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    Clinical Trial Results:
    A Phase Ib dose escalation/randomized Phase II, multicenter, open-label study of BYL719 in combination with cetuximab in patients with recurrent or metastatic head and neck squamous cell carcinoma

    Summary
    EudraCT number
    		 2011-006017-34
    Trial protocol
    		 NL   FR  
    Global end of trial date
    09 May 2016

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

    Trial information

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    Trial identification
    Sponsor protocol code
    CBYL719X2104
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, +41 613241111,
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, +41 613241111,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    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
    09 May 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 May 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    09 May 2016
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Phase Ib •Arm A and B: To estimate the maximum tolerated dose (MTD(s)) and/or recommended Phase II dose (RP2D) of BYL719 in combination with cetuximab in patients with recurrent or metastatic head and neck squamous cell carcinoma (RM HNSCC) in the following two arms: •Arm A: BYL719 administered orally as a film-coated whole tablet in patients able to swallow the tablets. •Arm B: BYL719 administered orally as a drinkable suspension prepared from film-coated crushed tablets in patients with swallowing dysfunction. •Arm C: To compare single-dose exposure of BYL719 dispersible tablet via G-tube in combination with cetuximab in RM HNSCC to that of Arm A (film-coated tablets). Phase II •Scheme 1: To assess the anti-tumor activity of BYL719 in combination with cetuximab vs. cetuximab as single-agent in RM HNSCC patients naïve to cetuximab. •Scheme 2: To assess the anti-tumor activity of BYL719 in combination with cetuximab in RM HNSCC cetuximab resistant patients.
    Protection of trial subjects
    The trial 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
    12 Nov 2012
    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: 9
    Country: Number of subjects enrolled
    Canada: 18
    Country: Number of subjects enrolled
    France: 25
    Country: Number of subjects enrolled
    Hong Kong: 1
    Country: Number of subjects enrolled
    Korea, Republic of: 21
    Country: Number of subjects enrolled
    Netherlands: 7
    Country: Number of subjects enrolled
    Singapore: 7
    Country: Number of subjects enrolled
    Taiwan: 31
    Country: Number of subjects enrolled
    United States: 61
    Worldwide total number of subjects
    180
    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)
    135
    From 65 to 84 years
    45
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 All patients have completed the trial.

    Pre-assignment
    Screening details
    		 45 patients enrolled in Phase Ib, 106 cetuximab naïve patients in Phase II were randomized to either BYL719+cet (N=71) or cet monotherapy (N=35). Of the 35 patients, 16 crossed over to BYL719+cet combo treatment. 29 patients enrolled in the non-randomized combo treatment arm (cet resistant patients).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A - 300mg BYL719+Cetuximab
    Arm description
    		 300 mg BYL719 as film-coated (FC) whole tablets with cetuximab in Phase Ib
    Arm type
    		 Experimental

    Investigational medicinal product name
    BYL719
    Investigational medicinal product code
    BYL719
    Other name
    Alpelisib
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    BYL719 at 300mg once daily (film-coated tablets without swallowing dysfunction) with cetuximab at 400 mg/m2 on cycle 1 Day 1 and 250 mg/m2 weekly.

    Arm title
    		 Arm A - 400mg BYL719+Cetuximab
    Arm description
    		 400 mg BYL719 as FC whole tablets with cetuximab in Phase Ib
    Arm type
    		 Experimental

    Investigational medicinal product name
    BYL719
    Investigational medicinal product code
    BYL719
    Other name
    Alpelisib
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    BYL719 at 400mg once daily (film-coated tablets without swallowing dysfunction) with cetuximab at 400 mg/m2 on cycle 1 Day 1 and 250 mg/m2 weekly.

    Arm title
    		 Arm B - BYL719 + Cetuximab, Oral suspension
    Arm description
    		 300mg BYL719 as crushed FC tablets with cetuxumab in patients with swallowing dysfunction in Phase Ib.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BYL719
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    BYL719 at 300mg once daily with cetuximab at 400 mg/m2 on cycle 1 Day 1 and 250 mg/m2 weekly. Patients with swallowing dysfunction without G tube, BYL719 film-coated tablets were administered as drinkable suspension by crushing the tablets and suspending them in water.

    Arm title
    		 Arm C - BYL719+Cetuximab, Dispersible tablets
    Arm description
    		 300mg BYL719 dispersible tablets with cetuxumab in patients with swallowing dysfunction administered via G-tube in Phase Ib.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BYL719
    Investigational medicinal product code
    BYL719
    Other name
    Pharmaceutical forms
    Dispersible tablet
    Routes of administration
    Gastroenteral use
    Dosage and administration details
    BYL719 dispersible tablets were suspended in water and administered via the gastronomy tube ( G-tube). BYL719 at 300mg once daily with cetuximab at 400 mg/m2 on cycle 1 Day 1 and 250 mg/m2 weekly.

    Arm title
    		 Arm 1 - BYL719+Cetuximab (randomized)
    Arm description
    		 300mg BYL719 with cetuxumab (Phase II) in patients resistant to or intolerant/ineligible for platinum-based chemotherapy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BYL719
    Investigational medicinal product code
    Other name
    Alpelisib
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    300 mg BYL719 was administered as whole tablet. Patients were instructed to take BYL719 daily in the morning approximately 1 hour after the start of a light breakfast at approximately the same time each day. Patients were to fast for 1 hour after the administration of BYL719. Cetuximab was administered intravenously weekly on Day 1, Day 8, Day 15, and Day 22 of every cycle at the study site with a ± 3 day time window.

    Arm title
    		 Arm 2 - Monotherapy Cetuximab (randomized)
    Arm description
    		 Cetuximab in Phase II in patients resistant to or intolerant/ineligible for platinum-based chemotherapy.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Cetuximab
    Investigational medicinal product code
    Other name
    erbitux
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cetuximab was administered intravenously weekly on Day 1, Day 8, Day 15, and Day 22 of every cycle at the study site with a ± 3 day time window. Cetuximab at 400 mg/m2 on cycle 1 Day 1 and 250 mg/m2 weekly

    Arm title
    		 Arm 3 - BYL719+Cetuximab (non-randomized)
    Arm description
    		 300mg BYL719 with cetuximab in Phase II in patients resistant to platinum-based therapy and cetuximab
    Arm type
    		 Experimental

    Investigational medicinal product name
    BYL719
    Investigational medicinal product code
    Other name
    Alpelisib
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    300 mg BYL719 was administered as whole tablet. Patients were instructed to take BYL719 daily in the morning approximately 1 hour after the start of a light breakfast at approximately the same time each day. Patients were to fast for 1 hour after the administration of BYL719. Cetuximab was administered intravenously weekly on Day 1, Day 8, Day 15, and Day 22 of every cycle at the study site with a ± 3 day time window.

    Number of subjects in period 1
    		Arm A - 300mg BYL719+Cetuximab Arm A - 400mg BYL719+Cetuximab Arm B - BYL719 + Cetuximab, Oral suspension Arm C - BYL719+Cetuximab, Dispersible tablets Arm 1 - BYL719+Cetuximab (randomized) Arm 2 - Monotherapy Cetuximab (randomized) Arm 3 - BYL719+Cetuximab (non-randomized)
    Started
    16
    5
    18
    6
    71
    35
    29
    Completed
    0
    0
    0
    0
    0
    0
    0
    Not completed
    16
    5
    18
    6
    71
    35
    29
         Adverse event, serious fatal
    1
    1
    1
    1
    7
    2
    2
         Consent withdrawn by subject
    2
    -
    2
    -
    6
    -
    1
         Physician decision
    2
    -
    -
    -
    2
    1
    1
         Disease progression
    6
    3
    10
    1
    41
    12
    15
         Adverse event, non-fatal
    5
    1
    5
    4
    15
    3
    9
         Cross-over patients to combo treatment
    -
    -
    -
    -
    -
    16
    -
         Subject/guardian decision
    -
    -
    -
    -
    -
    -
    1
         Protocol deviation
    -
    -
    -
    -
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A - 300mg BYL719+Cetuximab
    Reporting group description
    		 300 mg BYL719 as film-coated (FC) whole tablets with cetuximab in Phase Ib

    Reporting group title
    Arm A - 400mg BYL719+Cetuximab
    Reporting group description
    		 400 mg BYL719 as FC whole tablets with cetuximab in Phase Ib

    Reporting group title
    Arm B - BYL719 + Cetuximab, Oral suspension
    Reporting group description
    		 300mg BYL719 as crushed FC tablets with cetuxumab in patients with swallowing dysfunction in Phase Ib.

    Reporting group title
    Arm C - BYL719+Cetuximab, Dispersible tablets
    Reporting group description
    		 300mg BYL719 dispersible tablets with cetuxumab in patients with swallowing dysfunction administered via G-tube in Phase Ib.

    Reporting group title
    Arm 1 - BYL719+Cetuximab (randomized)
    Reporting group description
    		 300mg BYL719 with cetuxumab (Phase II) in patients resistant to or intolerant/ineligible for platinum-based chemotherapy.

    Reporting group title
    Arm 2 - Monotherapy Cetuximab (randomized)
    Reporting group description
    		 Cetuximab in Phase II in patients resistant to or intolerant/ineligible for platinum-based chemotherapy.

    Reporting group title
    Arm 3 - BYL719+Cetuximab (non-randomized)
    Reporting group description
    		 300mg BYL719 with cetuximab in Phase II in patients resistant to platinum-based therapy and cetuximab

    Reporting group values
    		 Arm A - 300mg BYL719+Cetuximab Arm A - 400mg BYL719+Cetuximab Arm B - BYL719 + Cetuximab, Oral suspension Arm C - BYL719+Cetuximab, Dispersible tablets Arm 1 - BYL719+Cetuximab (randomized) Arm 2 - Monotherapy Cetuximab (randomized) Arm 3 - BYL719+Cetuximab (non-randomized) Total
    Number of subjects
    		 16 5 18 6 71 35 29 180
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 13 2 14 3 55 25 23 135
        From 65-84 years
    		 3 3 4 3 16 10 6 45
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 52.8 ( 13.4 ) 62.6 ( 7.99 ) 56.7 ( 10.2 ) 60.5 ( 14.1 ) 57.2 ( 9.66 ) 57.1 ( 10.37 ) 56.9 ( 8.25 ) -
    Gender, Male/Female
    Units: Subjects
        Female
    		 7 1 4 2 16 4 10 44
        Male
    		 9 4 14 4 55 31 19 136

    End points

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    End points reporting groups
    Reporting group title
    Arm A - 300mg BYL719+Cetuximab
    Reporting group description
    		 300 mg BYL719 as film-coated (FC) whole tablets with cetuximab in Phase Ib

    Reporting group title
    Arm A - 400mg BYL719+Cetuximab
    Reporting group description
    		 400 mg BYL719 as FC whole tablets with cetuximab in Phase Ib

    Reporting group title
    Arm B - BYL719 + Cetuximab, Oral suspension
    Reporting group description
    		 300mg BYL719 as crushed FC tablets with cetuxumab in patients with swallowing dysfunction in Phase Ib.

    Reporting group title
    Arm C - BYL719+Cetuximab, Dispersible tablets
    Reporting group description
    		 300mg BYL719 dispersible tablets with cetuxumab in patients with swallowing dysfunction administered via G-tube in Phase Ib.

    Reporting group title
    Arm 1 - BYL719+Cetuximab (randomized)
    Reporting group description
    		 300mg BYL719 with cetuxumab (Phase II) in patients resistant to or intolerant/ineligible for platinum-based chemotherapy.

    Reporting group title
    Arm 2 - Monotherapy Cetuximab (randomized)
    Reporting group description
    		 Cetuximab in Phase II in patients resistant to or intolerant/ineligible for platinum-based chemotherapy.

    Reporting group title
    Arm 3 - BYL719+Cetuximab (non-randomized)
    Reporting group description
    		 300mg BYL719 with cetuximab in Phase II in patients resistant to platinum-based therapy and cetuximab

    Subject analysis set title
    0-0.16
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Posterior probabilities (%) that Pr(DLT) is in interval

    Subject analysis set title
    0.16-0.35
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Posterior probabilities (%) that Pr(DLT) is in interval

    Subject analysis set title
    0.35-1
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Posterior probabilities (%) that Pr(DLT) is in interval

    Subject analysis set title
    All Patients
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All patients in Phase Ib

    Subject analysis set title
    BYL719+ Cetuximab (randomized)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    300mg BYL719 with cetuximab (Phase II) in patients resistant to or intolerant/ineligible for platinum-based chemotherapy.

