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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 BRAFV600-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

    Results information
    Results version number
    		 v2
    This version publication date
    19 May 2016
    First version publication date
    07 Aug 2015
    Other versions
    		 v1 (removed from public view) , v3 , v4
    Version creation reason
    • Correction of full data set
    Error identified during QC that requires correction

    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
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    Roche Trial Information Hotline , F. Hoffmann-La Roche AG, 41 61 6878333, global.trial_information@roche.com
    Scientific contact
    Roche Trial Information Hotline , F. Hoffmann-La Roche AG, 41 61 6878333, 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
    Interim
    Date of interim/final analysis
    09 May 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of vemurafenib in combination with GDC-0973, compared with vemurafenib and placebo, in previously untreated BRAFV600 mutation-positive subjects with unresectable locally advanced or metastatic melanoma, as measured by prolongation of progression-free survival (PFS), as assessed by the study site investigator.
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    08 Jan 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 9
    Country: Number of subjects enrolled
    Norway: 5
    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
    Austria: 8
    Country: Number of subjects enrolled
    Belgium: 8
    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
    Italy: 95
    Country: Number of subjects enrolled
    Australia: 56
    Country: Number of subjects enrolled
    Canada: 18
    Country: Number of subjects enrolled
    Israel: 12
    Country: Number of subjects enrolled
    Russian Federation: 35
    Country: Number of subjects enrolled
    Switzerland: 2
    Country: Number of subjects enrolled
    United States: 33
    Country: Number of subjects enrolled
    New Zealand: 10
    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, Monitor, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo + Vemurafenib
    Arm description
    		 Subjects 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
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo orally once a day on days 1-21 of each 28-day treatment cycle. Treatment will be administered until disease progression, unacceptable toxicity or withdrawal of consent.

    Investigational medicinal product name
    vemurafenib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    60 mg orally twice a day on days 1-28 of each 28-day cycle. Treatment will be administered until disease progression, unacceptable toxicity or withdrawal of consent.

    Arm title
    		 Cobimetinib + Vemurafenib
    Arm description
    		 Subjects 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
    cobimetinib
    Investigational medicinal product code
    Other name
    GDC-0973
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    60 mg orally once a day on days 1-21 of each 28-day treatment cycle. Treatment will be administered until disease progression, unacceptable toxicity or withdrawal of consent

    Investigational medicinal product name
    vemurafenib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    960 mg orally twice a day on days 1-28 of each 28-day cycle. Treatment will be administered until disease progression, unacceptable toxicity or withdrawal of consent

    Number of subjects in period 1
    		Placebo + Vemurafenib Cobimetinib + Vemurafenib
    Started
    248
    247
    Completed
    181
    199
    Not completed
    67
    48
         Consent withdrawn by subject
    13
    10
         Physician decision
    -
    3
         Death
    51
    34
         Lost to follow-up
    3
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo + Vemurafenib
    Reporting group description
    		 Subjects 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 title
    Cobimetinib + Vemurafenib
    Reporting group description
    		 Subjects 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 values
    		 Placebo + Vemurafenib Cobimetinib + Vemurafenib Total
    Number of subjects
    		 248 247 495
    Age categorical
    Units: Subjects
        < 18
    		 0 0 0
        18 - 64
    		 179 183 362
        65 - 84
    		 68 60 128
        >= 85
    		 1 4 5
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 55.3 ± 13.8 54.9 ± 14 -
    Gender categorical
    Units: Subjects
        Female
    		 108 101 209
        Male
    		 140 146 286

    End points

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    End points reporting groups
    Reporting group title
    Placebo + Vemurafenib
    Reporting group description
    		 Subjects 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 title
    Cobimetinib + Vemurafenib
    Reporting group description
    		 Subjects 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.

