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    Clinical Trial Results:
    A Phase III, Double-Blind, Placebo-Controlled Study of Vemurafenib Versus Vemurafenib Plus GDC-0973 in Previously Untreated BRAF^600-Mutation Positive Patients with Unresectable Locally Advanced or Metastatic Melanoma

    Summary
    EudraCT number
    		 2012-003008-11
    Trial protocol
    		 GB   ES   CZ   AT   NO   DE   BE   SE   IT   NL   HU   FR  
    Global end of trial date
    21 Jul 2019

    Results information
    Results version number
    		 v4(current)
    This version publication date
    16 Jul 2020
    First version publication date
    07 Aug 2015
    Other versions
    		 v1 (removed from public view) , v2 , v3
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    GO28141
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01689519
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Hoffmann-La Roche
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Scientific contact
    Medical Communications, Hoffmann-La Roche, +41 616878333, global.trial_information@roche.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    23 Apr 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Jul 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of vemurafenib in combination with cobimetinib (GDC-0973), compared with vemurafenib and placebo, in previously untreated BRAF V600 mutation-positive patients with unresectable locally advanced or metastatic melanoma, as measured by progression-free survival (PFS), assessed by the study site investigator.
    Protection of trial subjects
    Written informed consent for participation in the study was obtained before performing any study-specific screening tests or evaluations.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    08 Jan 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy, Safety
    Long term follow-up duration
    		 5 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 56
    Country: Number of subjects enrolled
    Austria: 8
    Country: Number of subjects enrolled
    Belgium: 8
    Country: Number of subjects enrolled
    Canada: 18
    Country: Number of subjects enrolled
    Czech Republic: 24
    Country: Number of subjects enrolled
    France: 41
    Country: Number of subjects enrolled
    Germany: 47
    Country: Number of subjects enrolled
    Hungary: 18
    Country: Number of subjects enrolled
    Israel: 12
    Country: Number of subjects enrolled
    Italy: 95
    Country: Number of subjects enrolled
    Netherlands: 9
    Country: Number of subjects enrolled
    New Zealand: 10
    Country: Number of subjects enrolled
    Norway: 5
    Country: Number of subjects enrolled
    Russian Federation: 35
    Country: Number of subjects enrolled
    Spain: 32
    Country: Number of subjects enrolled
    Sweden: 13
    Country: Number of subjects enrolled
    United Kingdom: 29
    Country: Number of subjects enrolled
    United States: 33
    Country: Number of subjects enrolled
    Switzerland: 2
    Worldwide total number of subjects
    495
    EEA total number of subjects
    329
    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)
    362
    From 65 to 84 years
    128
    85 years and over
    5

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Written informed consent for participation in the study was obtained before performing any study-specific screening tests or evaluations.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cobimetinib + Vemurafenib
    Arm description
    		 Participants received cobimetinib 60 mg orally once daily on Days 1-21 of each 28 day cycle plus vemurafenib 960 mg orally twice a day on Days 1-28 of each 28 day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vemurafenib
    Investigational medicinal product code
    Other name
    RO518426
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received vemurafenib 960 milligrams (mg) orally twice a day on Days 1-28 of each 28-day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.

    Investigational medicinal product name
    Cobimetinib
    Investigational medicinal product code
    Other name
    GDC-0973 RO5514041 XL518
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received cobimetinib 60 mg orally once daily on Days 1-21 of each 28-day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.

    Arm title
    		 Placebo + Vemurafenib
    Arm description
    		 Participants received placebo orally once daily on Days 1-21 of each 28 day cycle plus vemurafenib 960 mg orally twice a day on Days 1-28 of each 28 day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received placebo orally once daily on Days 1-21 of each 28-day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest

    Investigational medicinal product name
    Vemurafenib
    Investigational medicinal product code
    Other name
    RO518426
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received vemurafenib 960 milligrams (mg) orally twice a day on Days 1-28 of each 28-day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.

    Number of subjects in period 1
    		Cobimetinib + Vemurafenib Placebo + Vemurafenib
    Started
    247
    248
    Completed
    0
    0
    Not completed
    247
    248
         Adverse event, serious fatal
    157
    167
         Physician decision
    4
    1
         Consent withdrawn by subject
    21
    20
         Unknown
    2
    4
         Lost to follow-up
    4
    8
         Study terminated by Spon6sor
    59
    48

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cobimetinib + Vemurafenib
    Reporting group description
    		 Participants received cobimetinib 60 mg orally once daily on Days 1-21 of each 28 day cycle plus vemurafenib 960 mg orally twice a day on Days 1-28 of each 28 day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.

    Reporting group title
    Placebo + Vemurafenib
    Reporting group description
    		 Participants received placebo orally once daily on Days 1-21 of each 28 day cycle plus vemurafenib 960 mg orally twice a day on Days 1-28 of each 28 day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.