    Subject analysis set title
    Monotherapy Cetuximab (randomized)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Cetuximab in Phase II in patients resistant to or intolerant/ineligible for platinum-based chemotherapy.

    Subject analysis set title
    BYL719+ Cetuximab (non-randomized)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    300mg BYL719 with cetuximab in patients resistant to platinum-based therapy and cetuximab in Phase II

    Subject analysis set title
    Arm C: BYL719+Cetixumab, Dispersible tablets
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    300mg BYL719 dispersible tablets with cetuxumab in patients with swallowing dysfunction administered via G-tube

    Subject analysis set title
    Arm A: 400mg BYL719 + Cetuximab
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    400 mg BYL719 as FC whole tablets with cetuximab

    Subject analysis set title
    Arm 2B - BYL719+Cetuximab
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    300mg BYL719 with cetuximab in Phase II in patients resistant to platinum-based therapy and cetuximab

    Subject analysis set title
    All Patients
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All patients

    Subject analysis set title
    Arm 3 - BYL719+Cetuximab
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    300mg BYL719 with cetuximab in Phase II in patients resistant to platinum-based therapy and cetuximab

    Subject analysis set title
    All Patients (Phase II)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All Patients in Phase II

    Subject analysis set title
    All Patients
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    BYL719 + Cetuximab in Phase II (non-randomized) in patients resistant to or intolerant/ineligible for platinum-based

    Subject analysis set title
    Arm B: BYL719 + Cetuximab, Oral suspension
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    300mg BYL719 as crushed FC tablets with cetuxumab in patients with swallowing dysfunction

    Subject analysis set title
    Arm 2B - BYL719+Cetuximab
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    300mg BYL719 with cetuximab in Phase II in patients resistant to platinum-based therapy and cetuximab

    Primary: Phase Ib Arms A: Posterior Distribution of Dose Limiting Toxicities (DLTs) at Recommended Phase 2 Dose in Cycle 1 (Cycle 1=28 days)

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    End point title
    		 Phase Ib Arms A: Posterior Distribution of Dose Limiting Toxicities (DLTs) at Recommended Phase 2 Dose in Cycle 1 (Cycle 1=28 days) [1]
    End point description
    Maximum Tolerated Doses (MTDs) and/or recommended Phase II doses (RP2Ds) of BYL719 in combination with cetuximab in patients with recurrent or metastatic head and neck squamous cell carcinoma (RM HNSCC) in arm A (BYL719 administered as a whole tablet in patients able to swallow the tablets). 6 months is an approximate timeframe.
    End point type
    Primary
    End point timeframe
    until disease progression or intolerable toxicity (approximately 6 months)
    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: Descriptive analyses.
    End point values
    		 0-0.16 0.16-0.35 0.35-1
    Number of subjects analysed
    15
    15
    15
    Units: Percentages
    number (not applicable)
        200 mg
    0.964
    0.035
    0.001
        300 mg
    0.764
    0.222
    0.15
        350 mg
    0.304
    0.543
    0.153
        400 mg
    0.086
    0.376
    0.538
    No statistical analyses for this end point

    Primary: Phase Ib Arms B: Posterior Distribution of Dose Limiting Toxicities (DLTs) at Recommended Phase 2 Dose in Cycle 1 (Cycle 1=28 days)

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    End point title
    		 Phase Ib Arms B: Posterior Distribution of Dose Limiting Toxicities (DLTs) at Recommended Phase 2 Dose in Cycle 1 (Cycle 1=28 days) [2]
    End point description
    Maximum Tolerated Doses (MTDs) and/or recommended Phase II doses (RP2Ds) of BYL719 in combination with cetuximab in patients with recurrent or metastatic head and neck squamous cell carcinoma (RM HNSCC) in arm B (crushed film-coated tablets as an oral suspension with swallowing dysfunction). 6 months is an approximate timeframe.
    End point type
    Primary
    End point timeframe
    until disease progression or intolerable toxicity (approximately 6 months)
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive analyses.
    End point values
    		 0-0.16 0.16-0.35 0.35-1
    Number of subjects analysed
    15
    15
    15
    Units: Percentages
    number (not applicable)
        200 mg
    0.836
    0.16
    0.004
        300 mg
    0.267
    0.664
    0.069
        350 mg
    0.054
    0.585
    0.361
        400 mg
    0.017
    0.346
    0.638
    No statistical analyses for this end point

    Primary: For Phase Ib: Incidence of Dose Limiting Toxicities (DLTs) in Cycle 1 (28 days)

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    End point title
    		 For Phase Ib: Incidence of Dose Limiting Toxicities (DLTs) in Cycle 1 (28 days) [3] [4]
    End point description
    Estimation of Maximum Tolerated Doses (MTDs) and/or recommended Phase II doses (RP2Ds) of BYL719 in combination with cetuximab in patients with recurrent or metastatic head and neck squamous cell carcinoma (RM HNSCC) in arm A (BYL719 administered as a whole tablet in patients able to swallow the tablets) and arm B (BYL719 administered as a drinkable suspension in patients with swallowing dysfunction). 6 months is an approximate timeframe.
    End point type
    Primary
    End point timeframe
    until disease progression or intolerable toxicity (approximately 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: Descriptive analyses.
    [4] - 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: Descriptive analyses.
    End point values
    		 Arm A - 300mg BYL719+Cetuximab Arm A - 400mg BYL719+Cetuximab Arm B - BYL719 + Cetuximab, Oral suspension Arm C - BYL719+Cetuximab, Dispersible tablets All Patients
    Number of subjects analysed
    11
    3
    13
    3
    30
    Units: Participants
    1
    2
    4
    2
    30
    No statistical analyses for this end point

    Primary: Phase II Arms 1 and 2: Progression Free Survival (PFS) as per RECIST v1.1 by central radiology review

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    End point title
    		 Phase II Arms 1 and 2: Progression Free Survival (PFS) as per RECIST v1.1 by central radiology review
    End point description
    Assessment of the anti-tumor activity of BYL719 in combination with cetuximab vs. cetuximab as single-agent in RM HNSCC patients naive to cetuximab. 6 months is an approximate timeframe.
    End point type
    Primary
    End point timeframe
    approximately 6 months
    End point values
    		 BYL719+ Cetuximab (randomized) Monotherapy Cetuximab (randomized)
    Number of subjects analysed
    71
    35
    Units: participants
        Number of PFS events
    46
    27
        Progression
    33
    25
        Number of censored
    25
    8
        Death
    13
    2
    Statistical analysis title
    		 PFS by central radiology review
    Statistical analysis description
    The hazard ratio was estimated using the Bayesian Cox proportional hazard (PH) model.
    Comparison groups
    BYL719+ Cetuximab (randomized) v Monotherapy Cetuximab (randomized)
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 median HR
    Point estimate
    0.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.643
         upper limit
    		 1.529
    Statistical analysis title
    		 PFS by central radiology review
    Comparison groups
    BYL719+ Cetuximab (randomized) v Monotherapy Cetuximab (randomized)
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.643
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.69
         upper limit
    		 1.82
    Statistical analysis title
    		 PFS by central radiology review
    Statistical analysis description
    Adjusted on Covariates: treatment, sum of longest diameters from central data [SLD (C)], Hemaglobin (Hgb) and White Blood Cells (WBC).
    Comparison groups
    BYL719+ Cetuximab (randomized) v Monotherapy Cetuximab (randomized)
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.039
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.3
         upper limit
    		 0.97

    Primary: Phase II Arm 3: Progression Free Survival (PFS) as per RECIST V1.1

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    End point title
    		 Phase II Arm 3: Progression Free Survival (PFS) as per RECIST V1.1 [5]
    End point description
    Assessment of the anti-tumor activity of BYL719 in combination with cetuximab in patients resistant to platinum-based therapy and cetuximab.
    End point type
    Primary
    End point timeframe
    approximately 6 months
    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: Descriptive analyses.
    End point values
    		 BYL719+ Cetuximab (non-randomized)
    Number of subjects analysed
    29
    Units: months
        median (confidence interval 95%)
    3.896 (2.868 to 5.241)
    No statistical analyses for this end point

    Primary: Phase Ib: Area under curve (AUC) 0-24 for BYL719 by Treatment

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    End point title
    		 Phase Ib: Area under curve (AUC) 0-24 for BYL719 by Treatment [6] [7]
    End point description
    Comparison of single-dose exposure of BYL719 dispersible tablet via G-tube in combination with cetuximab in RM HNSCC to that of Arm A (film-coated tables)
    End point type
    Primary
    End point timeframe
    6 months
    Notes
    [6] - 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: Descriptive analyses.
    [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: Descriptive analyses.
    End point values
    		 Arm A - 300mg BYL719+Cetuximab Arm C: BYL719+Cetixumab, Dispersible tablets Arm A: 400mg BYL719 + Cetuximab
    Number of subjects analysed
    15
    6
    5
    Units: hr*ng/mL
    median (full range (min-max))
        AUCinf
    22600 (16600 to 48500)
    24100 (9290 to 33200)
    27800 (17200 to 60100)
        AUC0_24
    18800 (5590 to 43400)
    19400 (7580 to 32100)
    26300 (16000 to 56100)
        AUClast
    19200 (5830 to 42700)
    22100 (4390 to 31800)
    26200 (15800 to 55600)
    No statistical analyses for this end point

    Secondary: Phase II: Progression Free Survival (PFS) as per RECIST v 1.1

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    End point title
    		 Phase II: Progression Free Survival (PFS) as per RECIST v 1.1
    End point description
    Phase II, Scheme 1 (Arm 2B): To further assess the anti-tumor activity of BYL719 + cetuximab in the setting of resistance to single agent cetuximab
    End point type
    Secondary
    End point timeframe
    approximately 6 months
    End point values
    		 Arm 2B - BYL719+Cetuximab
    Number of subjects analysed
    16
    Units: Participants
        Number of PFS
    12
        Progression
    9
        Death
    3
        Number of Censored
    4
    No statistical analyses for this end point

    Secondary: Phase Ib: Progression Free Survival (PFS) as per RECIST v1.1

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    End point title
    		 Phase Ib: Progression Free Survival (PFS) as per RECIST v1.1 [8]
    End point description
    Assessment of the preliminary anti-tumor activity of BYL719 in combination with cetuximab in arm A, B and C This endpoint was not analyzed because the trial terminated early.
    End point type
    Secondary
    End point timeframe
    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: Descriptive analyses.
    End point values
    		 Arm A - 300mg BYL719+Cetuximab Arm A - 400mg BYL719+Cetuximab Arm B - BYL719 + Cetuximab, Oral suspension Arm C - BYL719+Cetuximab, Dispersible tablets
    Number of subjects analysed
    0 [9]
    0 [10]
    0 [11]
    0 [12]
    Units: Participants
    Notes
    [9] - This endpoint was not analyzed because the trial terminated early.
    [10] - This endpoint was not analyzed because the trial terminated early.
    [11] - This endpoint was not analyzed because the trial terminated early.
    [12] - This endpoint was not analyzed because the trial terminated early.
    No statistical analyses for this end point

    Secondary: Phase II: Randomized Best overall response as per RECIST v1.1

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    End point title
    		 Phase II: Randomized Best overall response as per RECIST v1.1 [13]
    End point description
    Scheme 1 (Arms 1 and 2): Further assessment of the anti-tumor activity of BYL719 in combination with cetuximab vs. cetuximab as single-agent in RM HNSCC patients naive to cetuximab
    End point type
    Secondary
    End point timeframe
    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: Descriptive analyses.
    End point values
    		 Arm 1 - BYL719+Cetuximab (randomized) Arm 2 - Monotherapy Cetuximab (randomized) All Patients
    Number of subjects analysed
    71
    35
    106
    Units: Participants
        Complete Response
    1
    0
    1
        Partial Response
    6
    2
    8
        Stable Disease
    24
    8
    32
        Progressive Disease
    17
    12
    29
        Non-CR/Non-PD (NCRNPD)
    6
    10
    16
        Unknown
    17
    3
    20
    No statistical analyses for this end point

