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    Clinical Trial Results:
    A Phase Ib/II, open-label, multi-center, dose-finding study to assess the safety and efficacy of the oral combination of LDE225 and INC424 (Ruxolitinib) in subjects with myelofibrosis

    Summary
    EudraCT number
    		 2012-004023-20
    Trial protocol
    		 ES   GB   IE   IT   DE   NL   FR   DK   BE  
    Global end of trial date
    10 Apr 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Apr 2019
    First version publication date
    25 Apr 2019
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CLDE225X2116
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01787552
    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
    10 Apr 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Apr 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Primary objective : (Phase Ib) To establish the MTD and/or RPIID of the co-administration of LDE225 and INC424 in subjects with MF, who have not previously received therapy with a JAK inhibitor. (Phase II) To assess the efficacy of the co-administration of LDE225 and INC424 on spleen volume reduction as determined by centrally reviewed magnetic resonance imaging (MRI)/ computed tomography (CT).
    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
    08 May 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 3
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    Canada: 11
    Country: Number of subjects enrolled
    Denmark: 4
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    Germany: 8
    Country: Number of subjects enrolled
    United Kingdom: 7
    Country: Number of subjects enrolled
    Ireland: 1
    Country: Number of subjects enrolled
    Italy: 6
    Country: Number of subjects enrolled
    Netherlands: 3
    Country: Number of subjects enrolled
    Spain: 4
    Worldwide total number of subjects
    50
    EEA total number of subjects
    36
    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)
    18
    From 65 to 84 years
    32
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 50 subjects were enrolled in the study, of which 23 subjects were enrolled in Phase Ib part of dose-escalation phase and 27 subjects were enrolled in Phase Ib dose-expansion phase and Phase II Stage 1.

    Pre-assignment
    Screening details
    		 A total of 50 subjects were enrolled in the study, of which 23 subjects were enrolled in Phase Ib part of dose-escalation phase and 27 subjects were enrolled in Phase Ib dose-expansion phase and Phase II Stage 1.

    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
    		 LDE225 400mg + INC424 10mg (dose escalation phase)
    Arm description
    		 Participants who took a combination of LDE225 400mg and INC424 10mg in the dose escalation phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    INC424
    Investigational medicinal product code
    INC424
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants who took a combination of LDE225 400mg and INC424 10mg in the dose escalation phase.

    Investigational medicinal product name
    LDE225
    Investigational medicinal product code
    LDE225
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants who took a combination of LDE225 400mg and INC424 10mg in the dose escalation phase.

    Arm title
    		 LDE225 400mg + INC424 15 mg (dose escalation phase)
    Arm description
    		 Participants who took a combination of LDED225 400mg and INC424 15mg in the dose escalation phase
    Arm type
    		 Experimental

    Investigational medicinal product name
    INC424
    Investigational medicinal product code
    INC424
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants who took a combination of LDE225 400mg and INC424 10mg in the dose escalation phase.

    Investigational medicinal product name
    LDE225
    Investigational medicinal product code
    LDE225
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants who took a combination of LDE225 400mg and INC424 10mg in the dose escalation phase.

    Arm title
    		 LDE225 400mg + INC424 20mg (dose escalation phase)
    Arm description
    		 Participants who took a combination of LDED225 400mg and INC424 20mg in the dose escalation phase
    Arm type
    		 Experimental

    Investigational medicinal product name
    LDE225
    Investigational medicinal product code
    LDE225
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants who took a combination of LDE225 400mg and INC424 10mg in the dose escalation phase.

    Investigational medicinal product name
    INC424
    Investigational medicinal product code
    INC424
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants who took a combination of LDE225 400mg and INC424 10mg in the dose escalation phase.

    Arm title
    		 LDED225 400mg + INC424 20mg (dose expansion phase)
    Arm description
    		 Participants who took a combination of LDED225 400mg and INC424 20mg in the dose expansion phase
    Arm type
    		 Experimental

    Investigational medicinal product name
    INC424
    Investigational medicinal product code
    INC424
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants who took a combination of LDE225 400mg and INC424 10mg in the dose escalation phase.

    Investigational medicinal product name
    LDE225
    Investigational medicinal product code
    LDE225
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants who took a combination of LDE225 400mg and INC424 10mg in the dose escalation phase.

    Number of subjects in period 1
    		LDE225 400mg + INC424 10mg (dose escalation phase) LDE225 400mg + INC424 15 mg (dose escalation phase) LDE225 400mg + INC424 20mg (dose escalation phase) LDED225 400mg + INC424 20mg (dose expansion phase)
    Started
    8
    10
    5
    27
    Completed
    0
    1
    0
    0
    Not completed
    8
    9
    5
    27
         Adverse event, serious fatal
    -
    -
    -
    1
         Consent withdrawn by subject
    2
    -
    -
    4
         Physician decision
    2
    2
    1
    2
         Study terminated by Sponsor
    -
    -
    1
    3
         Adverse event, non-fatal
    2
    5
    2
    16
         Progressive Disease
    2
    2
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    LDE225 400mg + INC424 10mg (dose escalation phase)
    Reporting group description
    		 Participants who took a combination of LDE225 400mg and INC424 10mg in the dose escalation phase.