    Reporting group values
    		 Cobimetinib + Vemurafenib Placebo + Vemurafenib Total
    Number of subjects
    		 247 248 495
    Age Categorical
    Units:
        <=18 years
    		 0 0 0
        Between 18 and 65 years
    		 183 179 362
        >=65 years
    		 64 69 133
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 54.9 ( 14.0 ) 55.3 ( 13.8 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 101 108 209
        Male
    		 146 140 286
    Race/Ethnicity, Customized
    Units: Subjects
        Asian
    		 1 0 1
        More than one race
    		 1 1 2
        Native Hawaiian or other Pacific Islande
    		 0 1 1
        Black or African American
    		 0 0 0
        White
    		 227 235 462
        Unknown or Not Reported
    		 16 9 25
        Other
    		 2 2 4
    Race/Ethnicity, Customized
    Units: Subjects
        Hispanic or Latino
    		 14 12 26
        Not Hispanic or Latino
    		 213 223 436
        Not Stated
    		 16 10 26
        Unknown
    		 4 3 7

    End points

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    End points reporting groups
    Reporting group title
    Cobimetinib + Vemurafenib
    Reporting group description
    		 Participants received cobimetinib 60 mg orally once daily on Days 1-21 of each 28 day cycle plus vemurafenib 960 mg orally twice a day on Days 1-28 of each 28 day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.

    Reporting group title
    Placebo + Vemurafenib
    Reporting group description
    		 Participants received placebo orally once daily on Days 1-21 of each 28 day cycle plus vemurafenib 960 mg orally twice a day on Days 1-28 of each 28 day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.

    Primary: Progression-free survival

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    End point title
    		 Progression-free survival
    End point description
    Progression-free survival was defined as the time from randomization to the first occurrence of disease progression, as determined by the investigator using Response Evaluation Criteria in Solid Tumors v1.1, or death from any cause, whichever came first. Disease progression was defined as: (1) at least a 20% increase in the sum (the increase in the sum must be at least 5 mm) of diameters of target lesions, taking as reference the smallest sum during the study; (2) unequivocal progression of existing non-target lesions; or (3) the appearance of 1 or more new lesions. 9999 = not estimable, could not be calculated due to too few events
    End point type
    Primary
    End point timeframe
    Baseline to the 21 July 2019 data cut-off (up to 7 years, 6 months)
    End point values
    		 Cobimetinib + Vemurafenib Placebo + Vemurafenib
    Number of subjects analysed
    247
    248
    Units: Months
    median (confidence interval 95%)
        Primary Analysis: 9 May 2014
    9.90 (9.00 to 9999)
    6.20 (5.55 to 7.39)
        Post hoc Efficacy Analysis: 16 January 2015
    12.30 (9.50 to 13.4)
    7.20 (5.6 to 7.5)
        Extended 5-Year Analysis: 21 July 2019
    12.60 (9.50 to 14.8)
    7.20 (5.60 to 7.50)
    Statistical analysis title
    		 Primary Analysis 9 May 2014
    Statistical analysis description
    The analysis was stratified by geographic region and metastasis classification (disease stage).
    Comparison groups
    Cobimetinib + Vemurafenib v Placebo + Vemurafenib
    Number of subjects included in analysis
    495
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.39
         upper limit
    		 0.68
    Statistical analysis title
    		 Post hoc Efficacy Analysis: 16 January 2015
    Statistical analysis description
    The analysis was stratified by geographic region and metastasis classification (disease stage).
    Comparison groups
    Cobimetinib + Vemurafenib v Placebo + Vemurafenib
    Number of subjects included in analysis
    495
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.46
         upper limit
    		 0.72
    Statistical analysis title
    		 Extended 5-Year Analysis: 21 July 2019
    Statistical analysis description
    The analysis was stratified by geographic region and metastasis classification (disease stage).
    Comparison groups
    Cobimetinib + Vemurafenib v Placebo + Vemurafenib
    Number of subjects included in analysis
    495
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.53
         upper limit
    		 0.79

    Secondary: Overall survival

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    End point title
    		 Overall survival
    End point description
    Overall survival was defined as the time from randomization until the date of death from any cause. 0000 = not estimable, could not be calculated due to too few events 9999 = not estimable, could not be calculated due to too few events
    End point type
    Secondary
    End point timeframe
    Baseline to the 21 July 2019 data cut-off (up to 7 years, 6 months)
    End point values
    		 Cobimetinib + Vemurafenib Placebo + Vemurafenib
    Number of subjects analysed
    247
    248
    Units: Months
    median (confidence interval 95%)
        Primary Analysis 9 May 2014
    9999 (0000 to 9999)
    9999 (0000 to 9999)
        Post hoc Analysis 16 January 2015
    9999 (20.70 to 9999)
    17.00 (15.00 to 9999)
        Final Analysis 28 August 2015
    22.30 (20.30 to 9999)
    17.40 (15.00 to 19.80)
        Extended 5-year Analysis 21 July 2019
    22.50 (20.30 to 28.80)
    17.40 (15.00 to 19.80)
    Statistical analysis title
    		 Primary Analysis 9 May 2014
    Statistical analysis description
    The analysis was stratified by geographic region and metastasis classification (disease stage).
    Comparison groups
    Cobimetinib + Vemurafenib v Placebo + Vemurafenib
    Number of subjects included in analysis
    495
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0463
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.645
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.42
         upper limit
    		 1
    Statistical analysis title
    		 Post hoc Analysis 16 January 2015
    Statistical analysis description
    The analysis was stratified by geographic region and metastasis classification (disease stage).
    Comparison groups
    Cobimetinib + Vemurafenib v Placebo + Vemurafenib
    Number of subjects included in analysis
    495
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0034
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.49
         upper limit
    		 0.87
    Statistical analysis title
    		 Final Analysis 28 August 2015
    Statistical analysis description
    The analysis was stratified by geographic region and metastasis classification (disease stage).
    Comparison groups
    Cobimetinib + Vemurafenib v Placebo + Vemurafenib
    Number of subjects included in analysis
    495
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.005
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.55
         upper limit
    		 0.9