    Secondary: Phase II: Non-Randomized Best overall response as per RECIST v1.1

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    End point title
    		 Phase II: Non-Randomized Best overall response as per RECIST v1.1
    End point description
    Scheme 1 (Arm 3): Further assessment of the anti-tumor activity of BYL719 in combination with cetuximab vs. cetuximab as single-agent in RM HNSCC patients naive to cetuximab
    End point type
    Secondary
    End point timeframe
    approximately 6 months
    End point values
    		 Arm 3 - BYL719+Cetuximab
    Number of subjects analysed
    29
    Units: Participants
        Complete Response (CR)
    1
        Partial Response (PR)
    2
        Stable Disease (SD)
    8
        Progressive Disease (PD)
    5
        Non-CR/Non-PD (NCRNPD)
    6
        Unknown
    7
    No statistical analyses for this end point

    Secondary: Phase II: Randomized Overall Response Rate (ORR) and Disease Control Rate (DCR) as per RECIST v1.1

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    End point title
    		 Phase II: Randomized Overall Response Rate (ORR) and Disease Control Rate (DCR) as per RECIST v1.1 [14]
    End point description
    Assessment of the preliminary anti-tumor activity of BYL719 in combination with cetuximab in arms 1 and 2.
    End point type
    Secondary
    End point timeframe
    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: Descriptive analyses.
    End point values
    		 Arm 1 - BYL719+Cetuximab (randomized) Arm 2 - Monotherapy Cetuximab (randomized) All Patients (Phase II)
    Number of subjects analysed
    71
    35
    106
    Units: Percentages
    number (confidence interval 95%)
        Overall response rate (ORR) (CR or PR)
    9.9 (4.1 to 19.3)
    5.7 (0.7 to 19.2)
    8.5 (4 to 15.5)
        Disease control rate 1 (DCR 1) (CR or PR or SD)
    43.7 (31.9 to 56)
    28.6 (14.6 to 46.3)
    38.7 (29.4 to 48.6)
        DCR 2 (CR or PR or SD or Non-CR/Non-PD)
    52.1 (39.9 to 64.1)
    57.1 (39.4 to 73.7)
    53.8 (43.8 to 63.5)
    No statistical analyses for this end point

    Secondary: Phase II: Non-Randomized Overall Response Rate (ORR) and Disease Control Rate (DCR) as per RECIST v1.1

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    End point title
    		 Phase II: Non-Randomized Overall Response Rate (ORR) and Disease Control Rate (DCR) as per RECIST v1.1
    End point description
    Scheme 1 (arm 3): Assessment of the preliminary anti-tumor activity of BYL719 in combination with cetuximab in arm 3 (non-randomized arm)
    End point type
    Secondary
    End point timeframe
    approximately 6 months
    End point values
    		 Arm 3 - BYL719+Cetuximab
    Number of subjects analysed
    29
    Units: Percentages
    number (confidence interval 95%)
        Overall response rate (ORR) (CR or PR)
    10.3 (2.2 to 27.4)
        Disease control rate 1 (DCR 1) (CR or PR or SD)
    37.9 (20.7 to 57.7)
        DCR 2 (CR or PR or SD or Non-CR/Non-PD)
    58.6 (38.9 to 76.5)
    No statistical analyses for this end point

    Secondary: Phase II: Randomized Overall Survival (OS) by treatment

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    End point title
    		 Phase II: Randomized Overall Survival (OS) by treatment [15]
    End point description
    Scheme 1 (Arms 1 and 2): Further assessment of the anti-tumor activity of BYL719 in combination with cetuximab vs. cetuximab as single-agent in RM HNSCC patients naive to cetuximab
    End point type
    Secondary
    End point timeframe
    approximately 1 year
    Notes
    [15] - 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: Descriptive analyses.
    End point values
    		 Arm 1 - BYL719+Cetuximab (randomized) Arm 2 - Monotherapy Cetuximab (randomized)
    Number of subjects analysed
    71
    35
    Units: Patients
        Number of deaths
    51
    26
        Number of censored
    20
    9
    Statistical analysis title
    		 Radnomized OS by Treatment
    Comparison groups
    Arm 1 - BYL719+Cetuximab (randomized) v Arm 2 - Monotherapy Cetuximab (randomized)
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.313
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.79
         upper limit
    		 2.05

    Secondary: Phase II: Non-Randomized Overall Survival (OS) by treatment

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    End point title
    		 Phase II: Non-Randomized Overall Survival (OS) by treatment
    End point description
    Scheme 1 (Arm 3): Further assessment of the anti-tumor activity of BYL719 in combination with cetuximab vs. cetuximab as single-agent in RM HNSCC patients naive to cetuximab
    End point type
    Secondary
    End point timeframe
    approximately 1 year
    End point values
    		 Arm 3 - BYL719+Cetuximab
    Number of subjects analysed
    29
    Units: Patients
        Number of deaths
    13
        Number of censored
    10
    No statistical analyses for this end point

    Secondary: For Phase Ib: Overall Response Rate (ORR) and Disease Control Rate (DCR) as per RECIST v1.1

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    End point title
    		 For Phase Ib: Overall Response Rate (ORR) and Disease Control Rate (DCR) as per RECIST v1.1 [16]
    End point description
    Assessment of the preliminary anti-tumor activity of BYL719 in combination with cetuximab in arm A, B and C CR=complete response PR=partial response
    End point type
    Secondary
    End point timeframe
    approximately 6 months
    Notes
    [16] - 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: Descriptive analyses.
    End point values
    		 Arm A - 300mg BYL719+Cetuximab Arm A - 400mg BYL719+Cetuximab Arm B - BYL719 + Cetuximab, Oral suspension Arm C - BYL719+Cetuximab, Dispersible tablets All Patients
    Number of subjects analysed
    16
    5
    18
    6
    45
    Units: Percentages
    number (confidence interval 95%)
        ORR (CR) or PR)
    25.5 (7.3 to 52.4)
    0 (0 to 52.2)
    0 (0 to 18.5)
    0 (0 to 45.9)
    8.9 (2.5 to 21.2)
        DCR (CR or PR or Stable Disease or non-CR/Non-PD)
    75 (47.6 to 92.7)
    20 (0.5 to 71.6)
    50 (26 to 74)
    16.7 (0.4 to 64.1)
    51.1 (35.8 to 66.3)
    No statistical analyses for this end point

    Secondary: Phase II, Scheme 1 (arm 2B): Overall Response Rate (ORR) and Disease Control Rate (DCR) as per RECIST v1.1

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    End point title
    		 Phase II, Scheme 1 (arm 2B): Overall Response Rate (ORR) and Disease Control Rate (DCR) as per RECIST v1.1
    End point description
    Phase II: Scheme 1 (Arm 2B): To further assess the anti-tumor activity of BYL719 + cetuximab in the setting of resistance to single agent cetuximab. This endpoint was not analyzed because the trial terminated early due to slow enrolment.
    End point type
    Secondary
    End point timeframe
    Approximately 6 months
    End point values
    		 Arm 2B - BYL719+Cetuximab
    Number of subjects analysed
    0 [17]
    Units: percentages
        number (confidence interval 95%)
    ( to )
    Notes
    [17] - This endpoint was not analyzed because the trial terminated early due to slow enrolment.
    No statistical analyses for this end point

    Secondary: Phase II, Scheme 2 (Arm 2B): OS from the time of crossing over

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    End point title
    		 Phase II, Scheme 2 (Arm 2B): OS from the time of crossing over
    End point description
    Phase II, Scheme 1 (Arm 2B): To further assess the anti-tumor activity of BYL719 + cetuximab in the setting of resistance to single agent cetuximab. This endpoint was not analyzed because the trial terminated early due to slow enrolment.
    End point type
    Secondary
    End point timeframe
    approximately 1 year
    End point values
    		 Arm 2B - BYL719+Cetuximab
    Number of subjects analysed
    0 [18]
    Units: Patients
    Notes
    [18] - This endpoint was not analyzed because the trial terminated early due to slow enrolment.
    No statistical analyses for this end point

    Secondary: Phase Ib: Primary Plasma Pharmacokinetic Parameters for BYL719 by Treatment

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    End point title
    		 Phase Ib: Primary Plasma Pharmacokinetic Parameters for BYL719 by Treatment [19]
    End point description
    Non compartmental PK parameters derived after single dose at Cycle 1 Day 1
    End point type
    Secondary
    End point timeframe
    Day 1 Cycle 1
    Notes
    [19] - 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: Descriptive analyses.
    End point values
    		 Arm A - 300mg BYL719+Cetuximab Arm C: BYL719+Cetixumab, Dispersible tablets Arm A: 400mg BYL719 + Cetuximab Arm B: BYL719 + Cetuximab, Oral suspension
    Number of subjects analysed
    15
    6
    5
    17
    Units: hr*ng/mL
    median (full range (min-max))
        AUCinf
    22600 (16600 to 48500)
    24100 (9290 to 33200)
    27800 (17200 to 60100)
    27300 (15700 to 47400)
        AUC0_24
    18800 (5590 to 43400)
    19400 (7580 to 32100)
    26300 (16000 to 56100)
    25600 (14600 to 42100)
        AUClast
    19200 (5830 to 42700)
    22100 (4390 to 31800)
    26200 (15800 to 55600)
    2370 (1330 to 3710)
    No statistical analyses for this end point

    Secondary: Phase Ib: Cmax for BYL719 by Treatment

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    End point title
    		 Phase Ib: Cmax for BYL719 by Treatment [20]
    End point description
    Non compartmental Cmax derived after single dose at Cycle 1 Day 1
    End point type
    Secondary
    End point timeframe
    Day 1 Cycle 1
    Notes
    [20] - 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: Descriptive analyses.
    End point values
    		 Arm A - 300mg BYL719+Cetuximab Arm C: BYL719+Cetixumab, Dispersible tablets Arm A: 400mg BYL719 + Cetuximab Arm B: BYL719 + Cetuximab, Oral suspension
    Number of subjects analysed
    15
    6
    5
    17
    Units: ng/mL
        median (full range (min-max))
    2130 (303 to 4280)
    2010 (682 to 2980)
    2520 (1800 to 6240)
    2340 (1330 to 3710)
    No statistical analyses for this end point

    Secondary: Phase Ib: Tmax for BYL719 by Treatment

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    End point title
    		 Phase Ib: Tmax for BYL719 by Treatment [21]
    End point description
    Non compartmental Cmax derived after single dose at Cycle 1 Day 1
    End point type
    Secondary
    End point timeframe
    Day 1 Cycle 1
    Notes
    [21] - 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: Descriptive analyses.
    End point values
    		 Arm A - 300mg BYL719+Cetuximab Arm C: BYL719+Cetixumab, Dispersible tablets Arm A: 400mg BYL719 + Cetuximab Arm B: BYL719 + Cetuximab, Oral suspension
    Number of subjects analysed
    15
    6
    5
    17
    Units: hr
        median (full range (min-max))
    2.02 (1 to 24.8)
    3 (0.767 to 6)
    2.23 (1.58 to 3.02)
    2.97 (1 to 5.87)
    No statistical analyses for this end point

    Secondary: Phase Ib: Plasma Pharmacokinetic Parameters for BYL719 after continuous dose administration (steady state)

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    End point title
    		 Phase Ib: Plasma Pharmacokinetic Parameters for BYL719 after continuous dose administration (steady state) [22]
    End point description
    Non compartmental PK parameters derived after single dose at Cycle 1 Day 1
    End point type
    Secondary
    End point timeframe
    Day 1 Cycle 1
    Notes
    [22] - 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: Descriptive analyses.
    End point values
    		 Arm A - 300mg BYL719+Cetuximab Arm C: BYL719+Cetixumab, Dispersible tablets Arm B: BYL719 + Cetuximab, Oral suspension
    Number of subjects analysed
    15
    6
    17
    Units: hr*ng/mL
    median (full range (min-max))
        AUC (0-24)
    24600 (17900 to 44400)
    30500 (30500 to 30500)
    28500 (12700 to 53900)
        AUClast
    24500 (18000 to 76100)
    22100 (4390 to 31800)
    2370 (1330 to 3710)
    No statistical analyses for this end point

    Secondary: Phase Ib: Cmax for BYL719 after continuous dose administration (steady state)

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    End point title
    		 Phase Ib: Cmax for BYL719 after continuous dose administration (steady state) [23]
    End point description
    Non compartmental PK parameters derived after single dose at Cycle 1 Day 1
    End point type
    Secondary
    End point timeframe
    Day 1 Cycle 1
    Notes
    [23] - 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: Descriptive analyses.
    End point values
    		 Arm A - 300mg BYL719+Cetuximab Arm C: BYL719+Cetixumab, Dispersible tablets Arm B: BYL719 + Cetuximab, Oral suspension
    Number of subjects analysed
    15
    6
    17
    Units: ng/mL
        median (full range (min-max))
    2200 (1710 to 6520)
    2750 (2750 to 2750)
    2820 (373 to 4710)
    No statistical analyses for this end point