    Reporting group title
    LDE225 400mg + INC424 15 mg (dose escalation phase)
    Reporting group description
    		 Participants who took a combination of LDED225 400mg and INC424 15mg in the dose escalation phase

    Reporting group title
    LDE225 400mg + INC424 20mg (dose escalation phase)
    Reporting group description
    		 Participants who took a combination of LDED225 400mg and INC424 20mg in the dose escalation phase

    Reporting group title
    LDED225 400mg + INC424 20mg (dose expansion phase)
    Reporting group description
    		 Participants who took a combination of LDED225 400mg and INC424 20mg in the dose expansion phase

    Reporting group values
    		 LDE225 400mg + INC424 10mg (dose escalation phase) LDE225 400mg + INC424 15 mg (dose escalation phase) LDE225 400mg + INC424 20mg (dose escalation phase) LDED225 400mg + INC424 20mg (dose expansion phase) Total
    Number of subjects
    		 8 10 5 27 50
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0
        Adults (18-64 years)
    		 1 6 2 9 18
        From 65-84 years
    		 7 4 3 18 32
        85 years and over
    		 0 0 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 70.9 ( 5.19 ) 59.9 ( 11.59 ) 64.6 ( 13.18 ) 67.4 ( 10.02 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 1 5 1 8 15
        Male
    		 7 5 4 19 35
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0 0
        Asian
    		 2 0 0 1 3
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0
        Black or African American
    		 0 0 0 0 0
        White
    		 6 10 5 26 47
        More than one race
    		 0 0 0 0 0
        Unknown or Not Reported
    		 0 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    LDE225 400mg + INC424 10mg (dose escalation phase)
    Reporting group description
    		 Participants who took a combination of LDE225 400mg and INC424 10mg in the dose escalation phase.

    Reporting group title
    LDE225 400mg + INC424 15 mg (dose escalation phase)
    Reporting group description
    		 Participants who took a combination of LDED225 400mg and INC424 15mg in the dose escalation phase

    Reporting group title
    LDE225 400mg + INC424 20mg (dose escalation phase)
    Reporting group description
    		 Participants who took a combination of LDED225 400mg and INC424 20mg in the dose escalation phase

    Reporting group title
    LDED225 400mg + INC424 20mg (dose expansion phase)
    Reporting group description
    		 Participants who took a combination of LDED225 400mg and INC424 20mg in the dose expansion phase

    Primary: Number of participants with Dose Limiting Toxicities (DLTs). (Phase 1b)

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    End point title
    		 Number of participants with Dose Limiting Toxicities (DLTs). (Phase 1b) [1]
    End point description
    Established the maximum tolerated dose (MTD) and/or recommended phase II dose (RPllD) of LDE225 in combination with INC424
    End point type
    Primary
    End point timeframe
    6 weeks (42 days)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this primary outcome.
    End point values
    		 LDE225 400mg + INC424 10mg (dose escalation phase) LDE225 400mg + INC424 15 mg (dose escalation phase) LDE225 400mg + INC424 20mg (dose escalation phase) LDED225 400mg + INC424 20mg (dose expansion phase)
    Number of subjects analysed
    8
    10
    5
    27
    Units: Participants
        Blood creatine phosphokinase increased
    0
    2
    0
    1
    No statistical analyses for this end point

    Primary: Percentage of patients achieving >= 35% reduction in spleen volume

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    End point title
    		 Percentage of patients achieving >= 35% reduction in spleen volume [2] [3]
    End point description
    Reduction in spleen volume as measured by magnetic resonance imaging/Cat Scan (MRI/CT).
    End point type
    Primary
    End point timeframe
    Week 24 and Week 48
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this primary outcome.
    [3] - 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: This Outcome Measure was only collected on the LDE225 400mg +INC424 20mg (dose expansion phase) arm, N=27).
    End point values
    		 LDED225 400mg + INC424 20mg (dose expansion phase)
    Number of subjects analysed
    27
    Units: Percentage of Participants
    number (not applicable)
        Week 24
    44.4
        Week 48
    29.6
    No statistical analyses for this end point

    Secondary: Phase Ib and Phase II: Plasma pharmacokinetics (PK) parameters: Maximum Plasma Concentration(Cmax)

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    End point title
    		 Phase Ib and Phase II: Plasma pharmacokinetics (PK) parameters: Maximum Plasma Concentration(Cmax)
    End point description
    LDE225 and INC424 PK parameters: Maximum Plasma Concentration (Cmax)
    End point type
    Secondary
    End point timeframe
    Week 1 Day 1, Week 9 Day 1
    End point values
    		 LDE225 400mg + INC424 10mg (dose escalation phase) LDE225 400mg + INC424 15 mg (dose escalation phase) LDE225 400mg + INC424 20mg (dose escalation phase) LDED225 400mg + INC424 20mg (dose expansion phase)
    Number of subjects analysed
    8 [4]
    10 [5]
    5 [6]
    27 [7]
    Units: Unit by PK Parameter (ng/mL)
    arithmetic mean (standard deviation)
        LDE225 (Week 1, Day 1)
    326 ( 102 )
    307 ( 275 )
    205 ( 149 )
    328 ( 266 )
        LDE225 (Week 9, Day 1)
    933 ( 351 )
    831 ( 537 )
    1020 ( 429 )
    1070 ( 572 )
        INC424 (Week 1, Day 1)
    159 ( 48.0 )
    263 ( 115 )
    361 ( 94.8 )
    364 ( 148 )
        INC424 (Week 9, Day 1)
    178 ( 58.8 )
    283 ( 97.0 )
    295 ( 102 )
    371 ( 129 )
    Notes
    [4] - (n=6,8,8,8)
    [5] - (n=10,8,10,9)
    [6] - (n=5,5,5,4)
    [7] - (n=26,20,27,20)
    No statistical analyses for this end point

    Secondary: Phase Ib and Phase II: Plasma pharmacokinetics (PK) parameters: Time to Maximum Plasma Concentration(Tmax)