    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.
    End point type
    Primary
    End point timeframe
    Baseline to the 09 May 2014 data cut-off (up to 1 year, 4 months)
    End point values
    		 Placebo + Vemurafenib Cobimetinib + Vemurafenib
    Number of subjects analysed
    248
    247 [1]
    Units: months
        median (confidence interval 95%)
    6.21 (5.55 to 7.39)
    9.89 (9 to 999.99)
    Notes
    [1] - Upper limit of the confidence interval could not be calculated due to too few events. 999.99 = NE
    Statistical analysis title
    		 geographic region/metastasis classification
    Comparison groups
    Placebo + Vemurafenib v Cobimetinib + Vemurafenib
    Number of subjects included in analysis
    495
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.512
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.387
         upper limit
    		 0.679

    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.
    End point type
    Secondary
    End point timeframe
    Baseline to the 09 May 2014 data cut-off (up to 1 year, 4 months)
    End point values
    		 Placebo + Vemurafenib Cobimetinib + Vemurafenib
    Number of subjects analysed
    248 [2]
    247 [3]
    Units: months
        median (confidence interval 95%)
    999.99 (999.99 to 999.99)
    999.99 (999.99 to 999.99)
    Notes
    [2] - 999.99 = NE Not evaluable
    [3] - 999.99 = NE Not evaluable
    Statistical analysis title
    		 Stratified analysis
    Comparison groups
    Placebo + Vemurafenib v Cobimetinib + Vemurafenib
    Number of subjects included in analysis
    495
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0463
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.645
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.417
         upper limit
    		 0.996

    Secondary: Percentage of subjects with an objective response

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    End point title
    		 Percentage of subjects 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 09 May 2014 data cut-off (up to 1 year, 4 months)
    End point values
    		 Placebo + Vemurafenib Cobimetinib + Vemurafenib
    Number of subjects analysed
    248
    247
    Units: percentage of participants
        number (confidence interval 95%)
    44.8 (38.46 to 51.18)
    67.6 (61.39 to 73.41)
    Statistical analysis title
    		 Stratified analysis
    Statistical analysis description
    Stratified analysis by geographic region and metastasis classification (disease stage).
    Comparison groups
    Placebo + Vemurafenib v Cobimetinib + Vemurafenib
    Number of subjects included in analysis
    495
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Chi-squared
    Parameter type
    		 Difference in ratio
    Point estimate
    0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.49
         upper limit
    		 0.79