    Secondary: Percentage of participants with an objective response

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    End point title
    		 Percentage of participants with an objective response
    End point description
    An objective response was defined as a complete response or a partial response determined on two consecutive occasions ≥ 4 weeks apart. Responses were determined by Response Evaluation Criteria in Solid Tumors v1.1. A complete response was defined as the disappearance of all target lesions or the disappearance of all non-target lesions and normalization of tumor marker level. A partial response was defined as at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of the longest diameter of target lesions.
    End point type
    Secondary
    End point timeframe
    Baseline to the 21 July 2019 data cut-off (up to 7 years, 6 months)
    End point values
    		 Cobimetinib + Vemurafenib Placebo + Vemurafenib
    Number of subjects analysed
    247
    248
    Units: Percentage of participants
    number (confidence interval 95%)
        Primary Analysis: 9 May 2014
    67.60 (61.40 to 73.40)
    44.80 (38.50 to 51.12)
        Post hoc Efficacy Analysis: 16 January 2015
    69.60 (63.50 to 75.30)
    50.00 (43.60 to 56.40)
        Extended 5-Year Analysis: 21 July 2019
    69.90 (63.49 to 75.31)
    49.60 (43.21 to 55.99)
    Statistical analysis title
    		 Primary Analysis: 9 May 2014
    Comparison groups
    Cobimetinib + Vemurafenib v Placebo + Vemurafenib
    Number of subjects included in analysis
    495
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Chi-squared
    Parameter type
    		 Mean difference (final values)
    Point estimate
    22.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 14.1
         upper limit
    		 31.6
    Statistical analysis title
    		 Post hoc Efficacy Analysis: 16 January 2015
    Comparison groups
    Cobimetinib + Vemurafenib v Placebo + Vemurafenib
    Number of subjects included in analysis
    495
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Chi-squared
    Parameter type
    		 Mean difference (final values)
    Point estimate
    19.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 11
         upper limit
    		 28.3
    Statistical analysis title
    		 Extended 5-Year Analysis: 21 July 2019
    Comparison groups
    Cobimetinib + Vemurafenib v Placebo + Vemurafenib
    Number of subjects included in analysis
    495
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Chi-squared
    Parameter type
    		 Mean difference (final values)
    Point estimate
    20
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 11.4
         upper limit
    		 28.7

    Secondary: Duration of response

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    End point title
    		 Duration of response
    End point description
    Duration of response was defined as the time from first occurrence of a documented confirmed objective response until the time of disease progression, as determined by investigator review of tumor assessments using Response Evaluation Criteria in Solid Tumors v1.1 or death from any cause during the study. Disease progression was defined as: (1) at least a 20% increase in the sum (the increase in the sum must be at least 5 mm) of diameters of target lesions, taking as reference the smallest sum during the study; (2) unequivocal progression of existing non-target lesions; or (3) the appearance of 1 or more new lesions. 9999 = not estimable, could not be calculated due to too few events
    End point type
    Secondary
    End point timeframe
    Baseline to the 21 July 2019 data cut-off (up to 7 years, 6 months)
    End point values
    		 Cobimetinib + Vemurafenib Placebo + Vemurafenib
    Number of subjects analysed
    167
    111
    Units: Months
    median (confidence interval 95%)
        Primary Analysis: 9 May 2014
    9999 (9.30 to 9999)
    7.29 (5.78 to 9999)
        Extended 5-Year Analysis: 21 July 2019
    14.65 (12.9 to 19.3)
    9.23 (7.50 to 12.90)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Safety data cut-off: July 2019; up to 7 years, 6 months
    Adverse event reporting additional description
    Safety population: All participants who received at least 1 dose of study treatment (ie, cobimetinib/placebo or vemurafenib).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Cobimetinib + Vemurafenib
    Reporting group description
    		 Participants received cobimetinib 60 mg orally once daily on Days 1-21 of each 28 day cycle plus vemurafenib 960 mg orally twice a day on Days 1-28 of each 28 day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.