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    End point title
    		 Phase Ib and Phase II: Plasma pharmacokinetics (PK) parameters: Time to Maximum Plasma Concentration(Tmax)
    End point description
    LDE225 and INC424 PK parameters:Time to Maximum Plasma Concentration (Tmax)
    End point type
    Secondary
    End point timeframe
    Week 1 Day 1, Week 9 Day 1
    End point values
    		 LDE225 400mg + INC424 10mg (dose escalation phase) LDE225 400mg + INC424 15 mg (dose escalation phase) LDE225 400mg + INC424 20mg (dose escalation phase) LDED225 400mg + INC424 20mg (dose expansion phase)
    Number of subjects analysed
    8 [8]
    10 [9]
    5 [10]
    27 [11]
    Units: Unit by PK Parameter (hr)
    median (full range (min-max))
        LDE225 (Week 1, Day 1)
    3.01 (2.00 to 4.00)
    2.08 (1.50 to 4.22)
    2.00 (1.50 to 8.00)
    2.00 (1.00 to 6.00)
        LDE225 (Week 9, Day 1)
    1.79 (0.170 to 4.00)
    2.00 (1.50 to 4.00)
    2.00 (1.50 to 6.00)
    3.21 (1.50 to 23.9)
        INC424 (Week 1, Day 1)
    0.500 (0.500 to 2.00)
    0.575 (0.330 to 2.03)
    0.500 (0.500 to 0.970)
    0.580 (0.420 to 4.00)
        INC424 (Week 9, Day 1)
    0.875 (0.170 to 1.50)
    0.500 (0.500 to 1.52)
    1.00 (0.500 to 1.00)
    1.00 (0.330 to 2.00)
    Notes
    [8] - (n=6,8,8,8)
    [9] - (n=10,8,10,9)
    [10] - (n=5,5,5,4)
    [11] - (n=26,20,27,20)
    No statistical analyses for this end point

    Secondary: Phase Ib and Phase II: Plasma pharmacokinetics (PK) parameters: Area under the Curve(AUC)

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    End point title
    		 Phase Ib and Phase II: Plasma pharmacokinetics (PK) parameters: Area under the Curve(AUC)
    End point description
    LDE225 and INC424 PK parameters: Plasma Concentration Time Curve (AUC).
    End point type
    Secondary
    End point timeframe
    Week 1 Day 1, Week 9 Day 1
    End point values
    		 LDE225 400mg + INC424 10mg (dose escalation phase) LDE225 400mg + INC424 15 mg (dose escalation phase) LDE225 400mg + INC424 20mg (dose escalation phase) LDED225 400mg + INC424 20mg (dose expansion phase)
    Number of subjects analysed
    8 [12]
    10 [13]
    5 [14]
    27 [15]
    Units: Unit by PK Parameter (ng*hr/mL))
    median (full range (min-max))
        LDE225 (Week 1, Day 1)
    2400 (1990 to 4930)
    1640 (630 to 7720)
    1060 (505 to 2720)
    1770 (755 to 7290)
        LDE225 (Week 9, Day 1)
    14500 (11200 to 26800)
    11600 (6420 to 31000)
    16100 (13000 to 25900)
    14800 (7030 to 31800)
        INC424 (Week 1, Day 1)
    416 (369 to 791)
    795 (384 to 1550)
    1200 (766 to 1390)
    1200 (561 to 2590)
        INC424 (Week 9, Day 1)
    511 (271 to 803)
    945 (449 to 1650)
    1040 (692 to 1140)
    1360 (420 to 2290)
    Notes
    [12] - (n=6,6,8,8)
    [13] - (n=10,6,10,9)
    [14] - (n=4,4,5,4)
    [15] - (n=24,14,25,20)
    No statistical analyses for this end point

    Secondary: Phase Ib and Phase II: Percentage of patients experiencing improvement in bone marrow fibrosis by at least one grade

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    End point title
    		 Phase Ib and Phase II: Percentage of patients experiencing improvement in bone marrow fibrosis by at least one grade
    End point description
    The number of patients experiencing improvement in their bone marrow fibrosis by at least one grade and assessment of cellularity.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24, Week 48
    End point values
    		 LDE225 400mg + INC424 10mg (dose escalation phase) LDE225 400mg + INC424 15 mg (dose escalation phase) LDE225 400mg + INC424 20mg (dose escalation phase) LDED225 400mg + INC424 20mg (dose expansion phase)
    Number of subjects analysed
    8 [16]
    10 [17]
    5 [18]
    27 [19]
    Units: Percentage of Participants
    number (not applicable)
        Baseline
    0
    10.0
    0
    14.8
        Week 24
    12.5
    10.0
    0
    3.7
        Week 48
    0
    0
    0
    3.7
    Notes
    [16] - n=(0,1,0)
    [17] - (n=1,1,0)
    [18] - (n=0,0,0)
    [19] - (n=4,1,1)
    No statistical analyses for this end point

    Secondary: Phase Ib and Phase ll: Change in Pharmacodynamic Biomarkers: JAK2V617F allele burden

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    End point title
    		 Phase Ib and Phase ll: Change in Pharmacodynamic Biomarkers: JAK2V617F allele burden
    End point description
    Change in Pharmacodynamic Biomarkers: JAK2V617F allele burden were compared from Baseline to Week 24 and Week 48
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24, Week 48
    End point values
    		 LDE225 400mg + INC424 10mg (dose escalation phase) LDE225 400mg + INC424 15 mg (dose escalation phase) LDE225 400mg + INC424 20mg (dose escalation phase) LDED225 400mg + INC424 20mg (dose expansion phase)
    Number of subjects analysed
    8 [20]
    10 [21]
    5 [22]
    27 [23]
    Units: JAK2V617F allele burden
    median (full range (min-max))
        Baseline
    84.7 (48.4 to 95.1)
    61.7 (2.5 to 92.1)
    88.3 (52.7 to 94.4)
    55.4 (2.5 to 93.5)
        Week 24
    88.6 (49.8 to 94.1)
    48.0 (2.5 to 78.4)
    74.9 (52.1 to 89.6)
    43.8 (2.5 to 93.9)
        Week 48
    86.0 (20.1 to 94.1)
    54.3 (2.5 to 80.0)
    75.7 (56.9 to 90.0)
    46.1 (2.5 to 85.6)
    Notes
    [20] - (n=8,7,4)
    [21] - (n=10,6,3)
    [22] - (n=5,5,4)
    [23] - (n=27,21,13)
    No statistical analyses for this end point