    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 at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum of the longest diameter recorded since treatment started or the appearance of 1 or more new lesions and/or unequivocal progression of existing non-target lesions.
    End point type
    Secondary
    End point timeframe
    Baseline to the 09 May 2014 data cut-off (up to 1 year, 4 months)
    End point values
    		 Placebo + Vemurafenib Cobimetinib + Vemurafenib
    Number of subjects analysed
    248 [4]
    247 [5]
    Units: months
        median (confidence interval 95%)
    7.29 (5.78 to 999.99)
    999.99 (9.3 to 999.99)
    Notes
    [4] - Upper limit of the confidence interval could not be calculated due to too few events. 999.99 = NE
    [5] - Upper limit of the confidence interval could not be calculated due to too few events. 999.99 = NE
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from the time of each subject’s randomization into the study until their last visit until 28 days after the last dose of study drug or until 09 May 2014 data cut-off (up to 1 year, 4 months).
    Adverse event reporting additional description
    Safety population: All subjects 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
    16.1
    Reporting groups
    Reporting group title
    Cobimetinib + Vemurafenib
    Reporting group description
    		 Subjects 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
    		 Subjects 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
    114 / 247 (46.15%)
    76 / 248 (30.65%)
         number of deaths (all causes)
    6
    3
         number of deaths resulting from adverse events
    Vascular disorders
    HYPERTENSION
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 248 (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 / 247 (0.40%)
    0 / 248 (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 / 247 (0.40%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    DEATH
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    FATIGUE
         subjects affected / exposed
    1 / 247 (0.40%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    MALAISE
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PYREXIA
         subjects affected / exposed
    6 / 247 (2.43%)
    3 / 248 (1.21%)
         occurrences causally related to treatment / all
    6 / 7
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    INTERSTITIAL LUNG DISEASE
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 248 (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 / 247 (0.00%)
    3 / 248 (1.21%)
         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 / 247 (0.40%)
    0 / 248 (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
    1 / 247 (0.40%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    PULMONARY HAEMORRHAGE
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    3 / 247 (1.21%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    4 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    3 / 247 (1.21%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BLOOD ALKALINE PHOSPHATASE INCREASED
         subjects affected / exposed
    2 / 247 (0.81%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BLOOD CREATINE PHOSPHOKINASE INCREASED
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    EJECTION FRACTION DECREASED
         subjects affected / exposed
    1 / 247 (0.40%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ELECTROCARDIOGRAM QT PROLONGED
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LIPASE INCREASED
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LIVER FUNCTION TEST ABNORMAL
         subjects affected / exposed
    1 / 247 (0.40%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TRANSAMINASES INCREASED
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DEHYDRATION
         subjects affected / exposed
    5 / 247 (2.02%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIABETES MELLITUS
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPERGLYCAEMIA
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 248 (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
    1 / 247 (0.40%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPONATRAEMIA
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    FEMORAL NECK FRACTURE
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 248 (0.40%)
         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 / 247 (0.40%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TRAUMATIC HAEMATOMA
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 248 (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 / 247 (0.00%)
    1 / 248 (0.40%)
         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 / 247 (0.40%)
    0 / 248 (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
    3 / 247 (1.21%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CARDIAC ARREST
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 248 (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
    0 / 247 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    CARDIAC TAMPONADE
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 248 (0.40%)
         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
    1 / 247 (0.40%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PERICARDIAL EFFUSION
         subjects affected / exposed
    1 / 247 (0.40%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SUPRAVENTRICULAR TACHYCARDIA
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TACHYCARDIA
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 248 (0.40%)
         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
    2 / 247 (0.81%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    CEREBROVASCULAR ACCIDENT
         subjects affected / exposed
    2 / 247 (0.81%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CONVULSION
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 248 (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 / 247 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    EPILEPSY
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FACIAL PARESIS
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GRAND MAL CONVULSION
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEADACHE
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEMIPARESIS
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    HYDROCEPHALUS
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INTRACRANIAL PRESSURE INCREASED
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MYASTHENIA GRAVIS
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SPINAL CORD COMPRESSION
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 248 (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 / 247 (0.40%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VIITH NERVE PARALYSIS
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MANIA
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 248 (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 / 247 (0.00%)
    1 / 248 (0.40%)
         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 / 247 (1.21%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    IRIDOCYCLITIS
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 248 (0.40%)
         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
    3 / 247 (1.21%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    UVEITIS
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 248 (0.40%)
         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 / 247 (0.40%)
    2 / 248 (0.81%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    APHTHOUS STOMATITIS