    Reporting group title
    Placebo + Vemurafenib
    Reporting group description
    		 Participants received placebo orally once daily on Days 1-21 of each 28 day cycle plus vemurafenib 960 mg orally twice a day on Days 1-28 of each 28 day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.

    Serious adverse events
    		 Cobimetinib + Vemurafenib Placebo + Vemurafenib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    105 / 248 (42.34%)
    71 / 245 (28.98%)
         number of deaths (all causes)
    6
    5
         number of deaths resulting from adverse events
    1
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    ACANTHOMA
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ADENOCARCINOMA OF COLON
         subjects affected / exposed
    1 / 248 (0.40%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BENIGN NEOPLASM
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ENDOMETRIAL ADENOCARCINOMA
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROINTESTINAL TRACT ADENOMA
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    KAPOSI'S SARCOMA
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    KERATOACANTHOMA
         subjects affected / exposed
    0 / 248 (0.00%)
    4 / 245 (1.63%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LUNG ADENOCARCINOMA
         subjects affected / exposed
    0 / 248 (0.00%)
    2 / 245 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MALIGNANT MELANOMA IN SITU
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MUCINOUS BREAST CARCINOMA
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PAPILLOMA
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SQUAMOUS CELL CARCINOMA OF SKIN
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TRANSITIONAL CELL CARCINOMA
         subjects affected / exposed
    2 / 248 (0.81%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TUMOUR HAEMORRHAGE
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TUMOUR PAIN
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    HYPERTENSION
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPERTENSIVE CRISIS
         subjects affected / exposed
    2 / 248 (0.81%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SUBGALEAL HAEMATOMA
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VASCULITIS
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VENOUS THROMBOSIS LIMB
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    ASTHENIA
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHEST PAIN
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DEATH
         subjects affected / exposed
    1 / 248 (0.40%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    FATIGUE
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GAIT DISTURBANCE
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MALAISE
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PERIPHERAL SWELLING
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PYREXIA
         subjects affected / exposed
    7 / 248 (2.82%)
    3 / 245 (1.22%)
         occurrences causally related to treatment / all
    6 / 9
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    HYPERSENSITIVITY
         subjects affected / exposed
    3 / 248 (1.21%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SARCOIDOSIS
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    CERVICAL POLYP
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    ATELECTASIS
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    DYSPNOEA
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INTERSTITIAL LUNG DISEASE
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PLEURAL EFFUSION
         subjects affected / exposed
    0 / 248 (0.00%)
    3 / 245 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONITIS
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PULMONARY EMBOLISM
         subjects affected / exposed
    3 / 248 (1.21%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    PULMONARY HAEMORRHAGE
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    MANIA
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    4 / 248 (1.61%)
    2 / 245 (0.82%)
         occurrences causally related to treatment / all
    4 / 4
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    3 / 248 (1.21%)
    2 / 245 (0.82%)
         occurrences causally related to treatment / all
    3 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BLOOD ALKALINE PHOSPHATASE INCREASED
         subjects affected / exposed
    1 / 248 (0.40%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BLOOD CREATINE PHOSPHOKINASE INCREASED
         subjects affected / exposed
    2 / 248 (0.81%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BLOOD CREATININE INCREASED
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    EJECTION FRACTION DECREASED
         subjects affected / exposed
    1 / 248 (0.40%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ELECTROCARDIOGRAM QT PROLONGED
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ELECTROCARDIOGRAM T WAVE ABNORMAL
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GAMMA-GLUTAMYLTRANSFERASE INCREASED
         subjects affected / exposed
    3 / 248 (1.21%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HAEMOGLOBIN DECREASED
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LIPASE INCREASED
         subjects affected / exposed
    2 / 248 (0.81%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LIVER FUNCTION TEST INCREASED
         subjects affected / exposed
    1 / 248 (0.40%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    FACIAL BONES FRACTURE
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FALL
         subjects affected / exposed
    2 / 248 (0.81%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FEMORAL NECK FRACTURE
         subjects affected / exposed
    1 / 248 (0.40%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FRACTURE DISPLACEMENT
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OVERDOSE
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RIB FRACTURE
         subjects affected / exposed