    Secondary: Phase Ib: Tmax for BYL719 after continuous dose administration (steady state)

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    End point title
    		 Phase Ib: Tmax for BYL719 after continuous dose administration (steady state) [24]
    End point description
    Non compartmental PK parameters derived after single dose at Cycle 1 Day 1
    End point type
    Secondary
    End point timeframe
    Day 1 Cycle 1
    Notes
    [24] - 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: Descriptive analyses.
    End point values
    		 Arm A - 300mg BYL719+Cetuximab Arm C: BYL719+Cetixumab, Dispersible tablets Arm B: BYL719 + Cetuximab, Oral suspension
    Number of subjects analysed
    15
    6
    17
    Units: hr
        median (full range (min-max))
    3.15 (1.5 to 7.13)
    1 (1 to 1)
    3.15 (1.03 to 8)
    No statistical analyses for this end point

    Secondary: Phase Ib: Notable Abnormal Vital Signs by Treatment

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    End point title
    		 Phase Ib: Notable Abnormal Vital Signs by Treatment [25]
    End point description
    Characterization of the safety and tolerability of BYL719 in combination with cetuximab in arm A, B and C.
    End point type
    Secondary
    End point timeframe
    approximately 6 months
    Notes
    [25] - 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: Descriptive analyses.
    End point values
    		 Arm A - 300mg BYL719+Cetuximab Arm A - 400mg BYL719+Cetuximab Arm B - BYL719 + Cetuximab, Oral suspension Arm C - BYL719+Cetuximab, Dispersible tablets
    Number of subjects analysed
    15
    5
    18
    6
    Units: Participants
        Sitting Pulse rate (bpm): High only
    0
    0
    4
    4
        Sitting Pulse rate (bpm): Low only
    0
    0
    0
    0
        Sitting Pulse rate (bpm): High and low
    0
    0
    0
    0
        Sitting systolic B.P. (mmHg): High only
    1
    0
    1
    0
        Sitting systolic B.P. (mmHg): Low only
    1
    0
    0
    1
        Sitting systolic B.P. (mmHg): High and low
    0
    0
    1
    0
        Sitting diastolic B.P. (mmHg): High only
    0
    0
    1
    0
        Sitting diastolic B.P. (mmHg): Low only
    1
    0
    2
    0
        Sitting diastolic B.P. (mmHg): High and low
    0
    0
    0
    0
        Body Temperature (Celsius): High only
    0
    0
    0
    1
        Body Temperature (Celsius): Low only
    0
    0
    0
    0
        Body Temperature (Celsius): High and low
    0
    0
    0
    0
        Weight (kg): High only
    0
    0
    0
    0
        Weight (kg): Low only
    7
    1
    3
    3
        Weight (kg): High and low
    0
    0
    0
    0
        Respiratory Rate (bpm): High only
    0
    0
    2
    1
        Respiratory Rate (bpm): Low only
    0
    0
    0
    0
        Respiratory Rate (bpm): High and low
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Phase Ib: Number of patients with notable Electrocardiogram (ECG) abnormalities

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    End point title
    		 Phase Ib: Number of patients with notable Electrocardiogram (ECG) abnormalities [26]
    End point description
    Characterization of the safety and tolerability of BYL719 in combination with cetuximab in arm A, B and C.
    End point type
    Secondary
    End point timeframe
    baseline, post baseline
    Notes
    [26] - 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: Descriptive analyses.
    End point values
    		 Arm A - 300mg BYL719+Cetuximab Arm A - 400mg BYL719+Cetuximab Arm B - BYL719 + Cetuximab, Oral suspension Arm C - BYL719+Cetuximab, Dispersible tablets
    Number of subjects analysed
    15
    5
    18
    6
    Units: Participants
        QTcF (msec): Increase from baseline > 30
    149
    54
    1810
    61
        QTcF (msec): Increase from baseline > 60
    142
    50
    181
    60
        QTcB (msec): Increase from baseline > 30
    1411
    54
    1812
    61
        QTcB (msec): Increase from baseline > 60
    141
    50
    181
    61
        QT (msec): Increase from baseline > 30
    1
    54
    1810
    61
        QT (msec): Increase from baseline > 60
    144
    50
    183
    60
        VR (bpm): RR decrease > 25% & to a VR > 100
    140
    51
    181
    61
        VR (bpm): RR decrease > 25% & to a VR < 50
    140
    50
    180
    60
        PR (msec): increase > 25% & to a VR > 200
    140
    50
    180
    60
        QRS (msec): increase > 25% & to a VR > 110
    140
    50
    180
    60
    No statistical analyses for this end point

    Secondary: For Phase II: Notable Abnormal Vital Signs by Treatment

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    End point title
    		 For Phase II: Notable Abnormal Vital Signs by Treatment [27]
    End point description
    Characterization of the safety and tolerability of BYL719 in combination with cetuximab in arm 1, 2 and 2B.
    End point type
    Secondary
    End point timeframe
    approximately 6 months
    Notes
    [27] - 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: Descriptive analyses.
    End point values
    		 Arm 1 - BYL719+Cetuximab (randomized) Arm 2 - Monotherapy Cetuximab (randomized) Arm 2B - BYL719+Cetuximab
    Number of subjects analysed
    69
    35
    29
    Units: Participants
        Sitting Pulse rate (bpm): High only
    4
    3
    5
        Sitting Pulse rate (bpm): Low only
    1
    0
    1
        Sitting Pulse rate (bpm): High and low
    0
    0
    0
        Sitting systolic B.P. (mmHg): High only
    0
    1
    0
        Sitting systolic B.P. (mmHg): Low only
    11
    3
    1
        Sitting systolic B.P. (mmHg): High and low
    1
    0
    0
        Sitting diastolic B.P. (mmHg): High only
    1
    2
    0
        Sitting diastolic B.P. (mmHg): Low only
    4
    3
    2
        Sitting diastolic B.P. (mmHg): High and low
    1
    0
    0
        Body Temperature (Celsius): High only
    1
    0
    0
        Body Temperature (Celsius): Low only
    3
    1
    2
        Body Temperature (Celsius): High and low
    0
    0
    0
        Weight (kg): High only
    1
    4
    0
        Weight (kg): Low only
    31
    3
    9
        Weight (kg): High and low
    0
    0
    0
        Respiratory Rate (bpm): High only
    2
    0
    1
        Respiratory Rate (bpm): Low only
    2
    1
    4
        Respiratory Rate (bpm): High and low
    0
    0
    0
    No statistical analyses for this end point

    Secondary: For Phase II: Number of patients with notable Electrocardiogram (ECG) abnormalities

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    End point title
    		 For Phase II: Number of patients with notable Electrocardiogram (ECG) abnormalities [28]
    End point description
    Characterization of the safety and tolerability of BYL719 in combination with cetuximab in arm 1, 2 and 2B.
    End point type
    Secondary
    End point timeframe
    baseline, post baseline
    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: Descriptive analyses.
    End point values
    		 Arm 1 - BYL719+Cetuximab (randomized) Arm 2 - Monotherapy Cetuximab (randomized) Arm 2B - BYL719+Cetuximab
    Number of subjects analysed
    69
    35
    29
    Units: Participants
        QTcF (msec): Increase from baseline > 30
    6335
    324
    2815
        QTcF (msec): Increase from baseline > 60
    686
    321
    282
        QTcB (msec): Increase from baseline > 30
    6840
    3212
    2815
        QTcB (msec): Increase from baseline > 60
    687
    320
    282
        QT (msec): Increase from baseline > 30
    6843
    3213
    2823
        QT (msec): Increase from baseline > 60
    6817
    322
    285
        VR (bpm): RR decrease > 25% & to a VR > 100
    689
    324
    283
        VR (bpm): RR decrease > 25% & to a VR < 50
    681
    320
    280
        PR (msec): increase > 25% & to a VR > 200
    680
    310
    270
        QRS (msec): increase > 25% & to a VR > 110
    680
    320
    281
    No statistical analyses for this end point

    Secondary: Phase II: Progression Free Survival (PFS) based on Investigator's Assessment with treatment

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    End point title
    		 Phase II: Progression Free Survival (PFS) based on Investigator's Assessment with treatment
    End point description
    Assessment of the anti-tumor activity of BYL719 in combination with cetuximab vs. cetuximab as single-agent in RM HNSCC patients naive to cetuximab
    End point type
    Secondary
    End point timeframe
    approximately 6 months
    End point values
    		 BYL719+ Cetuximab (randomized) Monotherapy Cetuximab (randomized)
    Number of subjects analysed
    71
    35
    Units: Participants
    71
    35
    Statistical analysis title
    		 PFS based on Investigator Assessment
    Comparison groups
    BYL719+ Cetuximab (randomized) v Monotherapy Cetuximab (randomized)
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.235
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.49
         upper limit
    		 1.19
    Statistical analysis title
    		 PFS based on Investigator Assessment
    Statistical analysis description
    Adjusted on Covariates: treatment, sum of longest diameters from local data [SLD (L)], Hemaglobin (Hgb) and White Blood Cells (WBC).
    Comparison groups
    BYL719+ Cetuximab (randomized) v Monotherapy Cetuximab (randomized)
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.062
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4
         upper limit
    		 1.02

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Timeframe for AE
    Adverse event reporting additional description
    AE additional description
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Phase Ib@Oral tablets@BYL719 300mg@+ CETU
    Reporting group description
    		 Phase Ib@Oral tablets@BYL719 300mg@+ CETU

    Reporting group title
    Phase Ib@Oral tablets@BYL719 400mg@+ CETU
    Reporting group description
    		 Phase Ib@Oral tablets@BYL719 400mg@+ CETU

    Reporting group title
    Phase Ib@Oral suspension@BYL719 300mg@+ CETU
    Reporting group description
    		 Phase Ib@Oral suspension@BYL719 300mg@+ CETU

    Reporting group title
    Phase Ib@Disp. tablets@BYL719 300mg@+ CETU
    Reporting group description
    		 Phase Ib@Disp. tablets@BYL719 300mg@+ CETU

    Reporting group title
    Phase II@randomized@BYL719 300mg + CETU
    Reporting group description
    		 Phase II@randomized@BYL719 300mg + CETU

    Reporting group title
    Phase II@randomized@CETU
    Reporting group description
    		 Phase II@randomized@CETU

    Reporting group title
    Phase II@open label@BYL719 300mg + CETU
    Reporting group description
    		 Phase II@open label@BYL719 300mg + CETU

    Reporting group title
    All@patients
    Reporting group description
    		 All@patients