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIARRHOEA
         subjects affected / exposed
    3 / 247 (1.21%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CONSTIPATION
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIVERTICULAR PERFORATION
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DYSPHAGIA
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 248 (0.40%)
         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 / 247 (0.40%)
    0 / 248 (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 / 247 (0.40%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROOESOPHAGEAL REFLUX DISEASE
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 248 (0.40%)
         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 / 247 (0.00%)
    1 / 248 (0.40%)
         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 / 247 (0.40%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PANCREATITIS
         subjects affected / exposed
    1 / 247 (0.40%)
    2 / 248 (0.81%)
         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 / 247 (0.00%)
    1 / 248 (0.40%)
         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
    2 / 247 (0.81%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VOMITING
         subjects affected / exposed
    2 / 247 (0.81%)
    1 / 248 (0.40%)
         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
    1 / 247 (0.40%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPERSENSITIVITY
         subjects affected / exposed
    3 / 247 (1.21%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    DERMATITIS EXFOLIATIVE
         subjects affected / exposed
    0 / 247 (0.00%)
    2 / 248 (0.81%)
         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 / 247 (0.40%)
    1 / 248 (0.40%)
         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 / 247 (0.00%)
    1 / 248 (0.40%)
         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 / 247 (0.00%)
    1 / 248 (0.40%)
         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 / 247 (0.00%)
    1 / 248 (0.40%)
         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 / 247 (0.40%)
    0 / 248 (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 / 247 (1.62%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    4 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RASH GENERALISED
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RASH MORBILLIFORM
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 248 (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 / 247 (0.40%)
    0 / 248 (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
    CALCULUS URETERIC
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RENAL COLIC
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RENAL FAILURE ACUTE
         subjects affected / exposed
    2 / 247 (0.81%)
    2 / 248 (0.81%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RENAL INJURY
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 248 (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 / 247 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ARTHRITIS
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 248 (0.40%)
         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 / 247 (0.00%)
    1 / 248 (0.40%)
         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 / 247 (0.40%)
    0 / 248 (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 / 247 (0.00%)
    1 / 248 (0.40%)
         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 / 247 (0.40%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MYALGIA
         subjects affected / exposed
    1 / 247 (0.40%)
    1 / 248 (0.40%)
         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
    2 / 247 (0.81%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    POLYARTHRITIS
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 248 (0.40%)
         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 / 247 (0.40%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ADENOCARCINOMA OF COLON
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BASAL CELL CARCINOMA
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BENIGN NEOPLASM
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 248 (0.40%)
         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 / 247 (0.00%)
    3 / 248 (1.21%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MUCINOUS BREAST CARCINOMA
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 248 (0.40%)
         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 / 247 (0.00%)
    1 / 248 (0.40%)
         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
    1 / 247 (0.40%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TUMOUR HAEMORRHAGE
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    CELLULITIS
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 248 (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 / 247 (0.40%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DEVICE RELATED INFECTION
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIVERTICULITIS
         subjects affected / exposed
    1 / 247 (0.40%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROENTERITIS
         subjects affected / exposed
    1 / 247 (0.40%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROENTERITIS VIRAL
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 248 (0.40%)
         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 / 247 (0.40%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INFECTION
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONIA
         subjects affected / exposed
    2 / 247 (0.81%)
    2 / 248 (0.81%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    SEPSIS
         subjects affected / exposed
    1 / 247 (0.40%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SEPTIC SHOCK
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 248 (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
    1 / 247 (0.40%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VULVAL CELLULITIS
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 248 (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
    243 / 247 (98.38%)
    228 / 248 (91.94%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    SEBORRHOEIC KERATOSIS
         subjects affected / exposed
    9 / 247 (3.64%)
    13 / 248 (5.24%)
         occurrences all number
    9
    13
    SQUAMOUS CELL CARCINOMA OF SKIN
         subjects affected / exposed
    7 / 247 (2.83%)
    27 / 248 (10.89%)
         occurrences all number
    16
    55
    MELANOCYTIC NAEVUS
         subjects affected / exposed
    3 / 247 (1.21%)
    14 / 248 (5.65%)
         occurrences all number
    3
    21
    KERATOACANTHOMA
         subjects affected / exposed
    2 / 247 (0.81%)
    18 / 248 (7.26%)
         occurrences all number
    2
    22
    SKIN PAPILLOMA
         subjects affected / exposed
    11 / 247 (4.45%)
    25 / 248 (10.08%)
         occurrences all number
    13
    30
    Vascular disorders
    HYPERTENSION
         subjects affected / exposed
    35 / 247 (14.17%)
    19 / 248 (7.66%)
         occurrences all number
    40
    20
    General disorders and administration site conditions
    OEDEMA PERIPHERAL
         subjects affected / exposed
    27 / 247 (10.93%)
    25 / 248 (10.08%)
         occurrences all number
    30
    28
    FATIGUE
         subjects affected / exposed
    82 / 247 (33.20%)
    73 / 248 (29.44%)
         occurrences all number
    102
    80
    CHILLS
         subjects affected / exposed
    19 / 247 (7.69%)