    1 / 248 (0.40%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SKIN LACERATION
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    THORACIC VERTEBRAL FRACTURE
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TRAUMATIC HAEMATOMA
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    UPPER LIMB FRACTURE
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    ACUTE CORONARY SYNDROME
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ATRIAL FIBRILLATION
         subjects affected / exposed
    4 / 248 (1.61%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 8
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CARDIAC ARREST
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    CARDIAC FAILURE
         subjects affected / exposed
    1 / 248 (0.40%)
    2 / 245 (0.82%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    CARDIAC TAMPONADE
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MYOCARDIAL INFARCTION
         subjects affected / exposed
    2 / 248 (0.81%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    PERICARDIAL EFFUSION
         subjects affected / exposed
    0 / 248 (0.00%)
    4 / 245 (1.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SUPRAVENTRICULAR TACHYCARDIA
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TACHYCARDIA
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    CEREBRAL HAEMORRHAGE
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CEREBROVASCULAR ACCIDENT
         subjects affected / exposed
    2 / 248 (0.81%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COMA
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    DIZZINESS
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DYSARTHRIA
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DYSGEUSIA
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FACIAL PARALYSIS
         subjects affected / exposed
    2 / 248 (0.81%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FACIAL PARESIS
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GENERALISED TONIC-CLONIC SEIZURE
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HAEMORRHAGIC STROKE
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    HEADACHE
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEMIPARESIS
         subjects affected / exposed
    2 / 248 (0.81%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYDROCEPHALUS
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ISCHAEMIC STROKE
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MYASTHENIA GRAVIS
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PARAESTHESIA
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    POLYNEUROPATHY
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SEIZURE
         subjects affected / exposed
    3 / 248 (1.21%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SUBARACHNOID HAEMORRHAGE
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SYNCOPE
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    CHORIORETINOPATHY
         subjects affected / exposed
    3 / 248 (1.21%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    5 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    IRIDOCYCLITIS
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RETINAL DETACHMENT
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RETINAL HAEMORRHAGE
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SEROUS RETINAL DETACHMENT
         subjects affected / exposed
    2 / 248 (0.81%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    UVEITIS
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    ABDOMINAL PAIN
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    APHTHOUS ULCER
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COLITIS
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CONSTIPATION
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIARRHOEA
         subjects affected / exposed
    3 / 248 (1.21%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DYSPHAGIA
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTRIC ANTRAL VASCULAR ECTASIA
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROINTESTINAL HAEMORRHAGE
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROINTESTINAL PAIN
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROOESOPHAGEAL REFLUX DISEASE
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INGUINAL HERNIA
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INTESTINAL OBSTRUCTION
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INTESTINAL PERFORATION
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MELAENA
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OBSTRUCTION GASTRIC
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PANCREATITIS
         subjects affected / exposed
    1 / 248 (0.40%)
    2 / 245 (0.82%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PERIODONTAL DISEASE
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RECTAL POLYP
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SMALL INTESTINAL OBSTRUCTION
         subjects affected / exposed
    3 / 248 (1.21%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VOMITING
         subjects affected / exposed
    2 / 248 (0.81%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    CHOLECYSTITIS
         subjects affected / exposed
    0 / 248 (0.00%)
    2 / 245 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DRUG-INDUCED LIVER INJURY
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEPATITIS ACUTE
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    DERMATITIS EXFOLIATIVE GENERALISED
         subjects affected / exposed
    0 / 248 (0.00%)
    2 / 245 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DRUG REACTION WITH EOSINOPHILIA AND SYSTEMIC SYMPTOMS
         subjects affected / exposed
    1 / 248 (0.40%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ERYTHEMA MULTIFORME
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ERYTHEMA NODOSUM
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPERKERATOSIS
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PANNICULITIS