    Secondary: Phase Ib and Phase ll: Change in Pharmacodynamic Biomarkers: Cytokine Levels

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    End point title
    		 Phase Ib and Phase ll: Change in Pharmacodynamic Biomarkers: Cytokine Levels
    End point description
    Change in Pharmacodynamic Biomarkers: Cytokine levels were compared from Baseline to Week 24 and Week 48
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24, Week 48
    End point values
    		 LDE225 400mg + INC424 10mg (dose escalation phase) LDE225 400mg + INC424 15 mg (dose escalation phase) LDE225 400mg + INC424 20mg (dose escalation phase) LDED225 400mg + INC424 20mg (dose expansion phase)
    Number of subjects analysed
    8 [24]
    10 [25]
    5 [26]
    27 [27]
    Units: Level of Cytokine
    median (full range (min-max))
        Baseline
    0.80 (0.3 to 2.3)
    1.00 (0.6 to 1.5)
    0.588 (0.3 to 1.7)
    0.74 (0.3 to 3.7)
        Week 24
    0.75 (0.3 to 2.5)
    0.79 (0.3 to 1.4)
    1.10 (0.3 to 2.2)
    0.49 (0.49 to 2.0)
        Week 48
    0.68 (0.3 to 1.6)
    0.60 (0.5 to 0.9)
    0.49 (0.49 to 1.1)
    0.49 (0.49 to 2.6)
    Notes
    [24] - (n=8,7,4)
    [25] - (n=10,8,3)
    [26] - (n=5,5,4)
    [27] - (n=27,22,14)
    No statistical analyses for this end point

    Secondary: Phase Ib and Phase II: Change from Baseline in Percentage of patients having >= 50% reduction in total symptom score

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    End point title
    		 Phase Ib and Phase II: Change from Baseline in Percentage of patients having >= 50% reduction in total symptom score [28]
    End point description
    Change from Baseline in total symptom score as measured by the modified MFSAF (Myelofibrosis Symptom Assessment Form)
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24, Week 48
    Notes
    [28] - 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: This Outcome Measure was only collected on the LDE225 400mg +INC424 20mg (dose expansion phase) arm, N=27).
    End point values
    		 LDED225 400mg + INC424 20mg (dose expansion phase)
    Number of subjects analysed
    27
    Units: Percentage
    number (not applicable)
        Week 24
    48.1
        Week 48
    22.2
    No statistical analyses for this end point

    Secondary: Phase Ib andPhase II: Change from Baseline in total symptom score

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    End point title
    		 Phase Ib andPhase II: Change from Baseline in total symptom score [29]
    End point description
    Change from Baseline measured by the modified MFSAF (Myelofibrosis Symptom Assessment Form)
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24, Week 48
    Notes
    [29] - 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: This Outcome Measure was only collected on the LDE225 400mg +INC424 20mg (dose expansion phase) arm, N=27).
    End point values
    		 LDED225 400mg + INC424 20mg (dose expansion phase)
    Number of subjects analysed
    27
    Units: Percentage
    number (not applicable)
        Week 24
    22.2
        Week 48
    14.8
    No statistical analyses for this end point

    Secondary: Phase I and Phase II: Change in EORTC QLQ-C30 scores from Baseline (increase in best change)

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    End point title
    		 Phase I and Phase II: Change in EORTC QLQ-C30 scores from Baseline (increase in best change) [30]
    End point description
    Change in EORTC QLQ-C30 scores from Baseline. EORTC QLQ-C30 is the European Organization for Research and Treatment of Cancer, Quality of Life Questionnaire
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24, Week 48
    Notes
    [30] - 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: This Outcome Measure was only collected on the LDE225 400mg +INC424 20mg (dose expansion phase) arm, N=27).
    End point values
    		 LDED225 400mg + INC424 20mg (dose expansion phase)
    Number of subjects analysed
    27
    Units: Percentage
    number (not applicable)
        Week 24
    14.8
        Week 48
    11.1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All adverse events reported in this record are from date of First Patient First Treatment until Last Patient Last Visit
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    LDE225 400 mg + INC424 10 mg
    Reporting group description
    		 LDE225 400 mg + INC424 10 mg

    Reporting group title
    LDE225 400 mg + INC424 15 mg
    Reporting group description
    		 LDE225 400 mg + INC424 15 mg

    Reporting group title
    LDE225 400 mg + INC424 20 mg
    Reporting group description
    		 LDE225 400 mg + INC424 20 mg

    Reporting group title
    LDE225 400 mg + INC424 20 mg
    Reporting group description
    		 LDE225 400 mg + INC424 20 mg

    Reporting group title
    All Patients
    Reporting group description
    		 All Patients

