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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

    Results information
    Results version number
    		 v3
    This version publication date
    14 Aug 2016
    First version publication date
    07 Aug 2015
    Other versions
    		 v1 (removed from public view) , v2 , v4
    Version creation reason
    • New data added to full data set
    Updated data available

    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
    30 Sep 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 May 2014
    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 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
    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 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.
    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
    Received Treatment
    247
    246
    Completed
    82
    109
    Not completed
    166
    138
         Physician decision
    -
    3
         Death
    143
    116
         Lost to follow-up
    6
    2
         Withdrawal by subject
    17
    17

    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 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.

    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
    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 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.

    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. 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. Intent-to-treat population: All randomized subjects, regardless of whether or not study treatment was received.
    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] - 999.99 = not estimable, could not be calculated due to too few events.
    Statistical analysis title
    		 Stratified analysis
    Statistical analysis description
    The analysis was stratified 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
    		 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. Intent-to-treat population: All randomized subjects, regardless of whether or not study treatment was received.
    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 = not estimable, could not be calculated due to too few events.
    [3] - 999.99 = not estimable, could not be calculated due to too few events.
    Statistical analysis title
    		 Stratified analysis
    Statistical analysis description
    The analysis was stratified 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
    		 = 0.0463
    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. Intent-to-treat population: All randomized subjects, regardless of whether or not study treatment was received.
    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
    		 Difference in objective response rates
    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
    		 Mean difference (final values)
    Point estimate
    22.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 14.13
         upper limit
    		 31.58

    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. Intent-to-treat population: All randomized subjects, regardless of whether or not study treatment was received. Only subjects with an objective response were included in the analysis.
    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
    111 [4]
    167 [5]
    Units: months
        median (confidence interval 95%)
    7.29 (5.78 to 999.99)
    999.99 (9.3 to 999.99)
    Notes
    [4] - 999.99 = not estimable, could not be calculated due to too few events.
    [5] - 999.99 = not estimable, could not be calculated due to too few events.
    No statistical analyses for this end point

    Secondary: Overall Survival (Final Analysis)

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    End point title
    		 Overall Survival (Final Analysis)
    End point description
    Overall survival was defined as the time from randomization until the date of death from any cause. Intent-to-treat population: All randomized subjects, regardless of whether or not study treatment was received.
    End point type
    Secondary
    End point timeframe
    Baseline to the 28 August 2015 Overall Survival data cut-off (up to 2 years, 8 months)
    End point values
    		 Placebo + Vemurafenib Cobimetinib + Vemurafenib
    Number of subjects analysed
    248
    247 [6]
    Units: months
        median (confidence interval 95%)
    17.38 (15.01 to 19.81)
    22.28 (20.27 to 999.99)
    Notes
    [6] - 999.99 = not estimable, could not be calculated due to too few events.
    Statistical analysis title
    		 Stratified analysis
    Statistical analysis description
    The analysis was stratified 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
    		 = 0.005
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.702
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.548
         upper limit
    		 0.899

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from the time of each participant’s randomization into the study until their last visit until 28 days after the last dose of study drug (Safety data cut-off: 30 September 2015; up to 2 years, 9 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
    18.1
    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.