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PHOTOSENSITIVITY REACTION
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RASH
         subjects affected / exposed
    4 / 248 (1.61%)
    2 / 245 (0.82%)
         occurrences causally related to treatment / all
    4 / 4
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RASH GENERALISED
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RASH MACULAR
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RASH MACULO-PAPULAR
         subjects affected / exposed
    3 / 248 (1.21%)
    2 / 245 (0.82%)
         occurrences causally related to treatment / all
    3 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RASH MORBILLIFORM
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    URTICARIA
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    ACUTE KIDNEY INJURY
         subjects affected / exposed
    3 / 248 (1.21%)
    2 / 245 (0.82%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIABETIC NEPHROPATHY
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RENAL COLIC
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    URETEROLITHIASIS
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    HYPERTHYROIDISM
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BACK PAIN
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BURSITIS
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MUSCULAR WEAKNESS
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MUSCULOSKELETAL CHEST PAIN
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MUSCULOSKELETAL PAIN
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MYALGIA
         subjects affected / exposed
    1 / 248 (0.40%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PATHOLOGICAL FRACTURE
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    POLYARTHRITIS
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RHABDOMYOLYSIS
         subjects affected / exposed
    1 / 248 (0.40%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    ABDOMINAL SEPSIS
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ANAL ABSCESS
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ARTHRITIS BACTERIAL
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CAMPYLOBACTER GASTROENTERITIS
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CELLULITIS
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CLOSTRIDIUM DIFFICILE COLITIS
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    CLOSTRIDIUM DIFFICILE INFECTION
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DEVICE RELATED INFECTION
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ENTEROCOCCAL SEPSIS
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIVERTICULITIS
         subjects affected / exposed
    1 / 248 (0.40%)
    2 / 245 (0.82%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ERYSIPELAS
         subjects affected / exposed
    1 / 248 (0.40%)
    3 / 245 (1.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROENTERITIS
         subjects affected / exposed
    1 / 248 (0.40%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROENTERITIS CLOSTRIDIAL
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROENTERITIS VIRAL
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GENITOURINARY TRACT INFECTION
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROINTESTINAL BACTERIAL INFECTION
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GROIN ABSCESS
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONIA
         subjects affected / exposed
    6 / 248 (2.42%)
    3 / 245 (1.22%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    INFECTION
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SEPSIS
         subjects affected / exposed
    1 / 248 (0.40%)
    2 / 245 (0.82%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SEPTIC SHOCK
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TONSILLITIS
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TUBERCULOSIS
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    URINARY TRACT INFECTION
         subjects affected / exposed
    2 / 248 (0.81%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VULVAL CELLULITIS
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    WOUND INFECTION
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    DEHYDRATION
         subjects affected / exposed
    6 / 248 (2.42%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    2 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIABETES MELLITUS
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPERNATRAEMIA
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOKALAEMIA
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPONATRAEMIA
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TYPE 2 DIABETES MELLITUS
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cobimetinib + Vemurafenib Placebo + Vemurafenib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    239 / 248 (96.37%)
    236 / 245 (96.33%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    BASAL CELL CARCINOMA
         subjects affected / exposed
    16 / 248 (6.45%)
    6 / 245 (2.45%)
         occurrences all number
    33
    6
    KERATOACANTHOMA
         subjects affected / exposed
    5 / 248 (2.02%)
    20 / 245 (8.16%)
         occurrences all number
    6
    26
    MELANOCYTIC NAEVUS
         subjects affected / exposed
    5 / 248 (2.02%)
    17 / 245 (6.94%)
         occurrences all number
    5
    26
    SEBORRHOEIC KERATOSIS
         subjects affected / exposed
    15 / 248 (6.05%)
    21 / 245 (8.57%)
         occurrences all number
    15
    24
    SKIN PAPILLOMA
         subjects affected / exposed
    18 / 248 (7.26%)
    30 / 245 (12.24%)
         occurrences all number
    26
    36
    SQUAMOUS CELL CARCINOMA OF SKIN
         subjects affected / exposed
    10 / 248 (4.03%)
    33 / 245 (13.47%)
         occurrences all number
    25
    66
    Vascular disorders
    HYPERTENSION
         subjects affected / exposed
    50 / 248 (20.16%)
    30 / 245 (12.24%)
         occurrences all number
    60
    33
    General disorders and administration site conditions