    Serious adverse events
    		 LDE225 400 mg + INC424 10 mg LDE225 400 mg + INC424 15 mg LDE225 400 mg + INC424 20 mg LDE225 400 mg + INC424 20 mg All Patients
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 8 (62.50%)
    6 / 10 (60.00%)
    2 / 5 (40.00%)
    13 / 27 (48.15%)
    26 / 50 (52.00%)
         number of deaths (all causes)
    1
    1
    1
    1
    4
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 27 (3.70%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 10 (20.00%)
    0 / 5 (0.00%)
    3 / 27 (11.11%)
    5 / 50 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    3 / 3
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myoglobin blood increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 27 (3.70%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    1 / 27 (3.70%)
    2 / 50 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 2
    B-cell lymphoma
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 27 (3.70%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    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
    Cholangiocarcinoma
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic myeloid leukaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 27 (3.70%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    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
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meniscus injury
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 27 (3.70%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    2 / 27 (7.41%)
    2 / 50 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Extramedullary haemopoiesis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Face oedema
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 27 (3.70%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Pyrexia
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    3 / 27 (11.11%)
    5 / 50 (10.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 5
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 27 (3.70%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    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
    Diarrhoea
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    2 / 27 (7.41%)
    2 / 50 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer haemorrhage
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 10 (20.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    2 / 50 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 27 (3.70%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 27 (3.70%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myositis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 27 (3.70%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Diverticulitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 27 (3.70%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    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
    Erysipelas
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 27 (3.70%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    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
    Gastroenteritis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    2 / 27 (7.41%)
    2 / 50 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 27 (3.70%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 LDE225 400 mg + INC424 10 mg LDE225 400 mg + INC424 15 mg LDE225 400 mg + INC424 20 mg LDE225 400 mg + INC424 20 mg All Patients
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 8 (100.00%)
    10 / 10 (100.00%)
    5 / 5 (100.00%)
    27 / 27 (100.00%)
    50 / 50 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    1
    0
    0
    0
    1
    Atypical fibroxanthoma
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    1
    0
    0
    0
    1
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    0
    1
    Vascular disorders
    Aortic stenosis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    1
    0
    0
    0
    1
    Haematoma
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    1 / 27 (3.70%)
    3 / 50 (6.00%)
         occurrences all number
    1
    1
    0
    1
    3
    Hypertension
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    1 / 5 (20.00%)
    5 / 27 (18.52%)
    7 / 50 (14.00%)
         occurrences all number
    0
    1
    1
    5
    7
    Intermittent claudication
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    0
    1
    Peripheral venous disease
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    0
    0
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 8 (12.50%)
    2 / 10 (20.00%)
    1 / 5 (20.00%)
    3 / 27 (11.11%)
    7 / 50 (14.00%)
         occurrences all number
    1
    4
    1
    3
    9
    Catheter site bruise
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    0
    1
    Early satiety
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    1 / 27 (3.70%)
    2 / 50 (4.00%)
         occurrences all number
    0
    1
    0
    1
    2
    Fatigue
         subjects affected / exposed
    6 / 8 (75.00%)
    3 / 10 (30.00%)
    0 / 5 (0.00%)
    8 / 27 (29.63%)
    17 / 50 (34.00%)
         occurrences all number
    9
    3
    0
    11
    23
    Gait disturbance
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    2 / 27 (7.41%)
    2 / 50 (4.00%)
         occurrences all number
    0
    0
    0
    2
    2
    General physical health deterioration
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    1
    0
    0
    0
    1
    Influenza like illness
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    1 / 27 (3.70%)
    3 / 50 (6.00%)
         occurrences all number
    1
    1
    0
    1
    3
    Malaise
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    3 / 27 (11.11%)
    3 / 50 (6.00%)
         occurrences all number
    0
    0
    0
    4
    4
    Oedema peripheral
         subjects affected / exposed
    2 / 8 (25.00%)
    2 / 10 (20.00%)
    0 / 5 (0.00%)
    1 / 27 (3.70%)
    5 / 50 (10.00%)
         occurrences all number
    2
    4
    0
    1
    7
    Pyrexia
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 10 (20.00%)
    2 / 5 (40.00%)
    7 / 27 (25.93%)
    11 / 50 (22.00%)
         occurrences all number
    0
    3
    4
    7
    14
    Thirst
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    0
    1
    Reproductive system and breast disorders
    Erectile dysfunction
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    0
    0
    1
    Cough
         subjects affected / exposed
    1 / 8 (12.50%)
    3 / 10 (30.00%)
    2 / 5 (40.00%)
    5 / 27 (18.52%)
    11 / 50 (22.00%)
         occurrences all number
    1
    3
    2
    6
    12
    Dry throat
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    0
    0
    1
    Dysphonia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    2 / 27 (7.41%)
    3 / 50 (6.00%)
         occurrences all number
    0
    1
    0
    2
    3
    Dyspnoea
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 10 (20.00%)
    0 / 5 (0.00%)
    3 / 27 (11.11%)
    5 / 50 (10.00%)
         occurrences all number
    0
    2
    0
    3
    5
    Epistaxis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    2 / 5 (40.00%)
    3 / 27 (11.11%)
    5 / 50 (10.00%)
         occurrences all number
    0
    0
    2
    3
    5
    Oropharyngeal pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    2 / 27 (7.41%)