    12 / 248 (4.84%)
         occurrences all number
    19
    14
    PYREXIA
         subjects affected / exposed
    63 / 247 (25.51%)
    51 / 248 (20.56%)
         occurrences all number
    81
    63
    ASTHENIA
         subjects affected / exposed
    43 / 247 (17.41%)
    33 / 248 (13.31%)
         occurrences all number
    55
    36
    Respiratory, thoracic and mediastinal disorders
    OROPHARYNGEAL PAIN
         subjects affected / exposed
    11 / 247 (4.45%)
    18 / 248 (7.26%)
         occurrences all number
    11
    24
    DYSPNOEA
         subjects affected / exposed
    14 / 247 (5.67%)
    17 / 248 (6.85%)
         occurrences all number
    14
    17
    COUGH
         subjects affected / exposed
    18 / 247 (7.29%)
    26 / 248 (10.48%)
         occurrences all number
    21
    27
    Psychiatric disorders
    INSOMNIA
         subjects affected / exposed
    14 / 247 (5.67%)
    18 / 248 (7.26%)
         occurrences all number
    16
    18
    Investigations
    BLOOD CREATININE INCREASED
         subjects affected / exposed
    29 / 247 (11.74%)
    18 / 248 (7.26%)
         occurrences all number
    35
    21
    ELECTROCARDIOGRAM QT PROLONGED
         subjects affected / exposed
    9 / 247 (3.64%)
    12 / 248 (4.84%)
         occurrences all number
    10
    14
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    58 / 247 (23.48%)
    42 / 248 (16.94%)
         occurrences all number
    75
    47
    BLOOD CHOLESTEROL INCREASED
         subjects affected / exposed
    13 / 247 (5.26%)
    6 / 248 (2.42%)
         occurrences all number
    13
    6
    BLOOD ALKALINE PHOSPHATASE INCREASED
         subjects affected / exposed
    34 / 247 (13.77%)
    19 / 248 (7.66%)
         occurrences all number
    35
    23
    GAMMA-GLUTAMYLTRANSFERASE INCREASED
         subjects affected / exposed
    42 / 247 (17.00%)
    41 / 248 (16.53%)
         occurrences all number
    51
    54
    WEIGHT DECREASED
         subjects affected / exposed
    13 / 247 (5.26%)
    11 / 248 (4.44%)
         occurrences all number
    13
    13
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    54 / 247 (21.86%)
    29 / 248 (11.69%)
         occurrences all number
    64
    29
    BLOOD CREATINE PHOSPHOKINASE INCREASED
         subjects affected / exposed
    75 / 247 (30.36%)
    7 / 248 (2.82%)
         occurrences all number
    100
    7
    BLOOD BILIRUBIN INCREASED
         subjects affected / exposed
    19 / 247 (7.69%)
    14 / 248 (5.65%)
         occurrences all number
    22
    16
    EJECTION FRACTION DECREASED
         subjects affected / exposed
    18 / 247 (7.29%)
    6 / 248 (2.42%)
         occurrences all number
    19
    7
    Injury, poisoning and procedural complications
    SUNBURN
         subjects affected / exposed
    33 / 247 (13.36%)
    38 / 248 (15.32%)
         occurrences all number
    39
    53
    Nervous system disorders
    DYSGEUSIA
         subjects affected / exposed
    33 / 247 (13.36%)
    24 / 248 (9.68%)
         occurrences all number
    34
    24
    HEADACHE
         subjects affected / exposed
    36 / 247 (14.57%)
    35 / 248 (14.11%)
         occurrences all number
    45
    40
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    26 / 247 (10.53%)
    16 / 248 (6.45%)
         occurrences all number
    30
    17
    Eye disorders
    CHORIORETINOPATHY
         subjects affected / exposed
    27 / 247 (10.93%)
    1 / 248 (0.40%)
         occurrences all number
    29
    1
    RETINAL DETACHMENT
         subjects affected / exposed
    18 / 247 (7.29%)
    0 / 248 (0.00%)
         occurrences all number
    21
    0
    VISION BLURRED
         subjects affected / exposed
    23 / 247 (9.31%)
    5 / 248 (2.02%)
         occurrences all number
    23
    5
    Gastrointestinal disorders
    DYSPEPSIA
         subjects affected / exposed
    17 / 247 (6.88%)
    11 / 248 (4.44%)
         occurrences all number
    20
    11
    VOMITING
         subjects affected / exposed
    54 / 247 (21.86%)
    28 / 248 (11.29%)
         occurrences all number
    75
    32
    DIARRHOEA
         subjects affected / exposed
    142 / 247 (57.49%)
    67 / 248 (27.02%)
         occurrences all number
    230
    90
    NAUSEA
         subjects affected / exposed
    99 / 247 (40.08%)
    57 / 248 (22.98%)
         occurrences all number
    127
    66
    ABDOMINAL PAIN
         subjects affected / exposed
    23 / 247 (9.31%)
    17 / 248 (6.85%)
         occurrences all number
    26
    19
    CONSTIPATION
         subjects affected / exposed
    22 / 247 (8.91%)
    25 / 248 (10.08%)
         occurrences all number
    23
    27
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    9 / 247 (3.64%)
    13 / 248 (5.24%)
         occurrences all number
    9
    13
    Skin and subcutaneous tissue disorders
    ALOPECIA
         subjects affected / exposed
    35 / 247 (14.17%)
    70 / 248 (28.23%)
         occurrences all number
    36
    72
    DERMATITIS ACNEIFORM
         subjects affected / exposed
    33 / 247 (13.36%)
    22 / 248 (8.87%)
         occurrences all number
    40
    25
    ERYTHEMA
         subjects affected / exposed
    21 / 247 (8.50%)
    30 / 248 (12.10%)
         occurrences all number
    30
    37
    HYPERKERATOSIS
         subjects affected / exposed
    26 / 247 (10.53%)
    67 / 248 (27.02%)
         occurrences all number
    30
    107
    ACTINIC KERATOSIS
         subjects affected / exposed
    7 / 247 (2.83%)
    17 / 248 (6.85%)
         occurrences all number
    12
    21
    PHOTOSENSITIVITY REACTION
         subjects affected / exposed
    72 / 247 (29.15%)
    38 / 248 (15.32%)
         occurrences all number
    83
    42
    KERATOSIS PILARIS
         subjects affected / exposed
    8 / 247 (3.24%)
    22 / 248 (8.87%)
         occurrences all number
    8
    23
    RASH MACULO-PAPULAR
         subjects affected / exposed
    34 / 247 (13.77%)
    36 / 248 (14.52%)
         occurrences all number
    53
    44
    RASH
         subjects affected / exposed
    96 / 247 (38.87%)
    85 / 248 (34.27%)
         occurrences all number
    133
    105
    PRURITUS
         subjects affected / exposed
    47 / 247 (19.03%)
    41 / 248 (16.53%)
         occurrences all number
    59
    45
    DRY SKIN
         subjects affected / exposed
    31 / 247 (12.55%)
    37 / 248 (14.92%)
         occurrences all number
    33
    39
    Musculoskeletal and connective tissue disorders
    MYALGIA
         subjects affected / exposed
    25 / 247 (10.12%)
    23 / 248 (9.27%)
         occurrences all number
    32
    25
    MUSCULOSKELETAL PAIN
         subjects affected / exposed
    13 / 247 (5.26%)
    10 / 248 (4.03%)
         occurrences all number
    13
    12
    PAIN IN EXTREMITY
         subjects affected / exposed
    19 / 247 (7.69%)
    32 / 248 (12.90%)
         occurrences all number
    24
    42
    ARTHRALGIA
         subjects affected / exposed
    83 / 247 (33.60%)
    96 / 248 (38.71%)
         occurrences all number
    114
    143
    Infections and infestations
    NASOPHARYNGITIS
         subjects affected / exposed
    13 / 247 (5.26%)
    9 / 248 (3.63%)
         occurrences all number
    15
    10
    FOLLICULITIS
         subjects affected / exposed
    14 / 247 (5.67%)
    10 / 248 (4.03%)
         occurrences all number
    14
    11
    Metabolism and nutrition disorders
    DECREASED APPETITE
         subjects affected / exposed
    48 / 247 (19.43%)
    46 / 248 (18.55%)
         occurrences all number
    58
    52

