 / 33 (9.09%)
    1 / 9 (11.11%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    1
    0
    1
    0
    3
    1
    1
    SOMNOLENCE
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    1 / 6 (16.67%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    4 / 33 (12.12%)
    1 / 9 (11.11%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    1
    0
    1
    0
    4
    1
    1
    TREMOR
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    0
    0
    VITH NERVE PARALYSIS
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    0
    0
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    0
    0
    LEUKOPENIA
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    2 / 33 (6.06%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    0
    2
    0
    0
    NEUTROPENIA
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    1 / 9 (11.11%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    1
    1
    THROMBOCYTOPENIA
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    2 / 33 (6.06%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    2
    1
    0
    0
    0
    0
    3
    0
    0
    Eye disorders
    DIPLOPIA
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    0
    0
    VISION BLURRED
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
    1 / 9 (11.11%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    1
    Gastrointestinal disorders
    ABDOMINAL PAIN
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    2 / 33 (6.06%)
    1 / 9 (11.11%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    2
    1
    1
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    0
    0
    CONSTIPATION
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 5 (40.00%)
    1 / 6 (16.67%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    5 / 33 (15.15%)
    3 / 9 (33.33%)
    3 / 10 (30.00%)
         occurrences all number
    0
    2
    1
    1
    0
    0
    1
    5
    3
    3
    DIARRHOEA
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    1 / 6 (16.67%)
    1 / 4 (25.00%)
    1 / 6 (16.67%)
    2 / 7 (28.57%)
    1 / 5 (20.00%)
    7 / 33 (21.21%)
    1 / 9 (11.11%)
    1 / 10 (10.00%)
         occurrences all number
    0
    2
    1
    1
    1
    3
    1
    9
    2
    2
    DYSPEPSIA
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    2 / 6 (33.33%)
    2 / 7 (28.57%)
    1 / 5 (20.00%)
    6 / 33 (18.18%)
    1 / 9 (11.11%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    0
    0
    2
    2
    1
    6
    1
    1
    DYSPHAGIA
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    2 / 33 (6.06%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    2
    0
    0
    GASTROOESOPHAGEAL REFLUX DISEASE
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    1 / 33 (3.03%)
    1 / 9 (11.11%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    1
    1
    1
    HAEMORRHOIDS
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    1
    0
    0
    NAUSEA
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    2 / 6 (33.33%)
    1 / 4 (25.00%)
    1 / 6 (16.67%)
    3 / 7 (42.86%)
    2 / 5 (40.00%)
    10 / 33 (30.30%)
    2 / 9 (22.22%)
    2 / 10 (20.00%)
         occurrences all number
    0
    2
    2
    1
    1
    4
    2
    12
    2
    2
    RECTAL ULCER HAEMORRHAGE
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    0
    0
    STOMATITIS
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    2 / 33 (6.06%)
    1 / 9 (11.11%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    2
    1
    1
    VOMITING
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    2 / 5 (40.00%)
    5 / 33 (15.15%)
    1 / 9 (11.11%)
    1 / 10 (10.00%)
         occurrences all number
    0
    3
    1
    0
    0
    1
    2
    7
    1
    1
    Hepatobiliary disorders
    HEPATIC STEATOSIS
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    1
    0
    0
    HYPERBILIRUBINAEMIA
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    0
    0
    Skin and subcutaneous tissue disorders
    ALOPECIA
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
    1 / 9 (11.11%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    1
    DERMATITIS ACNEIFORM
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    0
    0
    DRY SKIN
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    2 / 5 (40.00%)
    2 / 33 (6.06%)
    1 / 9 (11.11%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    2
    1
    1
    PRURITUS
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 5 (20.00%)
    3 / 33 (9.09%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    1
    3
    0
    0
    RASH
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    1 / 33 (3.03%)
    1 / 9 (11.11%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    2
    1
    1
    RASH MACULAR
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    1
    0
    0
    RASH MACULO-PAPULAR
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 5 (20.00%)
    2 / 33 (6.06%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    2
    0
    0
    SKIN ATROPHY
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    1
    0
    0
    Renal and urinary disorders
    ACUTE KIDNEY INJURY
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
    1 / 9 (11.11%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    1
    CHRONIC KIDNEY DISEASE