    2 / 50 (4.00%)
         occurrences all number
    0
    0
    0
    2
    2
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 10 (20.00%)
    0 / 5 (0.00%)
    1 / 27 (3.70%)
    3 / 50 (6.00%)
         occurrences all number
    0
    2
    0
    1
    3
    Insomnia
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    2 / 27 (7.41%)
    4 / 50 (8.00%)
         occurrences all number
    2
    0
    0
    2
    4
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 8 (12.50%)
    2 / 10 (20.00%)
    1 / 5 (20.00%)
    2 / 27 (7.41%)
    6 / 50 (12.00%)
         occurrences all number
    1
    4
    2
    2
    9
    Amylase increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    2
    0
    2
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 8 (12.50%)
    3 / 10 (30.00%)
    1 / 5 (20.00%)
    2 / 27 (7.41%)
    7 / 50 (14.00%)
         occurrences all number
    1
    4
    2
    2
    9
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    1
    0
    0
    0
    1
    Blood bilirubin increased
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    2 / 27 (7.41%)
    4 / 50 (8.00%)
         occurrences all number
    1
    0
    3
    2
    6
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 8 (12.50%)
    2 / 10 (20.00%)
    3 / 5 (60.00%)
    12 / 27 (44.44%)
    18 / 50 (36.00%)
         occurrences all number
    1
    8
    6
    20
    35
    Blood creatinine increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    3 / 27 (11.11%)
    3 / 50 (6.00%)
         occurrences all number
    0
    0
    0
    3
    3
    Blood prolactin increased
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    0
    0
    1
    Blood uric acid increased
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    1 / 27 (3.70%)
    2 / 50 (4.00%)
         occurrences all number
    0
    1
    0
    1
    2
    Cytomegalovirus test
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    0
    0
    1
    Electrocardiogram QT prolonged
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    1
    0
    0
    0
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    1 / 5 (20.00%)
    0 / 27 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    0
    2
    1
    0
    3
    International normalised ratio increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    0
    1
    Lipase increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    3
    0
    3
    Low density lipoprotein increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    2 / 5 (40.00%)
    1 / 27 (3.70%)
    3 / 50 (6.00%)
         occurrences all number
    0
    0
    3
    1
    4
    Platelet count decreased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    4 / 27 (14.81%)
    4 / 50 (8.00%)
         occurrences all number
    0
    0
    0
    4
    4
    Prothrombin level increased
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    1
    0
    0
    0
    1
    Prothrombin time prolonged
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    0
    1
    Weight decreased
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    2 / 27 (7.41%)
    4 / 50 (8.00%)
         occurrences all number
    2
    0
    0
    2
    4
    Weight increased
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    1 / 27 (3.70%)
    3 / 50 (6.00%)
         occurrences all number
    1
    1
    0
    1
    3
    Injury, poisoning and procedural complications
    Animal bite
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    2 / 27 (7.41%)
    2 / 50 (4.00%)
         occurrences all number
    0
    0
    0
    2
    2
    Contusion
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 10 (0.00%)
    2 / 5 (40.00%)
    3 / 27 (11.11%)
    6 / 50 (12.00%)
         occurrences all number
    4
    0
    3
    5
    12
    Fall
         subjects affected / exposed
    2 / 8 (25.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    1 / 27 (3.70%)
    4 / 50 (8.00%)
         occurrences all number
    2
    1
    0
    1
    4
    Hyphaema
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    1
    0
    0
    0
    1
    Laceration
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    0
    1
    Meniscus injury
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    0
    0
    1
    Procedural hypotension
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    0
    0
    1
    Scratch
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    0
    1
    Spinal compression fracture
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    0
    0
    1
    Tooth fracture
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    0
    0
    1
    Cardiac disorders
    Supraventricular extrasystoles
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    1
    0
    0
    0
    1
    Nervous system disorders
    Amnesia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    1
    0
    0
    0
    1
    Carpal tunnel syndrome
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    0
    1
    Cerebral ischaemia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    1
    0
    0
    0
    1
    Dizziness
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    4 / 27 (14.81%)
    5 / 50 (10.00%)
         occurrences all number
    2
    0
    0
    4
    6
    Dysaesthesia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    0
    0
    1
    Dysgeusia
         subjects affected / exposed
    3 / 8 (37.50%)
    4 / 10 (40.00%)
    3 / 5 (60.00%)
    9 / 27 (33.33%)
    19 / 50 (38.00%)
         occurrences all number
    4
    4
    3
    10
    21
    Head discomfort
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    0
    0
    1
    Headache
         subjects affected / exposed
    1 / 8 (12.50%)
    2 / 10 (20.00%)
    0 / 5 (0.00%)
    5 / 27 (18.52%)
    8 / 50 (16.00%)
         occurrences all number
    1
    3
    0
    6
    10
    Hypoaesthesia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    1
    0
    0
    0
    1
    Memory impairment
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    2 / 27 (7.41%)
    3 / 50 (6.00%)
         occurrences all number
    0
    1
    0
    2
    3
    Muscle contractions involuntary
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    1 / 5 (20.00%)
    0 / 27 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    0
    1
    1
    0
    2
    Paraesthesia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    1
    0
    0
    0
    1
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    0
    0
    1
    Post herpetic neuralgia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 27 (3.70%)
    2 / 50 (4.00%)
         occurrences all number
    1
    0
    0
    1
    2
    Restless legs syndrome
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    2
    0
    2
    Syncope
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    0
    0
    1
    Transient ischaemic attack
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    1
    0
    0
    0
    1
    Tremor
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    2 / 27 (7.41%)
    2 / 50 (4.00%)
         occurrences all number
    0
    0
    0
    2
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    5 / 8 (62.50%)
    4 / 10 (40.00%)
    4 / 5 (80.00%)
    16 / 27 (59.26%)
    29 / 50 (58.00%)
         occurrences all number
    14
    5
    7
    23
    49
    Extramedullary haemopoiesis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    0