    Serious adverse events
    		 Phase Ib@Oral tablets@BYL719 300mg@+ CETU Phase Ib@Oral tablets@BYL719 400mg@+ CETU Phase Ib@Oral suspension@BYL719 300mg@+ CETU Phase Ib@Disp. tablets@BYL719 300mg@+ CETU Phase II@randomized@BYL719 300mg + CETU Phase II@randomized@CETU Phase II@open label@BYL719 300mg + CETU All@patients
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 15 (60.00%)
    4 / 5 (80.00%)
    12 / 18 (66.67%)
    4 / 6 (66.67%)
    40 / 69 (57.97%)
    15 / 35 (42.86%)
    15 / 29 (51.72%)
    99 / 178 (55.62%)
         number of deaths (all causes)
    1
    2
    3
    2
    14
    8
    3
    33
         number of deaths resulting from adverse events
    0
    2
    1
    0
    4
    1
    1
    9
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour haemorrhage
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    2 / 69 (2.90%)
    2 / 35 (5.71%)
    1 / 29 (3.45%)
    5 / 178 (2.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 2
    0 / 3
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 1
    0 / 0
    0 / 3
    Tumour necrosis
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    1 / 29 (3.45%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    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
    Tumour pain
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    1 / 35 (2.86%)
    1 / 29 (3.45%)
    2 / 178 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 69 (1.45%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    3 / 3
    0 / 0
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    Embolism
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 69 (1.45%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    1 / 35 (2.86%)
    0 / 29 (0.00%)
    2 / 178 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Hypotension
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Gastrostomy
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
    1 / 69 (1.45%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    2 / 178 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 69 (1.45%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    Chills
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 69 (1.45%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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 / 1
    0 / 0
    0 / 0
    0 / 1
    Fatigue
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 69 (1.45%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    2 / 69 (2.90%)
    1 / 35 (2.86%)
    0 / 29 (0.00%)
    3 / 178 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 1
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 2
    Pain
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 69 (1.45%)
    0 / 35 (0.00%)
    1 / 29 (3.45%)
    2 / 178 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    1 / 6 (16.67%)
    4 / 69 (5.80%)
    1 / 35 (2.86%)
    0 / 29 (0.00%)
    8 / 178 (4.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 4
    0 / 1
    0 / 0
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug hypersensitivity
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    1 / 35 (2.86%)
    1 / 29 (3.45%)
    2 / 178 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    Respiratory, thoracic and mediastinal disorders
    Aspiration
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    2 / 69 (2.90%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    3 / 178 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 5 (20.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    3 / 69 (4.35%)
    1 / 35 (2.86%)
    1 / 29 (3.45%)
    6 / 178 (3.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 3
    0 / 1
    0 / 1
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 3
    Interstitial lung disease
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 69 (1.45%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    Laryngeal oedema
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    1 / 35 (2.86%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung infiltration
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 69 (1.45%)
    0 / 35 (0.00%)
    1 / 29 (3.45%)
    2 / 178 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 69 (1.45%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    1 / 69 (1.45%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    2 / 178 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Pneumonia aspiration
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    2 / 178 (1.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 69 (1.45%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    2 / 178 (1.12%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Pneumothorax
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 69 (1.45%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Productive cough
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    1 / 29 (3.45%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    1 / 1
    1 / 1
    Pulmonary air leakage
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 69 (1.45%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    2 / 69 (2.90%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    2 / 178 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Pulmonary haemorrhage
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 69 (1.45%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Respiratory distress
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 69 (1.45%)
    1 / 35 (2.86%)
    0 / 29 (0.00%)
    3 / 178 (1.69%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Respiratory failure
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 69 (1.45%)
    1 / 35 (2.86%)
    1 / 29 (3.45%)
    3 / 178 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
    0 / 3
    Stridor
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    1 / 29 (3.45%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    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
    Product issues
    Device dislocation
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 5 (20.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 69 (1.45%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Feeding tube complication
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 69 (1.45%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Pneumocephalus
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 69 (1.45%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    1 / 35 (2.86%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Tracheal obstruction
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Wound secretion
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 69 (1.45%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
    1 / 69 (1.45%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    2 / 178 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 1
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 69 (1.45%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 5 (20.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    Pulseless electrical activity
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 69 (1.45%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Nervous system disorders
    Carotid artery perforation
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    1 / 35 (2.86%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Cerebrovascular accident
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    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
    Embolic cerebral infarction
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    1 / 35 (2.86%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Somnolence
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 69 (1.45%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 69 (1.45%)
    0 / 35 (0.00%)
    1 / 29 (3.45%)
    2 / 178 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Neutropenia
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 69 (1.45%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 69 (1.45%)
    0 / 35 (0.00%)
    1 / 29 (3.45%)
    2 / 178 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    2 / 69 (2.90%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    3 / 178 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    2 / 69 (2.90%)
    1 / 35 (2.86%)
    1 / 29 (3.45%)
    5 / 178 (2.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    1 / 2
    0 / 1
    0 / 1
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Enterocolitis
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    1 / 29 (3.45%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    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
    Large intestine perforation
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    1 / 35 (2.86%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mouth haemorrhage
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    2 / 29 (6.90%)
    2 / 178 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 69 (1.45%)
    0 / 35 (0.00%)
    1 / 29 (3.45%)
    2 / 178 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophageal fistula
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    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
    Oesophageal haemorrhage
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    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
    Oesophageal ulcer
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 5 (20.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Oesophagitis
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 69 (1.45%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    2 / 35 (5.71%)
    0 / 29 (0.00%)
    2 / 178 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Vomiting
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 69 (1.45%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Erythema nodosum
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    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
    Swelling face
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ketonuria
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    1 / 29 (3.45%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    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
    Renal injury
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    1 / 35 (2.86%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 69 (1.45%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    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
    Fistula
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 69 (1.45%)
    0 / 35 (0.00%)
    1 / 29 (3.45%)
    2 / 178 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 5 (20.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    3 / 69 (4.35%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    4 / 178 (2.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    3 / 3
    0 / 0
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    2 / 2
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 69 (1.45%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    1 / 35 (2.86%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Trismus
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 69 (1.45%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal infection
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    1 / 35 (2.86%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Brain abscess
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 69 (1.45%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    2 / 69 (2.90%)
    1 / 35 (2.86%)
    0 / 29 (0.00%)
    3 / 178 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 1
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Device related infection
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    1 / 35 (2.86%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea infectious
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    1 / 35 (2.86%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    1 / 35 (2.86%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epiglottitis
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 69 (1.45%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    1 / 35 (2.86%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Lung infection
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    2 / 29 (6.90%)
    2 / 178 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 1
    0 / 1
    Osteomyelitis
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 69 (1.45%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 5 (0.00%)
    4 / 18 (22.22%)
    1 / 6 (16.67%)
    8 / 69 (11.59%)
    1 / 35 (2.86%)
    4 / 29 (13.79%)
    20 / 178 (11.24%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    2 / 4
    0 / 1
    1 / 9
    0 / 1
    2 / 4
    5 / 21
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 1
    1 / 5
    0 / 1
    0 / 0
    1 / 10
    Post procedural infection
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Purulent discharge
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    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
    Sepsis
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    4 / 69 (5.80%)
    1 / 35 (2.86%)
    0 / 29 (0.00%)
    6 / 178 (3.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 4
    0 / 1
    0 / 0
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 3
    0 / 0
    0 / 0
    1 / 3
    Septic shock
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    1 / 6 (16.67%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    2 / 178 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Superinfection
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 69 (1.45%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    1 / 35 (2.86%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    2 / 35 (5.71%)
    0 / 29 (0.00%)
    2 / 178 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Wound infection
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    2 / 69 (2.90%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    3 / 178 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 2
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    3 / 69 (4.35%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    3 / 178 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    3 / 3
    0 / 0
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    Dehydration
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 69 (1.45%)
    0 / 35 (0.00%)
    1 / 29 (3.45%)
    2 / 178 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 69 (1.45%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Hyperglycaemia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    2 / 6 (33.33%)
    7 / 69 (10.14%)
    0 / 35 (0.00%)
    5 / 29 (17.24%)
    15 / 178 (8.43%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    2 / 2
    7 / 7
    0 / 0
    5 / 5
    15 / 15
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    Hypernatraemia
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 69 (1.45%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypophosphataemia
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    1 / 35 (2.86%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Tumour lysis syndrome
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 5 (20.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Phase Ib@Oral tablets@BYL719 300mg@+ CETU Phase Ib@Oral tablets@BYL719 400mg@+ CETU Phase Ib@Oral suspension@BYL719 300mg@+ CETU Phase Ib@Disp. tablets@BYL719 300mg@+ CETU Phase II@randomized@BYL719 300mg + CETU Phase II@randomized@CETU Phase II@open label@BYL719 300mg + CETU All@patients
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 15 (100.00%)
    5 / 5 (100.00%)
    18 / 18 (100.00%)
    6 / 6 (100.00%)
    69 / 69 (100.00%)
    35 / 35 (100.00%)
    29 / 29 (100.00%)
    177 / 178 (99.44%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    2 / 29 (6.90%)
    3 / 178 (1.69%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    2
    3
    Tumour haemorrhage
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
    0 / 69 (0.00%)
    1 / 35 (2.86%)
    0 / 29 (0.00%)
    2 / 178 (1.12%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    2
    Tumour necrosis
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    Tumour pain
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 5 (20.00%)
    1 / 18 (5.56%)
    3 / 6 (50.00%)
    4 / 69 (5.80%)
    2 / 35 (5.71%)
    2 / 29 (6.90%)
    13 / 178 (7.30%)
         occurrences all number
    0
    1
    1
    3
    4
    3
    2
    14
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    1 / 29 (3.45%)
    2 / 178 (1.12%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    1
    2
    Embolism
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    1
    Flushing
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    1 / 29 (3.45%)
    2 / 178 (1.12%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    1
    2
    Haematoma
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    1
    Hypertension
         subjects affected / exposed
    3 / 15 (20.00%)
    1 / 5 (20.00%)
    2 / 18 (11.11%)
    0 / 6 (0.00%)
    5 / 69 (7.25%)
    3 / 35 (8.57%)
    4 / 29 (13.79%)
    18 / 178 (10.11%)
         occurrences all number
    3
    1
    3
    0
    6
    10
    4
    27
    Hypotension
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    4 / 69 (5.80%)
    3 / 35 (8.57%)
    1 / 29 (3.45%)
    9 / 178 (5.06%)
         occurrences all number
    0
    0
    2
    0
    4
    3
    1
    10
    Lymphoedema
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 69 (1.45%)
    1 / 35 (2.86%)
    0 / 29 (0.00%)
    3 / 178 (1.69%)
         occurrences all number
    2
    0
    0
    0
    1
    1
    0
    4
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    1 / 6 (16.67%)
    4 / 69 (5.80%)
    1 / 35 (2.86%)
    3 / 29 (10.34%)
    11 / 178 (6.18%)
         occurrences all number
    1
    0
    1
    1
    5
    1
    3
    12
    Chills
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    3 / 69 (4.35%)
    4 / 35 (11.43%)
    1 / 29 (3.45%)
    10 / 178 (5.62%)
         occurrences all number
    1
    0
    2
    0
    3
    4
    1
    11
    Cyst rupture
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 5 (20.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    Face oedema
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 5 (20.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    3 / 69 (4.35%)
    1 / 35 (2.86%)
    1 / 29 (3.45%)
    7 / 178 (3.93%)
         occurrences all number
    1
    1
    0
    0
    4
    1
    1
    8
    Facial pain
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    5 / 69 (7.25%)
    2 / 35 (5.71%)
    0 / 29 (0.00%)
    8 / 178 (4.49%)
         occurrences all number
    1
    0
    0
    0
    5
    3
    0
    9
    Fatigue
         subjects affected / exposed
    5 / 15 (33.33%)
    2 / 5 (40.00%)
    5 / 18 (27.78%)
    0 / 6 (0.00%)
    22 / 69 (31.88%)
    8 / 35 (22.86%)
    14 / 29 (48.28%)
    56 / 178 (31.46%)
         occurrences all number
    5
    2
    5
    0
    22
    10
    17
    61
    Gait disturbance
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    1
    General physical health deterioration
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    2 / 69 (2.90%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    3 / 178 (1.69%)
         occurrences all number
    1
    0
    0
    0
    2
    0
    0
    3
    Localised oedema
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 5 (20.00%)
    1 / 18 (5.56%)
    1 / 6 (16.67%)
    0 / 69 (0.00%)
    1 / 35 (2.86%)
    2 / 29 (6.90%)
    6 / 178 (3.37%)
         occurrences all number
    0
    1
    1
    1
    0
    1
    2
    6
    Malaise
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
    1 / 69 (1.45%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    2 / 178 (1.12%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    2
    Mucosal dryness
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    1
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    1 / 35 (2.86%)
    2 / 29 (6.90%)