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    1
    0
    0
    CYSTITIS NONINFECTIVE
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    0
    0
    HAEMATURIA
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    1
    0
    0
    MICTURITION URGENCY
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    0
    0
    URINARY INCONTINENCE
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 5 (20.00%)
    4 / 33 (12.12%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    1
    1
    4
    0
    0
    URINARY RETENTION
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    2 / 33 (6.06%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    1
    2
    0
    0
    Musculoskeletal and connective tissue disorders
    BACK PAIN
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    0
    0
    MUSCLE SPASMS
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    1
    0
    0
    MUSCULAR WEAKNESS
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    3 / 33 (9.09%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    1
    3
    0
    0
    MUSCULOSKELETAL PAIN
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 33 (0.00%)
    1 / 9 (11.11%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    1
    MYALGIA
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    2 / 7 (28.57%)
    0 / 5 (0.00%)
    2 / 33 (6.06%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    2
    0
    0
    PAIN IN EXTREMITY
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    1 / 33 (3.03%)
    1 / 9 (11.11%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    1
    1
    1
    Infections and infestations
    ORAL HERPES
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    1 / 33 (3.03%)
    1 / 9 (11.11%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    1
    1
    1
    ORCHITIS
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    0
    0
    Metabolism and nutrition disorders
    DECREASED APPETITE
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 5 (40.00%)
    1 / 6 (16.67%)
    1 / 4 (25.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    6 / 33 (18.18%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    2
    1
    1
    1
    1
    0
    6
    0
    0
    HYPERGLYCAEMIA
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 5 (40.00%)
    0 / 6 (0.00%)
    2 / 4 (50.00%)
    1 / 6 (16.67%)
    2 / 7 (28.57%)
    0 / 5 (0.00%)
    7 / 33 (21.21%)
    1 / 9 (11.11%)
    1 / 10 (10.00%)
         occurrences all number
    0
    3
    0
    3
    1
    2
    0
    9
    1
    1
    HYPERURICAEMIA
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    0
    0
    HYPOALBUMINAEMIA
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    1
    0
    0
    HYPOGLYCAEMIA
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    0
    0
    HYPOKALAEMIA
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    0
    0
    HYPONATRAEMIA
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 33 (3.03%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    0
    0
    HYPOPHOSPHATAEMIA
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    2 / 7 (28.57%)
    0 / 5 (0.00%)
    4 / 33 (12.12%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    2
    0
    4
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Aug 2013
    Added clarification to the collection and analysis of the pre-screening tumor samples, as requested from regulatory health authorities. In addition, guidelines for clarification in the completion of psychiatric questionnaires GAD-7 and PHQ-9 were added.
    07 Jul 2014
    1) Tablet formulation was developed with higher dosage strengths. 2) For local pre-screening performed during dose escalation, a threshold for PTEN negativity was introduced. 3) For the Phase II part of the study, no local pre-screening was allowed. PTEN pre-screening was to be done centrally for all patients in order to achieve comparable results and to allow testing for other molecular markers for those patients who had given their consent. 4) Clarification was added regarding the use of corticosteroids for the treatment arms as well as the surgical arm. 5) For patients in Phase II, who consented to additional biomarker assessments, HGF mRNA expression in tumor samples was to be measured.
    02 Mar 2015
    To introduce a second arm with INC280 monotherapy into the Phase II part, in order to investigate single agent INC280 in c-MET altered GBM patients (c-MET amplified GCN >5), fusion or mutant).
    03 Aug 2015
    To provide additional information and guidance to Investigators for the management of liver toxicities.
    30 Mar 2016
    This amendment provided additional guidance to Investigators for the management of liver toxicities and specifically work-up guidelines for potential Drug Induced Liver Injury (DILI) cases. Specific guidance for actions to be taken on the study treatment (e.g. discontinuation) and for monitoring of liver function tests was implemented and clarified.

    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.
    At the end of Phase Ib, it was decided not to enroll patients in the two Phase II arms evaluating INC280 with buparlisib. The phase II INC280 single agent arm was halted before it reached target enrollment due to lack of objective clinical response.
    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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