    0
    1
    Leukocytosis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    1
    0
    0
    0
    1
    Neutropenia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 27 (3.70%)
    2 / 50 (4.00%)
         occurrences all number
    1
    0
    0
    1
    2
    Thrombocytopenia
         subjects affected / exposed
    3 / 8 (37.50%)
    2 / 10 (20.00%)
    3 / 5 (60.00%)
    7 / 27 (25.93%)
    15 / 50 (30.00%)
         occurrences all number
    4
    2
    6
    15
    27
    Eye disorders
    Retinal detachment
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    1
    0
    0
    0
    1
    Vision blurred
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    1
    0
    0
    0
    1
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    1 / 27 (3.70%)
    3 / 50 (6.00%)
         occurrences all number
    1
    0
    2
    1
    4
    Abdominal distension
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    1 / 27 (3.70%)
    2 / 50 (4.00%)
         occurrences all number
    0
    1
    0
    1
    2
    Abdominal pain
         subjects affected / exposed
    2 / 8 (25.00%)
    3 / 10 (30.00%)
    0 / 5 (0.00%)
    4 / 27 (14.81%)
    9 / 50 (18.00%)
         occurrences all number
    2
    3
    0
    4
    9
    Abdominal pain upper
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    1 / 27 (3.70%)
    2 / 50 (4.00%)
         occurrences all number
    0
    0
    1
    1
    2
    Bile acid malabsorption
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    0
    1
    Constipation
         subjects affected / exposed
    2 / 8 (25.00%)
    1 / 10 (10.00%)
    1 / 5 (20.00%)
    7 / 27 (25.93%)
    11 / 50 (22.00%)
         occurrences all number
    3
    1
    2
    9
    15
    Diarrhoea
         subjects affected / exposed
    3 / 8 (37.50%)
    3 / 10 (30.00%)
    4 / 5 (80.00%)
    11 / 27 (40.74%)
    21 / 50 (42.00%)
         occurrences all number
    4
    5
    7
    16
    32
    Diverticulum
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    0
    1
    Diverticulum intestinal
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    0
    0
    1
    Dry mouth
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    3 / 27 (11.11%)
    3 / 50 (6.00%)
         occurrences all number
    0
    0
    0
    3
    3
    Duodenal ulcer
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    1 / 27 (3.70%)
    2 / 50 (4.00%)
         occurrences all number
    0
    0
    1
    1
    2
    Dyspepsia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    1 / 27 (3.70%)
    2 / 50 (4.00%)
         occurrences all number
    0
    1
    0
    1
    2
    Flatulence
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    0
    0
    1
    Functional gastrointestinal disorder
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    0
    1
    Gastric ulcer
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    0
    1
    Gastric varices
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    0
    1
    Gastritis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    1 / 5 (20.00%)
    0 / 27 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    0
    1
    1
    0
    2
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    1 / 27 (3.70%)
    2 / 50 (4.00%)
         occurrences all number
    0
    1
    0
    1
    2
    Haematochezia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    1 / 5 (20.00%)
    0 / 27 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    0
    1
    1
    0
    2
    Melaena
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    0
    0
    1
    Nausea
         subjects affected / exposed
    3 / 8 (37.50%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    8 / 27 (29.63%)
    12 / 50 (24.00%)
         occurrences all number
    3
    2
    0
    9
    14
    Stomatitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    1 / 27 (3.70%)
    2 / 50 (4.00%)
         occurrences all number
    0
    0
    1
    1
    2
    Toothache
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    1 / 27 (3.70%)
    2 / 50 (4.00%)
         occurrences all number
    0
    0
    1
    1
    2
    Vomiting
         subjects affected / exposed
    3 / 8 (37.50%)
    2 / 10 (20.00%)
    1 / 5 (20.00%)
    5 / 27 (18.52%)
    11 / 50 (22.00%)
         occurrences all number
    3
    2
    2
    5
    12
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    0 / 27 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    1
    0
    1
    0
    2
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    1
    0
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    1 / 27 (3.70%)
    2 / 50 (4.00%)
         occurrences all number
    0
    1
    0
    1
    2
    Alopecia
         subjects affected / exposed
    3 / 8 (37.50%)
    7 / 10 (70.00%)
    3 / 5 (60.00%)
    12 / 27 (44.44%)
    25 / 50 (50.00%)
         occurrences all number
    3
    7
    3
    12
    25
    Erythema
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    0
    1
    Hair growth abnormal
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    2 / 27 (7.41%)
    2 / 50 (4.00%)
         occurrences all number
    0
    0
    0
    3
    3
    Hyperkeratosis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    0
    1
    Madarosis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    1 / 27 (3.70%)
    2 / 50 (4.00%)
         occurrences all number
    0
    0
    1
    1
    2
    Night sweats
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    1 / 5 (20.00%)
    3 / 27 (11.11%)
    5 / 50 (10.00%)
         occurrences all number
    0
    1
    1
    4
    6
    Onychoclasis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    0
    1
    Pruritus
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 10 (20.00%)
    2 / 5 (40.00%)
    0 / 27 (0.00%)
    4 / 50 (8.00%)
         occurrences all number
    0
    2
    2
    0
    4
    Pruritus generalised
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    2 / 5 (40.00%)
    0 / 27 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    0
    0
    2
    0
    2
    Rash
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    2 / 27 (7.41%)
    4 / 50 (8.00%)
         occurrences all number
    1
    1
    0
    2
    4
    Skin discolouration
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    0
    0
    1
    Swelling face
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    0
    0
    1
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    1 / 27 (3.70%)
    2 / 50 (4.00%)
         occurrences all number
    0
    1
    0
    1
    2
    Haematuria
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    0
    0
    1
    Urinary retention
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 8 (25.00%)
    2 / 10 (20.00%)
    0 / 5 (0.00%)
    1 / 27 (3.70%)
    5 / 50 (10.00%)
         occurrences all number
    2
    3
    0
    1
    6
    Back pain
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 10 (20.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    0
    2
    0
    0
    2
    Bone pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    2 / 27 (7.41%)
    2 / 50 (4.00%)
         occurrences all number
    0
    0
    0
    2
    2
    Joint lock
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    0
    0
    1
    Muscle fatigue
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    0