    ASTHENIA
         subjects affected / exposed
    51 / 248 (20.56%)
    43 / 245 (17.55%)
         occurrences all number
    96
    50
    CHILLS
         subjects affected / exposed
    25 / 248 (10.08%)
    14 / 245 (5.71%)
         occurrences all number
    28
    17
    FATIGUE
         subjects affected / exposed
    93 / 248 (37.50%)
    83 / 245 (33.88%)
         occurrences all number
    137
    99
    OEDEMA PERIPHERAL
         subjects affected / exposed
    38 / 248 (15.32%)
    28 / 245 (11.43%)
         occurrences all number
    49
    32
    PYREXIA
         subjects affected / exposed
    77 / 248 (31.05%)
    60 / 245 (24.49%)
         occurrences all number
    130
    77
    Respiratory, thoracic and mediastinal disorders
    COUGH
         subjects affected / exposed
    28 / 248 (11.29%)
    32 / 245 (13.06%)
         occurrences all number
    36
    37
    DYSPNOEA
         subjects affected / exposed
    19 / 248 (7.66%)
    19 / 245 (7.76%)
         occurrences all number
    26
    23
    OROPHARYNGEAL PAIN
         subjects affected / exposed
    19 / 248 (7.66%)
    22 / 245 (8.98%)
         occurrences all number
    20
    28
    Psychiatric disorders
    ANXIETY
         subjects affected / exposed
    16 / 248 (6.45%)
    11 / 245 (4.49%)
         occurrences all number
    18
    12
    DEPRESSION
         subjects affected / exposed
    15 / 248 (6.05%)
    11 / 245 (4.49%)
         occurrences all number
    17
    11
    INSOMNIA
         subjects affected / exposed
    19 / 248 (7.66%)
    27 / 245 (11.02%)
         occurrences all number
    24
    31
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    65 / 248 (26.21%)
    44 / 245 (17.96%)
         occurrences all number
    94
    48
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    64 / 248 (25.81%)
    29 / 245 (11.84%)
         occurrences all number
    87
    30
    BLOOD ALKALINE PHOSPHATASE INCREASED
         subjects affected / exposed
    46 / 248 (18.55%)
    26 / 245 (10.61%)
         occurrences all number
    67
    30
    BLOOD BILIRUBIN INCREASED
         subjects affected / exposed
    20 / 248 (8.06%)
    17 / 245 (6.94%)
         occurrences all number
    29
    22
    BLOOD CHOLESTEROL INCREASED
         subjects affected / exposed
    16 / 248 (6.45%)
    10 / 245 (4.08%)
         occurrences all number
    19
    10
    BLOOD CREATINE PHOSPHOKINASE INCREASED
         subjects affected / exposed
    90 / 248 (36.29%)
    10 / 245 (4.08%)
         occurrences all number
    171
    13
    BLOOD CREATININE INCREASED
         subjects affected / exposed
    45 / 248 (18.15%)
    20 / 245 (8.16%)
         occurrences all number
    59
    25
    BLOOD LACTATE DEHYDROGENASE INCREASED
         subjects affected / exposed
    15 / 248 (6.05%)
    8 / 245 (3.27%)
         occurrences all number
    30
    8
    EJECTION FRACTION DECREASED
         subjects affected / exposed
    31 / 248 (12.50%)
    12 / 245 (4.90%)
         occurrences all number
    46
    13
    ELECTROCARDIOGRAM QT PROLONGED
         subjects affected / exposed
    12 / 248 (4.84%)
    13 / 245 (5.31%)
         occurrences all number
    15
    19
    GAMMA-GLUTAMYLTRANSFERASE INCREASED
         subjects affected / exposed
    57 / 248 (22.98%)
    45 / 245 (18.37%)
         occurrences all number
    82
    61
    WEIGHT DECREASED
         subjects affected / exposed
    18 / 248 (7.26%)
    14 / 245 (5.71%)
         occurrences all number
    20
    17
    Injury, poisoning and procedural complications
    SUNBURN
         subjects affected / exposed
    37 / 248 (14.92%)
    45 / 245 (18.37%)
         occurrences all number
    60
    68
    Nervous system disorders
    DIZZINESS
         subjects affected / exposed
    18 / 248 (7.26%)
    7 / 245 (2.86%)
         occurrences all number
    18
    8
    DYSGEUSIA
         subjects affected / exposed
    27 / 248 (10.89%)
    16 / 245 (6.53%)
         occurrences all number
    29
    17
    HEADACHE
         subjects affected / exposed
    50 / 248 (20.16%)
    41 / 245 (16.73%)
         occurrences all number
    76
    50
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    51 / 248 (20.56%)
    21 / 245 (8.57%)
         occurrences all number
    76
    26
    Eye disorders
    CHORIORETINOPATHY
         subjects affected / exposed
    30 / 248 (12.10%)
    4 / 245 (1.63%)
         occurrences all number
    36
    9
    VISION BLURRED
         subjects affected / exposed
    32 / 248 (12.90%)
    8 / 245 (3.27%)
         occurrences all number
    37
    9
    Gastrointestinal disorders
    ABDOMINAL PAIN
         subjects affected / exposed
    30 / 248 (12.10%)
    20 / 245 (8.16%)
         occurrences all number
    37
    23
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    15 / 248 (6.05%)
    18 / 245 (7.35%)
         occurrences all number
    17
    21
    CONSTIPATION
         subjects affected / exposed
    27 / 248 (10.89%)
    29 / 245 (11.84%)
         occurrences all number
    37
    31
    DIARRHOEA
         subjects affected / exposed
    151 / 248 (60.89%)
    84 / 245 (34.29%)
         occurrences all number
    311
    162
    DYSPEPSIA
         subjects affected / exposed
    19 / 248 (7.66%)
    13 / 245 (5.31%)
         occurrences all number
    22
    15
    NAUSEA
         subjects affected / exposed
    108 / 248 (43.55%)
    67 / 245 (27.35%)
         occurrences all number
    184
    83
    STOMATITIS
         subjects affected / exposed
    17 / 248 (6.85%)
    3 / 245 (1.22%)
         occurrences all number
    27
    3
    VOMITING
         subjects affected / exposed
    69 / 248 (27.82%)
    33 / 245 (13.47%)
         occurrences all number
    108
    42
    Skin and subcutaneous tissue disorders
    ACTINIC KERATOSIS
         subjects affected / exposed
    13 / 248 (5.24%)
    27 / 245 (11.02%)
         occurrences all number
    32
    31
    ALOPECIA
         subjects affected / exposed
    42 / 248 (16.94%)
    75 / 245 (30.61%)
         occurrences all number