    4 / 178 (2.25%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    2
    4
    Oedema peripheral
         subjects affected / exposed
    2 / 15 (13.33%)
    1 / 5 (20.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    4 / 69 (5.80%)
    1 / 35 (2.86%)
    3 / 29 (10.34%)
    11 / 178 (6.18%)
         occurrences all number
    2
    1
    0
    0
    5
    2
    3
    13
    Pyrexia
         subjects affected / exposed
    3 / 15 (20.00%)
    0 / 5 (0.00%)
    5 / 18 (27.78%)
    2 / 6 (33.33%)
    6 / 69 (8.70%)
    3 / 35 (8.57%)
    3 / 29 (10.34%)
    22 / 178 (12.36%)
         occurrences all number
    3
    0
    6
    2
    7
    3
    3
    24
    Secretion discharge
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    1 / 29 (3.45%)
    2 / 178 (1.12%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    1
    2
    Submandibular mass
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    1
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    2 / 69 (2.90%)
    2 / 35 (5.71%)
    1 / 29 (3.45%)
    6 / 178 (3.37%)
         occurrences all number
    0
    0
    1
    0
    2
    2
    1
    6
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Aspiration
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    2 / 69 (2.90%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    3 / 178 (1.69%)
         occurrences all number
    1
    0
    0
    0
    2
    0
    0
    3
    Atelectasis
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    Cough
         subjects affected / exposed
    2 / 15 (13.33%)
    1 / 5 (20.00%)
    4 / 18 (22.22%)
    1 / 6 (16.67%)
    15 / 69 (21.74%)
    7 / 35 (20.00%)
    6 / 29 (20.69%)
    36 / 178 (20.22%)
         occurrences all number
    2
    1
    4
    1
    20
    9
    6
    43
    Dysphonia
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 5 (20.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    5 / 69 (7.25%)
    0 / 35 (0.00%)
    4 / 29 (13.79%)
    12 / 178 (6.74%)
         occurrences all number
    1
    1
    1
    0
    5
    0
    4
    12
    Dyspnoea
         subjects affected / exposed
    1 / 15 (6.67%)
    2 / 5 (40.00%)
    3 / 18 (16.67%)
    1 / 6 (16.67%)
    11 / 69 (15.94%)
    5 / 35 (14.29%)
    3 / 29 (10.34%)
    26 / 178 (14.61%)
         occurrences all number
    1
    2
    3
    1
    13
    5
    3
    28
    Epistaxis
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 5 (20.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    3 / 69 (4.35%)
    1 / 35 (2.86%)
    1 / 29 (3.45%)
    7 / 178 (3.93%)
         occurrences all number
    0
    1
    3
    0
    3
    2
    2
    11
    Haemoptysis
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    3 / 69 (4.35%)
    1 / 35 (2.86%)
    1 / 29 (3.45%)
    6 / 178 (3.37%)
         occurrences all number
    0
    0
    1
    0
    3
    1
    1
    6
    Hypoxia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    1
    Lung disorder
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
    1 / 69 (1.45%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    2 / 178 (1.12%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    2
    Nasal congestion
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    Nasal dryness
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    1 / 35 (2.86%)
    0 / 29 (0.00%)
    2 / 178 (1.12%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    0
    2
    Oropharyngeal pain
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    4 / 18 (22.22%)
    0 / 6 (0.00%)
    4 / 69 (5.80%)
    3 / 35 (8.57%)
    1 / 29 (3.45%)
    13 / 178 (7.30%)
         occurrences all number
    1
    0
    4
    0
    4
    3
    1
    13
    Pharyngeal inflammation
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    1
    Pleural effusion
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    2 / 18 (11.11%)
    0 / 6 (0.00%)
    2 / 69 (2.90%)
    1 / 35 (2.86%)
    0 / 29 (0.00%)
    5 / 178 (2.81%)
         occurrences all number
    0
    0
    2
    0
    2
    1
    0
    5
    Pneumonia aspiration
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    1 / 6 (16.67%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    2 / 178 (1.12%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    0
    2
    Productive cough
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    1 / 6 (16.67%)
    5 / 69 (7.25%)
    2 / 35 (5.71%)
    1 / 29 (3.45%)
    10 / 178 (5.62%)
         occurrences all number
    0
    0
    1
    1
    5
    2
    1
    10
    Pulmonary mass
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    Pulmonary oedema
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    Respiratory distress
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    Rhinitis allergic
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    1
    Rhinorrhoea
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    2 / 69 (2.90%)
    3 / 35 (8.57%)
    0 / 29 (0.00%)
    6 / 178 (3.37%)
         occurrences all number
    1
    0
    0
    0
    2
    3
    0
    6
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 5 (20.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    1 / 29 (3.45%)
    2 / 178 (1.12%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    1
    2
    Anxiety
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    5 / 69 (7.25%)
    1 / 35 (2.86%)
    2 / 29 (6.90%)
    10 / 178 (5.62%)
         occurrences all number
    1
    0
    1
    0
    6
    2
    3
    13
    Depression
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    5 / 69 (7.25%)
    1 / 35 (2.86%)
    1 / 29 (3.45%)
    10 / 178 (5.62%)
         occurrences all number
    2
    0
    1
    0
    5
    1
    1
    10
    Insomnia
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    1 / 6 (16.67%)
    6 / 69 (8.70%)
    4 / 35 (11.43%)
    1 / 29 (3.45%)
    13 / 178 (7.30%)
         occurrences all number
    0
    0
    1
    1
    6
    4
    1
    13
    Irritability
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 69 (1.45%)
    0 / 35 (0.00%)
    2 / 29 (6.90%)
    4 / 178 (2.25%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    2
    4
    Sleep disorder
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    2 / 29 (6.90%)
    2 / 178 (1.12%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    2
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
    3 / 69 (4.35%)
    1 / 35 (2.86%)
    0 / 29 (0.00%)
    6 / 178 (3.37%)
         occurrences all number
    1
    0
    0
    1
    5
    1
    0
    8
    Amylase increased
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    3 / 69 (4.35%)
    2 / 35 (5.71%)
    1 / 29 (3.45%)
    6 / 178 (3.37%)
         occurrences all number
    0
    0
    0
    0
    7
    4
    2
    13
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
    3 / 69 (4.35%)
    1 / 35 (2.86%)
    0 / 29 (0.00%)
    7 / 178 (3.93%)
         occurrences all number
    3
    0
    0
    1
    4
    1
    0
    9
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    5 / 69 (7.25%)
    3 / 35 (8.57%)
    1 / 29 (3.45%)
    10 / 178 (5.62%)
         occurrences all number
    0
    0
    1
    0
    5
    3
    1
    10
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 15 (6.67%)
    2 / 5 (40.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 69 (1.45%)
    2 / 35 (5.71%)
    1 / 29 (3.45%)
    7 / 178 (3.93%)
         occurrences all number
    1
    2
    0
    0
    1
    2
    1
    7
    Blood creatinine increased
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    2 / 18 (11.11%)
    0 / 6 (0.00%)
    7 / 69 (10.14%)
    1 / 35 (2.86%)
    1 / 29 (3.45%)
    11 / 178 (6.18%)
         occurrences all number
    0
    0
    3
    0
    15
    1
    1
    20
    Blood glucose increased
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    1 / 35 (2.86%)
    0 / 29 (0.00%)
    2 / 178 (1.12%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    2
    Blood testosterone decreased
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    2 / 29 (6.90%)
    4 / 178 (2.25%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    3
    5
    Electrocardiogram QT prolonged
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    4 / 69 (5.80%)
    1 / 35 (2.86%)
    0 / 29 (0.00%)
    7 / 178 (3.93%)
         occurrences all number
    1
    0
    2
    0
    7
    1
    0
    11
    Electrocardiogram T wave abnormal
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    Electrocardiogram T wave inversion
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 5 (20.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    1
    Glycosylated haemoglobin increased
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    2 / 69 (2.90%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    3 / 178 (1.69%)
         occurrences all number
    1
    0
    0
    0
    2
    0
    0
    3
    Lipase increased
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    5 / 69 (7.25%)
    3 / 35 (8.57%)
    1 / 29 (3.45%)
    10 / 178 (5.62%)
         occurrences all number
    0
    0
    1
    0
    15
    6
    1
    23
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 5 (20.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    4 / 69 (5.80%)
    1 / 35 (2.86%)
    2 / 29 (6.90%)
    9 / 178 (5.06%)
         occurrences all number
    0
    2
    1
    0
    5
    1
    2
    11
    Troponin increased
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 5 (20.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    Weight decreased
         subjects affected / exposed
    6 / 15 (40.00%)
    2 / 5 (40.00%)
    6 / 18 (33.33%)
    3 / 6 (50.00%)
    27 / 69 (39.13%)
    7 / 35 (20.00%)
    11 / 29 (37.93%)
    62 / 178 (34.83%)
         occurrences all number
    6
    2
    6
    3
    27
    7
    11
    62
    Weight increased
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    2 / 35 (5.71%)
    0 / 29 (0.00%)
    2 / 178 (1.12%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    0
    3
    Injury, poisoning and procedural complications
    Feeding tube complication
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
    1 / 69 (1.45%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    2 / 178 (1.12%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    2
    Gastrointestinal stoma complication
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    1 / 29 (3.45%)
    2 / 178 (1.12%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    2
    Infusion related reaction
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 69 (1.45%)
    2 / 35 (5.71%)
    0 / 29 (0.00%)
    3 / 178 (1.69%)
         occurrences all number
    0
    0
    0
    0
    1
    2
    0
    3
    Limb injury
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    1
    Procedural pain
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    2 / 35 (5.71%)
    0 / 29 (0.00%)
    2 / 178 (1.12%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    2
    Skin abrasion
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    2 / 178 (1.12%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    2
    Stoma site erythema
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    1
    Stoma site ulcer
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    1
    Tracheal obstruction
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    Wound
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 5 (20.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 69 (1.45%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    2 / 178 (1.12%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    0
    2
    Wound secretion
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    2 / 6 (33.33%)
    2 / 69 (2.90%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    4 / 178 (2.25%)
         occurrences all number
    0
    0
    0
    3
    3
    0
    0
    6
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    Atrial fibrillation
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    Cardiac arrest
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    2
    Cardiomegaly
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    Palpitations
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    1 / 29 (3.45%)
    2 / 178 (1.12%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    1
    2
    Pericardial effusion
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
    1 / 69 (1.45%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    2 / 178 (1.12%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    2
    Sinus bradycardia
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    Sinus tachycardia
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    1 / 29 (3.45%)
    2 / 178 (1.12%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    1
    2
    Tachycardia
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    1 / 6 (16.67%)
    0 / 69 (0.00%)
    1 / 35 (2.86%)
    2 / 29 (6.90%)
    5 / 178 (2.81%)
         occurrences all number
    0
    0
    1
    1
    0
    1
    2
    5
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    1
    Dizziness
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 5 (0.00%)
    2 / 18 (11.11%)
    1 / 6 (16.67%)
    5 / 69 (7.25%)
    1 / 35 (2.86%)
    5 / 29 (17.24%)
    16 / 178 (8.99%)
         occurrences all number
    2
    0
    2
    1
    5
    1
    5
    16
    Dysaesthesia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    1
    Dysgeusia
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 5 (0.00%)
    2 / 18 (11.11%)
    0 / 6 (0.00%)
    2 / 69 (2.90%)
    1 / 35 (2.86%)
    4 / 29 (13.79%)
    11 / 178 (6.18%)
         occurrences all number
    2
    0
    2
    0
    2
    1
    4
    11
    Headache
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 5 (0.00%)
    4 / 18 (22.22%)
    0 / 6 (0.00%)
    7 / 69 (10.14%)
    4 / 35 (11.43%)
    3 / 29 (10.34%)
    20 / 178 (11.24%)
         occurrences all number
    3
    0
    6
    0
    7
    4
    3
    23
    Hemiparesis
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    1
    Lethargy
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 69 (1.45%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    2 / 178 (1.12%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    2
    Paraesthesia
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    3 / 69 (4.35%)
    1 / 35 (2.86%)
    0 / 29 (0.00%)
    5 / 178 (2.81%)
         occurrences all number
    0
    0
    1
    0
    3
    1
    0
    5
    Parosmia
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    1
    Peripheral motor neuropathy
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    1 / 29 (3.45%)
    2 / 178 (1.12%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    1
    2
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    3 / 69 (4.35%)
    1 / 35 (2.86%)
    3 / 29 (10.34%)
    8 / 178 (4.49%)
         occurrences all number
    0
    0
    1
    0
    3
    1
    3
    8
    Presyncope
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    1
    Somnolence
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 5 (20.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 69 (1.45%)
    1 / 35 (2.86%)
    1 / 29 (3.45%)
    5 / 178 (2.81%)
         occurrences all number
    1
    1
    0
    0
    1
    1
    1
    5
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    2 / 6 (33.33%)
    9 / 69 (13.04%)
    6 / 35 (17.14%)
    7 / 29 (24.14%)
    25 / 178 (14.04%)
         occurrences all number
    0
    0
    1
    2
    10
    7
    9
    29
    Lymph node pain
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    1
    Lymphadenopathy
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    Thrombocytopenia
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    1 / 29 (3.45%)
    2 / 178 (1.12%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    2
    Ear and labyrinth disorders
    Tympanic membrane perforation
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    1
    Eye disorders
    Conjunctival hyperaemia
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    Diplopia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    1 / 35 (2.86%)
    0 / 29 (0.00%)
    2 / 178 (1.12%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    2
    Dry eye
         subjects affected / exposed
    3 / 15 (20.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    2 / 69 (2.90%)
    2 / 35 (5.71%)
    1 / 29 (3.45%)
    8 / 178 (4.49%)
         occurrences all number
    3
    0
    0
    0
    2
    2
    1
    8
    Eye irritation
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    1
    Eye pain
         subjects affected / exposed
    2 / 15 (13.33%)
    1 / 5 (20.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    3 / 178 (1.69%)
         occurrences all number
    2
    1
    0
    0
    0
    0
    0
    3
    Ocular hyperaemia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    1
    Vision blurred
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 5 (20.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    3 / 69 (4.35%)
    0 / 35 (0.00%)
    2 / 29 (6.90%)
    7 / 178 (3.93%)
         occurrences all number
    1
    1
    0
    0
    3
    0
    2
    7
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    2 / 69 (2.90%)
    1 / 35 (2.86%)
    1 / 29 (3.45%)
    5 / 178 (2.81%)
         occurrences all number
    0
    0
    1
    0
    2
    1
    1
    5
    Abdominal distension
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    3 / 69 (4.35%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    4 / 178 (2.25%)
         occurrences all number
    1
    0
    0
    0
    3
    0
    0
    4
    Abdominal pain
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    3 / 69 (4.35%)
    0 / 35 (0.00%)
    2 / 29 (6.90%)
    6 / 178 (3.37%)
         occurrences all number
    1
    0
    0
    0
    3
    0
    2
    6
    Abdominal pain upper
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    2 / 35 (5.71%)
    1 / 29 (3.45%)
    4 / 178 (2.25%)
         occurrences all number
    0
    0
    1
    0
    0
    4
    1
    6
    Anal incontinence
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    1
    Ascites
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 69 (1.45%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    2 / 178 (1.12%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    2
    Constipation
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 5 (0.00%)
    4 / 18 (22.22%)
    3 / 6 (50.00%)
    9 / 69 (13.04%)
    7 / 35 (20.00%)
    5 / 29 (17.24%)
    30 / 178 (16.85%)
         occurrences all number
    5
    0
    4
    3
    10
    7
    6
    35
    Dental caries
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    1 / 35 (2.86%)
    0 / 29 (0.00%)
    2 / 178 (1.12%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    2
    Diarrhoea
         subjects affected / exposed
    7 / 15 (46.67%)
    2 / 5 (40.00%)
    10 / 18 (55.56%)
    2 / 6 (33.33%)
    29 / 69 (42.03%)
    5 / 35 (14.29%)
    13 / 29 (44.83%)
    68 / 178 (38.20%)
         occurrences all number
    13
    4
    20
    5
    43
    6
    17
    108
    Dry mouth
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    4 / 69 (5.80%)
    3 / 35 (8.57%)
    3 / 29 (10.34%)
    11 / 178 (6.18%)
         occurrences all number
    1
    0
    0
    0
    4
    3
    3
    11
    Dyspepsia
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    1 / 6 (16.67%)
    7 / 69 (10.14%)
    1 / 35 (2.86%)
    3 / 29 (10.34%)
    13 / 178 (7.30%)
         occurrences all number
    0
    0
    1
    1
    7
    1
    3
    13
    Dysphagia
         subjects affected / exposed
    3 / 15 (20.00%)
    1 / 5 (20.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    13 / 69 (18.84%)
    2 / 35 (5.71%)
    5 / 29 (17.24%)
    25 / 178 (14.04%)
         occurrences all number
    3
    1
    1
    0
    14
    3
    5
    27
    Gastritis
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 69 (1.45%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    2 / 178 (1.12%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    2