    0
    1
    Muscle spasms
         subjects affected / exposed
    3 / 8 (37.50%)
    6 / 10 (60.00%)
    4 / 5 (80.00%)
    18 / 27 (66.67%)
    31 / 50 (62.00%)
         occurrences all number
    3
    9
    8
    29
    49
    Muscle twitching
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    0
    0
    1
    Muscular weakness
         subjects affected / exposed
    1 / 8 (12.50%)
    4 / 10 (40.00%)
    1 / 5 (20.00%)
    2 / 27 (7.41%)
    8 / 50 (16.00%)
         occurrences all number
    1
    4
    1
    2
    8
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    3 / 27 (11.11%)
    4 / 50 (8.00%)
         occurrences all number
    0
    0
    1
    3
    4
    Musculoskeletal pain
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    2
    0
    0
    0
    2
    Myalgia
         subjects affected / exposed
    1 / 8 (12.50%)
    3 / 10 (30.00%)
    0 / 5 (0.00%)
    9 / 27 (33.33%)
    13 / 50 (26.00%)
         occurrences all number
    2
    4
    0
    16
    22
    Osteoarthritis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    0
    0
    1
    Pain in extremity
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    3 / 27 (11.11%)
    5 / 50 (10.00%)
         occurrences all number
    1
    0
    1
    6
    8
    Polyarthritis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    0
    0
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    1 / 27 (3.70%)
    3 / 50 (6.00%)
         occurrences all number
    1
    1
    0
    1
    3
    Cystitis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    1 / 27 (3.70%)
    2 / 50 (4.00%)
         occurrences all number
    0
    2
    0
    1
    3
    Ear infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    0
    1
    Escherichia infection
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    0
    0
    1
    Folliculitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    3 / 27 (11.11%)
    3 / 50 (6.00%)
         occurrences all number
    0
    0
    0
    3
    3
    Fungal skin infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    0
    1
    Gastroenteritis viral
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    1
    0
    0
    0
    1
    Herpes zoster
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    2 / 27 (7.41%)
    3 / 50 (6.00%)
         occurrences all number
    1
    0
    0
    2
    3
    Influenza
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    2 / 27 (7.41%)
    2 / 50 (4.00%)
         occurrences all number
    0
    0
    0
    2
    2
    Nasopharyngitis
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 10 (20.00%)
    2 / 5 (40.00%)
    2 / 27 (7.41%)
    6 / 50 (12.00%)
         occurrences all number
    0
    2
    2
    6
    10
    Oesophageal candidiasis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    0
    1
    Oral herpes
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    1
    0
    0
    0
    1
    Pharyngitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    0
    1
    Pneumonia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    2 / 27 (7.41%)
    4 / 50 (8.00%)
         occurrences all number
    1
    0
    1
    2
    4
    Tooth infection
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 27 (3.70%)
    2 / 50 (4.00%)
         occurrences all number
    1
    0
    0
    1
    2
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 8 (12.50%)
    3 / 10 (30.00%)
    1 / 5 (20.00%)
    2 / 27 (7.41%)
    7 / 50 (14.00%)
         occurrences all number
    2
    3
    1
    3
    9
    Urinary tract infection
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    2 / 27 (7.41%)
    4 / 50 (8.00%)
         occurrences all number
    1
    1
    0
    3
    5
    Urinary tract infection bacterial
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    1
    3
    0
    0
    4
    Wound infection
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    0
    0
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    3 / 8 (37.50%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    4 / 27 (14.81%)
    7 / 50 (14.00%)
         occurrences all number
    4
    0
    0
    4
    8
    Hyperkalaemia
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    2
    1
    0
    0
    3
    Hypertriglyceridaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    3
    0
    3
    Hyperuricaemia
         subjects affected / exposed
    1 / 8 (12.50%)
    3 / 10 (30.00%)
    1 / 5 (20.00%)
    1 / 27 (3.70%)
    6 / 50 (12.00%)
         occurrences all number
    1
    4
    1
    1
    7
    Hypocalcaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    0
    1
    Hypokalaemia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    1
    0
    0
    0
    1
    Hypomagnesaemia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    1
    0
    0
    0
    1
    Hyponatraemia
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 27 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    1
    1
    0
    0
    2
    Increased appetite
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    1 / 27 (3.70%)
    2 / 50 (4.00%)
         occurrences all number
    0
    1
    0
    1
    2
    Iron deficiency
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    0 / 27 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Aug 2014
    Issued after thirty six subjects were screened, 30 subjects treated, and six subjects were screen failures in the Phase Ib part of the study. Five of the treated subjects have discontinued treatment due to disease progression, adverse events, physician decision or subject decision. Out of nine subjects in the DDS at the 400mg LDE225 qd + 15 mg INC424 bid dose level, two DLTs occurred during the 6 week (42 day) DLT observation period. The MTD was not reached and instead the RPIID was defined as the 400mg LDE225 qd + 20mg INC424 bid dose level. Subjects enrolled in the Phase Ib safety expansion cohort at 400mg LDE225 qd + 20mg INC424 bid were being observed in order to confirm the RPIID. Following major changes were introduced: Addition of an exploratory endpoint to assess the levels of LDE225 in bone marrow, updates to the guidance for contraception based on a recent population pharmacokinetic analysis and updates to the muscle toxicity section for CK elevation.
    06 Feb 2015
    Issued after 57 subjects were screened, 50 subjects treated (30 in the Phase Ib part and 20 in the Stage 1, Phase II part), and 7 subjects were screen failures. Fourteen of the treated subjects have discontinued treatment due to disease progression, adverse events, physician decision or subject decision. The RPIID was confirmed as the 400mg LDE225 qd + 20 mg INC424 bid dose level. Subjects enrolled in the Stage 1, Phase II part of the study are currently being observed for 24 weeks, and an interim analysis was to occur at the end of the observation period. Following major changes were introduced: Add a treatment extension phase for subjects who complete 2 years of study treatment and are deriving clinical benefit according to the investigator until other alternatives to receive study treatment from the sponsor become available.

    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.
    Please refer to detailed description regarding reason for early termination of study.
    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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