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Oct 2012
    Version 2 of the protocol included the following changes: correction of typographical errors; relocation of some text and minor editing for greater clarity
    24 Apr 2013
    Version 3 of the protocol included the following changes: added PFS as assessed by independent review as a secondary endpoint; clarified exclusion criteria 4 to allow subjects with previously resected early stage melanoma into the study; added cardiac events/Grade ≥ 2 LVEF reduction as AESIs; revised guidelines for cases of emergency unblinding to allow investigators the ability to unblind without the Sponsor’s approval; change in reporting windows for pregnancy and pregnant partners, for LVEF, dermatology, and ophthalmology exams after Cycle 2; revised guidelines on corrected QT interval (QTc) monitoring/cardiac consult to be more conservative; updated safety information on the cobimetinib plus vemurafenib combination; further clarified procedures described in the protocol to enhance readability and understanding; changed “GDC-0973” to “cobimetinib” throughout the document.
    12 Sep 2013
    Version 4 of the protocol included the following changes: updated safety information for consistency with the vemurafenib Investigator’s Brochure; updated and further clarified procedures described in the protocol to enhance readability and understanding.
    17 Mar 2014
    Protocol Version 4 Addendum 1, In response to a request from Health Canada, the protocol was revised to include lipase and amylase testing to confirm diagnosis in suspected cases of pancreatitis. At this time, the Canadian addendum to the protocol has not been incorporated a global amendment and therefore has not been implemented globally.

    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
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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