    Gastritis erosive
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 5 (20.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
    6 / 69 (8.70%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    9 / 178 (5.06%)
         occurrences all number
    2
    0
    0
    1
    6
    0
    0
    9
    Glossodynia
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    1 / 35 (2.86%)
    3 / 29 (10.34%)
    4 / 178 (2.25%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    3
    4
    Haemorrhoids
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    1
    Melaena
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    1
    Mouth haemorrhage
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 5 (20.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 69 (1.45%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    2 / 178 (1.12%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    0
    2
    Mouth ulceration
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    2 / 69 (2.90%)
    1 / 35 (2.86%)
    0 / 29 (0.00%)
    6 / 178 (3.37%)
         occurrences all number
    3
    0
    1
    0
    3
    1
    0
    8
    Nausea
         subjects affected / exposed
    6 / 15 (40.00%)
    1 / 5 (20.00%)
    4 / 18 (22.22%)
    1 / 6 (16.67%)
    16 / 69 (23.19%)
    4 / 35 (11.43%)
    11 / 29 (37.93%)
    43 / 178 (24.16%)
         occurrences all number
    6
    1
    4
    1
    23
    6
    18
    59
    Odynophagia
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    4 / 69 (5.80%)
    0 / 35 (0.00%)
    1 / 29 (3.45%)
    5 / 178 (2.81%)
         occurrences all number
    0
    0
    0
    0
    4
    0
    1
    5
    Oesophageal fistula
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    2 / 18 (11.11%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    2 / 178 (1.12%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    2
    Oesophageal ulcer
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 5 (20.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    Oesophagitis
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 5 (20.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    Oral pain
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 5 (20.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    4 / 69 (5.80%)
    2 / 35 (5.71%)
    1 / 29 (3.45%)
    9 / 178 (5.06%)
         occurrences all number
    0
    1
    1
    0
    5
    3
    1
    11
    Salivary gland mucocoele
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    Stomatitis
         subjects affected / exposed
    7 / 15 (46.67%)
    2 / 5 (40.00%)
    8 / 18 (44.44%)
    1 / 6 (16.67%)
    31 / 69 (44.93%)
    6 / 35 (17.14%)
    12 / 29 (41.38%)
    67 / 178 (37.64%)
         occurrences all number
    8
    2
    10
    1
    39
    6
    15
    81
    Vomiting
         subjects affected / exposed
    3 / 15 (20.00%)
    1 / 5 (20.00%)
    3 / 18 (16.67%)
    2 / 6 (33.33%)
    15 / 69 (21.74%)
    2 / 35 (5.71%)
    6 / 29 (20.69%)
    32 / 178 (17.98%)
         occurrences all number
    3
    3
    3
    4
    20
    6
    16
    55
    Skin and subcutaneous tissue disorders
    Cold sweat
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    Decubitus ulcer
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 69 (1.45%)
    2 / 35 (5.71%)
    0 / 29 (0.00%)
    3 / 178 (1.69%)
         occurrences all number
    0
    0
    0
    0
    1
    2
    0
    3
    Dermal cyst
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 5 (20.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    Dermatitis
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    2 / 69 (2.90%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    3 / 178 (1.69%)
         occurrences all number
    1
    0
    0
    0
    2
    0
    0
    3
    Dermatitis acneiform
         subjects affected / exposed
    7 / 15 (46.67%)
    2 / 5 (40.00%)
    4 / 18 (22.22%)
    0 / 6 (0.00%)
    21 / 69 (30.43%)
    8 / 35 (22.86%)
    5 / 29 (17.24%)
    47 / 178 (26.40%)
         occurrences all number
    9
    2
    5
    0
    22
    10
    11
    59
    Dry skin
         subjects affected / exposed
    4 / 15 (26.67%)
    2 / 5 (40.00%)
    2 / 18 (11.11%)
    1 / 6 (16.67%)
    18 / 69 (26.09%)
    6 / 35 (17.14%)
    10 / 29 (34.48%)
    43 / 178 (24.16%)
         occurrences all number
    4
    2
    4
    1
    18
    6
    11
    46
    Erythema
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    2 / 69 (2.90%)
    2 / 35 (5.71%)
    4 / 29 (13.79%)
    8 / 178 (4.49%)
         occurrences all number
    0
    0
    0
    0
    2
    2
    4
    8
    Erythema nodosum
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    1
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    3 / 69 (4.35%)
    2 / 35 (5.71%)
    0 / 29 (0.00%)
    5 / 178 (2.81%)
         occurrences all number
    0
    0
    0
    0
    3
    2
    0
    5
    Papule
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
    2 / 69 (2.90%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    3 / 178 (1.69%)
         occurrences all number
    0
    0
    0
    1
    3
    0
    0
    4
    Pruritus
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 5 (20.00%)
    1 / 18 (5.56%)
    1 / 6 (16.67%)
    11 / 69 (15.94%)
    2 / 35 (5.71%)
    1 / 29 (3.45%)
    18 / 178 (10.11%)
         occurrences all number
    2
    1
    1
    2
    13
    2
    1
    22
    Rash
         subjects affected / exposed
    7 / 15 (46.67%)
    0 / 5 (0.00%)
    4 / 18 (22.22%)
    2 / 6 (33.33%)
    26 / 69 (37.68%)
    14 / 35 (40.00%)
    7 / 29 (24.14%)
    60 / 178 (33.71%)
         occurrences all number
    9
    0
    4
    2
    28
    16
    9
    68
    Rash maculo-papular
         subjects affected / exposed
    3 / 15 (20.00%)
    0 / 5 (0.00%)
    2 / 18 (11.11%)
    0 / 6 (0.00%)
    11 / 69 (15.94%)
    2 / 35 (5.71%)
    3 / 29 (10.34%)
    21 / 178 (11.80%)
         occurrences all number
    5
    0
    4
    0
    15
    2
    3
    29
    Rash papular
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    2 / 69 (2.90%)
    0 / 35 (0.00%)
    1 / 29 (3.45%)
    4 / 178 (2.25%)
         occurrences all number
    0
    0
    1
    0
    2
    0
    1
    4
    Skin discolouration
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    1
    Skin fissures
         subjects affected / exposed
    4 / 15 (26.67%)
    1 / 5 (20.00%)
    2 / 18 (11.11%)
    0 / 6 (0.00%)
    12 / 69 (17.39%)
    4 / 35 (11.43%)
    7 / 29 (24.14%)
    30 / 178 (16.85%)
         occurrences all number
    5
    1
    2
    0
    20
    5
    8
    41
    Skin striae
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    1
    Skin toxicity
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
    4 / 69 (5.80%)
    3 / 35 (8.57%)
    2 / 29 (6.90%)
    10 / 178 (5.62%)
         occurrences all number
    0
    0
    0
    1
    4
    5
    2
    12
    Skin ulcer
         subjects affected / exposed
    3 / 15 (20.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    5 / 69 (7.25%)
    0 / 35 (0.00%)
    2 / 29 (6.90%)
    11 / 178 (6.18%)
         occurrences all number
    3
    0
    1
    0
    5
    0
    3
    12
    Urticaria
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    4 / 69 (5.80%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    4 / 178 (2.25%)
         occurrences all number
    0
    0
    0
    0
    4
    0
    0
    4
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 5 (20.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    Dysuria
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    2 / 35 (5.71%)
    0 / 29 (0.00%)
    2 / 178 (1.12%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    2
    Pollakiuria
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
    1 / 69 (1.45%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    2 / 178 (1.12%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    2
    Renal failure
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    1
    Urinary incontinence
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    1
    Urinary retention
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    1 / 29 (3.45%)
    2 / 178 (1.12%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    2
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 15 (13.33%)
    1 / 5 (20.00%)
    2 / 18 (11.11%)
    0 / 6 (0.00%)
    5 / 69 (7.25%)
    4 / 35 (11.43%)
    1 / 29 (3.45%)
    15 / 178 (8.43%)
         occurrences all number
    3
    1
    2
    0
    6
    4
    3
    19
    Bone pain
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    1 / 69 (1.45%)
    2 / 35 (5.71%)
    0 / 29 (0.00%)
    4 / 178 (2.25%)
         occurrences all number
    0
    0
    1
    0
    1
    3
    0
    5
    Muscle spasms
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 5 (20.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    2 / 69 (2.90%)
    0 / 35 (0.00%)
    1 / 29 (3.45%)
    4 / 178 (2.25%)
         occurrences all number
    0
    1
    0
    0
    2
    0
    1
    4
    Muscular weakness
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    4 / 69 (5.80%)
    2 / 35 (5.71%)
    0 / 29 (0.00%)
    6 / 178 (3.37%)
         occurrences all number
    0
    0
    0
    0
    4
    2
    0
    6
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 5 (20.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    2 / 69 (2.90%)
    2 / 35 (5.71%)
    0 / 29 (0.00%)
    5 / 178 (2.81%)
         occurrences all number
    0
    1
    0
    0
    2
    2
    0
    5
    Musculoskeletal pain
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 69 (1.45%)
    2 / 35 (5.71%)
    2 / 29 (6.90%)
    5 / 178 (2.81%)
         occurrences all number
    0
    0
    0
    0
    1
    2
    2
    5
    Musculoskeletal stiffness
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 69 (1.45%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    2 / 178 (1.12%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    2
    Myalgia
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 5 (20.00%)
    2 / 18 (11.11%)
    0 / 6 (0.00%)
    4 / 69 (5.80%)
    1 / 35 (2.86%)
    2 / 29 (6.90%)
    10 / 178 (5.62%)
         occurrences all number
    0
    1
    2
    0
    4
    1
    2
    10
    Neck pain
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    1 / 6 (16.67%)
    6 / 69 (8.70%)
    4 / 35 (11.43%)
    3 / 29 (10.34%)
    15 / 178 (8.43%)
         occurrences all number
    0
    0
    1
    1
    7
    4
    4
    17
    Pain in extremity
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    4 / 69 (5.80%)
    0 / 35 (0.00%)
    2 / 29 (6.90%)
    7 / 178 (3.93%)
         occurrences all number
    1
    0
    0
    0
    7
    0
    3
    11
    Trismus
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    3 / 69 (4.35%)
    1 / 35 (2.86%)
    2 / 29 (6.90%)
    6 / 178 (3.37%)
         occurrences all number
    0
    0
    0
    0
    3
    1
    2
    6
    Infections and infestations
    Candida infection
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    3 / 69 (4.35%)
    2 / 35 (5.71%)
    0 / 29 (0.00%)
    6 / 178 (3.37%)
         occurrences all number
    1
    0
    0
    0
    3
    2
    0
    6
    Cellulitis
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    2 / 69 (2.90%)
    2 / 35 (5.71%)
    1 / 29 (3.45%)
    6 / 178 (3.37%)
         occurrences all number
    1
    0
    0
    0
    3
    3
    1
    8
    Conjunctivitis
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    1 / 69 (1.45%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    2 / 178 (1.12%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    0
    2
    Ear infection
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 69 (1.45%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    2 / 178 (1.12%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    2
    Folliculitis
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    3 / 69 (4.35%)
    5 / 35 (14.29%)
    2 / 29 (6.90%)
    12 / 178 (6.74%)
         occurrences all number
    1
    0
    1
    0
    3
    5
    2
    12
    Herpes virus infection
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    1
    Herpes zoster
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
    0 / 69 (0.00%)
    1 / 35 (2.86%)
    1 / 29 (3.45%)
    3 / 178 (1.69%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    1
    3
    Klebsiella sepsis
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 5 (20.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    Lung infection
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    3 / 69 (4.35%)
    0 / 35 (0.00%)
    1 / 29 (3.45%)
    6 / 178 (3.37%)
         occurrences all number
    1
    0
    1
    0
    3
    0
    1
    6
    Nail infection
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 69 (1.45%)
    0 / 35 (0.00%)
    2 / 29 (6.90%)
    4 / 178 (2.25%)
         occurrences all number
    2
    0
    0
    0
    1
    0
    2
    5
    Oral candidiasis
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    4 / 69 (5.80%)
    1 / 35 (2.86%)
    0 / 29 (0.00%)
    5 / 178 (2.81%)
         occurrences all number
    0
    0
    0
    0
    4
    1
    0
    5
    Paronychia
         subjects affected / exposed
    6 / 15 (40.00%)
    1 / 5 (20.00%)
    5 / 18 (27.78%)
    1 / 6 (16.67%)
    15 / 69 (21.74%)
    6 / 35 (17.14%)
    9 / 29 (31.03%)
    43 / 178 (24.16%)
         occurrences all number
    6
    1
    5
    1
    18
    11
    11
    53
    Rash pustular
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    3 / 69 (4.35%)
    1 / 35 (2.86%)
    0 / 29 (0.00%)
    6 / 178 (3.37%)
         occurrences all number
    1
    0
    1
    0
    3
    1
    0
    6
    Rhinitis
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 5 (20.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    1 / 35 (2.86%)
    0 / 29 (0.00%)
    3 / 178 (1.69%)
         occurrences all number
    0
    1
    1
    0
    0
    1
    0
    3
    Sinusitis
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    1
    Skin infection
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    2 / 69 (2.90%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    4 / 178 (2.25%)
         occurrences all number
    2
    0
    0
    0
    2
    0
    0
    4
    Stoma site infection
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    1 / 69 (1.45%)
    0 / 35 (0.00%)
    1 / 29 (3.45%)
    3 / 178 (1.69%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    1
    3
    Tooth infection
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 69 (1.45%)
    1 / 35 (2.86%)
    2 / 29 (6.90%)
    4 / 178 (2.25%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    2
    4
    Urinary tract infection
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    2 / 29 (6.90%)
    3 / 178 (1.69%)
         occurrences all number
    3
    0
    0
    0
    0
    0
    2
    5
    Viral infection
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    1
    Wound infection
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 69 (1.45%)
    0 / 35 (0.00%)
    2 / 29 (6.90%)
    4 / 178 (2.25%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    2
    4
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    6 / 15 (40.00%)
    1 / 5 (20.00%)
    4 / 18 (22.22%)
    1 / 6 (16.67%)
    26 / 69 (37.68%)
    5 / 35 (14.29%)
    10 / 29 (34.48%)
    53 / 178 (29.78%)
         occurrences all number
    7
    1
    4
    1
    28
    5
    10
    56
    Dehydration
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 5 (20.00%)
    0 / 18 (0.00%)
    3 / 6 (50.00%)
    5 / 69 (7.25%)
    1 / 35 (2.86%)
    3 / 29 (10.34%)
    13 / 178 (7.30%)
         occurrences all number
    0
    2
    0
    3
    6
    1
    3
    15
    Glucose tolerance impaired
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 5 (20.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    Hypercalcaemia
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 5 (20.00%)
    3 / 18 (16.67%)
    1 / 6 (16.67%)
    4 / 69 (5.80%)
    1 / 35 (2.86%)
    1 / 29 (3.45%)
    12 / 178 (6.74%)
         occurrences all number
    1
    1
    3
    1
    5
    1
    1
    13
    Hyperglycaemia
         subjects affected / exposed
    8 / 15 (53.33%)
    2 / 5 (40.00%)
    10 / 18 (55.56%)
    5 / 6 (83.33%)
    42 / 69 (60.87%)
    5 / 35 (14.29%)
    16 / 29 (55.17%)
    88 / 178 (49.44%)
         occurrences all number
    14
    6
    15
    9
    103
    5
    30
    182
    Hyperkalaemia
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    1 / 69 (1.45%)
    0 / 35 (0.00%)
    1 / 29 (3.45%)
    3 / 178 (1.69%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    1
    3
    Hypermagnesaemia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 69 (1.45%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    2 / 178 (1.12%)
         occurrences all number
    2
    0
    0
    0
    1
    0
    0
    3
    Hypernatraemia
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    2 / 6 (33.33%)
    1 / 69 (1.45%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    4 / 178 (2.25%)
         occurrences all number
    0
    0
    1
    2
    1
    0
    0
    4
    Hyperosmolar state
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    1 / 6 (16.67%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    1
    Hypertriglyceridaemia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    1 / 35 (2.86%)
    0 / 29 (0.00%)
    2 / 178 (1.12%)
         occurrences all number
    1
    0
    0
    0
    0
    2
    0
    3
    Hyperuricaemia
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    1 / 35 (2.86%)
    0 / 29 (0.00%)
    2 / 178 (1.12%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    0
    2
    Hypoalbuminaemia
         subjects affected / exposed
    2 / 15 (13.33%)
    1 / 5 (20.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    5 / 69 (7.25%)
    4 / 35 (11.43%)
    2 / 29 (6.90%)
    15 / 178 (8.43%)
         occurrences all number
    2
    1
    1
    0
    6
    4
    2
    16
    Hypocalcaemia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    5 / 69 (7.25%)
    2 / 35 (5.71%)
    1 / 29 (3.45%)
    10 / 178 (5.62%)
         occurrences all number
    1
    0
    1
    0
    8
    2
    1
    13
    Hypoglycaemia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 69 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    1
    Hypokalaemia
         subjects affected / exposed
    5 / 15 (33.33%)
    0 / 5 (0.00%)
    4 / 18 (22.22%)
    1 / 6 (16.67%)
    13 / 69 (18.84%)
    3 / 35 (8.57%)
    8 / 29 (27.59%)
    34 / 178 (19.10%)
         occurrences all number
    14
    0
    6
    1
    26
    4
    14
    65
    Hypomagnesaemia
         subjects affected / exposed
    8 / 15 (53.33%)
    2 / 5 (40.00%)
    6 / 18 (33.33%)
    1 / 6 (16.67%)
    18 / 69 (26.09%)
    8 / 35 (22.86%)
    12 / 29 (41.38%)
    55 / 178 (30.90%)
         occurrences all number
    17
    2
    6
    1
    33
    14
    16
    89
    Hyponatraemia
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 5 (20.00%)
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    7 / 69 (10.14%)
    3 / 35 (8.57%)
    3 / 29 (10.34%)
    15 / 178 (8.43%)
         occurrences all number
    1
    1
    0
    0
    8
    3
    3
    16
    Hypophagia
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    3 / 69 (4.35%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    4 / 178 (2.25%)
         occurrences all number
    0
    0
    1
    0
    3
    0
    0
    4
    Hypophosphataemia
         subjects affected / exposed
    2 / 15 (13.33%)
    1 / 5 (20.00%)
    4 / 18 (22.22%)
    1 / 6 (16.67%)
    5 / 69 (7.25%)
    5 / 35 (14.29%)
    2 / 29 (6.90%)
    20 / 178 (11.24%)
         occurrences all number
    2
    3
    6
    1
    7
    10
    2
    31
    Malnutrition
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    1 / 69 (1.45%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    2 / 178 (1.12%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    0
    2