    44
    78
    DRY SKIN
         subjects affected / exposed
    37 / 248 (14.92%)
    42 / 245 (17.14%)
         occurrences all number
    40
    46
    DERMATITIS ACNEIFORM
         subjects affected / exposed
    37 / 248 (14.92%)
    22 / 245 (8.98%)
         occurrences all number
    47
    26
    ERYTHEMA
         subjects affected / exposed
    32 / 248 (12.90%)
    36 / 245 (14.69%)
         occurrences all number
    56
    57
    HYPERKERATOSIS
         subjects affected / exposed
    31 / 248 (12.50%)
    74 / 245 (30.20%)
         occurrences all number
    39
    130
    KERATOSIS PILARIS
         subjects affected / exposed
    13 / 248 (5.24%)
    26 / 245 (10.61%)
         occurrences all number
    14
    30
    PALMAR-PLANTAR ERYTHRODYSAESTHESIA SYNDROME
         subjects affected / exposed
    18 / 248 (7.26%)
    9 / 245 (3.67%)
         occurrences all number
    23
    10
    PHOTOSENSITIVITY REACTION
         subjects affected / exposed
    86 / 248 (34.68%)
    48 / 245 (19.59%)
         occurrences all number
    119
    58
    PRURITUS
         subjects affected / exposed
    51 / 248 (20.56%)
    48 / 245 (19.59%)
         occurrences all number
    85
    54
    RASH
         subjects affected / exposed
    101 / 248 (40.73%)
    97 / 245 (39.59%)
         occurrences all number
    158
    121
    RASH MACULO-PAPULAR
         subjects affected / exposed
    37 / 248 (14.92%)
    37 / 245 (15.10%)
         occurrences all number
    61
    47
    SOLAR DERMATITIS
         subjects affected / exposed
    18 / 248 (7.26%)
    14 / 245 (5.71%)
         occurrences all number
    34
    23
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    96 / 248 (38.71%)
    105 / 245 (42.86%)
         occurrences all number
    172
    179
    BACK PAIN
         subjects affected / exposed
    21 / 248 (8.47%)
    15 / 245 (6.12%)
         occurrences all number
    30
    15
    MUSCULOSKELETAL PAIN
         subjects affected / exposed
    17 / 248 (6.85%)
    16 / 245 (6.53%)
         occurrences all number
    18
    19
    MYALGIA
         subjects affected / exposed
    41 / 248 (16.53%)
    33 / 245 (13.47%)
         occurrences all number
    53
    37
    PAIN IN EXTREMITY
         subjects affected / exposed
    32 / 248 (12.90%)
    40 / 245 (16.33%)
         occurrences all number
    51
    54
    Infections and infestations
    CONJUNCTIVITIS
         subjects affected / exposed
    18 / 248 (7.26%)
    8 / 245 (3.27%)
         occurrences all number
    19
    10
    FOLLICULITIS
         subjects affected / exposed
    19 / 248 (7.66%)
    12 / 245 (4.90%)
         occurrences all number
    22
    15
    NASOPHARYNGITIS
         subjects affected / exposed
    23 / 248 (9.27%)
    18 / 245 (7.35%)
         occurrences all number
    29
    21
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    14 / 248 (5.65%)
    11 / 245 (4.49%)
         occurrences all number
    18
    15
    URINARY TRACT INFECTION
         subjects affected / exposed
    17 / 248 (6.85%)
    11 / 245 (4.49%)
         occurrences all number
    25
    13
    Metabolism and nutrition disorders
    DECREASED APPETITE
         subjects affected / exposed
    55 / 248 (22.18%)
    50 / 245 (20.41%)
         occurrences all number
    75
    55
    HYPONATRAEMIA
         subjects affected / exposed
    13 / 248 (5.24%)
    3 / 245 (1.22%)
         occurrences all number
    19
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Jan 2014
    Changes that allow for symmetry in the treatment of patients receiving rituximab or obinutuzumab in case of hepatitis B reactivation. Changes to clarify that either antibody should be held in case of serious infection. clarification that patients with mantle cell lymphoma (MCL) and small lymphocytic lymphoma (SLL) were not eligible for the dose escalation portion of the study for safety reasons.
    23 May 2014
    Changes amended following identification of higher incidence of thrombocytopenia and hemorrhagic events in patients receiving obinutuzumab. Guidelines for management of patients with thrombocytopenia, especially during the first cycle have been added.
    01 Oct 2014
    An exploratory analysis of minimal residual disease has been added. Language has been added indicating the possibility of continued cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) treatment for up to eight cycles in selected patients who are tolerating therapy well and for whom it is felt by the investigator to be appropriate. Response criteria have been updated to be consistent with the 2014 Lugano Classification. Safety language has been updated.
    24 Apr 2015
    GDC-0199 dosing schedule updated. Characterization of the pharmacokinetics of the cyclophosphamide, doxorubicin and vincristine (CHO) components was deleted from the Pharmacokinetic Objectives as detailed characterization cannot be achieved with the current PK sampling scheme.
    07 Dec 2015
    An interim safety analysis has been added after 20 patients in the R-CHOP arm in the Phase II portion of the study have completed two cycles of treatment in order to confirm the safety and tolerability of the combination therapy at the venetoclax. The primary objectives of Phase II of the study have been modified to include assessment of efficacy of R-CHOP+ Venetoclax in patients with co-expression of both Bcl-2 and c-Myc. The term PET/CT will be replaced with PET-CT throughout the protocol.
    10 Oct 2016
    Venetoclax nonclinical toxicology section updated based on recent data findings. Twelve month Progression Free Survival (PFS) was added as a secondary efficacy objective. Information was added regarding the decision to not open Arm B in Phase II in DLBCL on the basis of information from the GOYA study results.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/30850381
    For support, Contact us.
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    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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