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Mar 2013
    To facilitate enrollment in the Phase Ib portion of the protocol, patients who had received prior cetuximab or other EGFR-targeted antibodies treatments for recurrent or metastatic diseases were allowed to be included in the Phase Ib part of the study. A new arm (Arm B) was added to the Phase Ib part to explore a drinkable suspension (prepared from crushed BYL719 tablets) as an alternative method of administration of BYL719 in patients with swallowing dysfunction who were unable to swallow the BYL719 whole tablets. If the MTD/RP2D of Arm A and Arm B were same, then the administration of BYL719 as a drinkable suspension in patients with swallowing dysfunction may be allowed during the Phase II part of the study.
    20 May 2013
    Introduced the requirement of risk assessment and safety monitoring for the potential development of tumor lysis syndrome (TLS) in all patients treated in the study due to an event of death due to TLS. These changes were implemented immediately following the event with an Urgent Safety Measure.
    24 Oct 2013
    The patient population for the Phase II part of the study was expanded to include two additional clinical settings to test the efficacy of the combination of BYL719 and cetuximab in patients who have developed resistance to cetuximab. The first additional setting was to assess the activity of the combination in the Arm 2 cross-over population where patients who were platinum resistant (or intolerant/ineligible) and cetuximab naïve received single agent cetuximab as the first treatment on this study. At disease progression and thus development of resistance to single agent cetuximab, these patients had the option to cross-over to combination therapy with BYL719 and cetuximab to determine if the combination has efficacy in the setting of resistance to single agent cetuximab. The second additional setting was to assess the activity of BYL719 and cetuximab in the second line setting after disease progression following first line therapy with both platinum and cetuximab.
    07 Apr 2014
    A dose level of 250 mg BYL719 once daily was added as the first dose reduction level for the patients enrolled in the study. The second dose reduction was defined at 200 mgBYL719 once daily instead of 150 mg. Guidelines for the management of pneumonitis were added. In addition, ongoing monitoring of the safety and efficacy data during Phase II was described.
    24 Jul 2014
    Introduced a new formulation of BYL719 as a dispersible tablet for administration via gastrostomy tube (G or PEG tube) in a third Arm of the Phase Ib. Modified inclusion criteria to enroll patients in Phase II Arm 3 with stable grade 2 or less cetuximab-related skin toxicity.
    02 Jun 2015
    Introduced a mandatory baseline chest high-resolution computed tomography (CT) scan for safety purposes for all the newly enrolled patients to confirm no relevant pulmonary complications were present before starting study treatment.

    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.
    Recruitment of new patients who were resistant to both platinum & cetuximab into Arm 3 was halted due to slow enrollment. The study was terminated early and health authorities were informed.
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    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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