    Serious adverse events
    		 Placebo + Vemurafenib Cobimetinib + Vemurafenib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    69 / 246 (28.05%)
    92 / 247 (37.25%)
         number of deaths (all causes)
    142
    117
         number of deaths resulting from adverse events
    1
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acanthoma
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenocarcinoma of colon
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign neoplasm
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal tract adenoma
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Kaposi's sarcoma
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Keratoacanthoma
         subjects affected / exposed
    4 / 246 (1.63%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucinous breast carcinoma
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Papilloma
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    0 / 246 (0.00%)
    2 / 247 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subgaleal haematoma
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vasculitis
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 246 (0.41%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Fatigue
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    3 / 246 (1.22%)
    6 / 247 (2.43%)
         occurrences causally related to treatment / all
    2 / 3
    6 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 246 (0.00%)
    3 / 247 (1.21%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sarcoidosis
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Cervical polyp
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Atelectasis
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    3 / 246 (1.22%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 246 (0.41%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Mania
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (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
    2 / 246 (0.81%)
    4 / 247 (1.62%)
         occurrences causally related to treatment / all
    2 / 2
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 246 (0.81%)
    3 / 247 (1.21%)
         occurrences causally related to treatment / all
    2 / 2
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 246 (0.41%)
    1 / 247 (0.40%)
         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
    0 / 246 (0.00%)
    2 / 247 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ejection fraction decreased
         subjects affected / exposed
    1 / 246 (0.41%)
    1 / 247 (0.40%)
         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
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrocardiogram T wave abnormal
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 246 (0.41%)
    2 / 247 (0.81%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lipase increased
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    1 / 246 (0.41%)
    1 / 247 (0.40%)
         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
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 246 (0.00%)
    2 / 247 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 246 (0.41%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laceration
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 246 (0.41%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (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
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 246 (0.41%)
    4 / 247 (1.62%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure
         subjects affected / exposed
    1 / 246 (0.41%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Cardiac tamponade
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    4 / 246 (1.63%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 246 (0.41%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 246 (0.00%)
    2 / 247 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coma
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Dizziness
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysarthria
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysgeusia
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial paresis
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (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
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polyneuropathy
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 246 (0.00%)
    3 / 247 (1.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VIIIth nerve paralysis
         subjects affected / exposed
    1 / 246 (0.41%)
    2 / 247 (0.81%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Chorioretinopathy
         subjects affected / exposed
    0 / 246 (0.00%)
    3 / 247 (1.21%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Iridocyclitis
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    0 / 246 (0.00%)
    4 / 247 (1.62%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uveitis
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 246 (0.41%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aphthous ulcer
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 246 (0.00%)
    3 / 247 (1.21%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticular perforation
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric antral vascular ectasia
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         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
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstruction gastric
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    2 / 246 (0.81%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periodontal disease
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal polyp
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 246 (0.00%)
    3 / 247 (1.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 246 (0.41%)
    2 / 247 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    2 / 246 (0.81%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis exfoliative
         subjects affected / exposed
    2 / 246 (0.81%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug reaction with eosinophilia and systemic symptoms
         subjects affected / exposed
    1 / 246 (0.41%)
    1 / 247 (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
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erythema nodosum
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkeratosis
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Panniculitis
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    1 / 246 (0.41%)
    4 / 247 (1.62%)
         occurrences causally related to treatment / all
    1 / 1
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash generalised
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash macular
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    2 / 246 (0.81%)
    3 / 247 (1.21%)
         occurrences causally related to treatment / all
    2 / 2
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash morbilliform
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 246 (0.81%)
    3 / 247 (1.21%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Calculus ureteric
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic nephropathy
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (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
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         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
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bursitis
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    1 / 246 (0.41%)
    1 / 247 (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
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polyarthritis
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    1 / 246 (0.41%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Anal abscess
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (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
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Clostridium difficile infection
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    2 / 246 (0.81%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterococcal sepsis
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    2 / 246 (0.81%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 246 (0.41%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis clostridial
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal bacterial infection
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         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
    1 / 246 (0.41%)
    0 / 247 (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
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 246 (1.22%)
    4 / 247 (1.62%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sepsis
         subjects affected / exposed
    2 / 246 (0.81%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tuberculosis
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 246 (0.41%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vulval cellulitis
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 246 (0.00%)
    5 / 247 (2.02%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo + Vemurafenib Cobimetinib + Vemurafenib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    235 / 246 (95.53%)
    238 / 247 (96.36%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    6 / 246 (2.44%)
    15 / 247 (6.07%)
         occurrences all number
    6
    28
    Keratoacanthoma
         subjects affected / exposed
    20 / 246 (8.13%)
    4 / 247 (1.62%)
         occurrences all number
    26
    5
    Melanocytic naevus
         subjects affected / exposed
    20 / 246 (8.13%)
    5 / 247 (2.02%)
         occurrences all number
    31
    5
    Seborrhoeic keratosis
         subjects affected / exposed
    20 / 246 (8.13%)
    15 / 247 (6.07%)
         occurrences all number
    21
    15
    Skin papilloma
         subjects affected / exposed
    31 / 246 (12.60%)
    17 / 247 (6.88%)
         occurrences all number
    36
    22
    Squamous cell carcinoma of skin
         subjects affected / exposed
    31 / 246 (12.60%)
    10 / 247 (4.05%)
         occurrences all number
    64
    25
    Vascular disorders
    Hypertension
         subjects affected / exposed
    20 / 246 (8.13%)
    38 / 247 (15.38%)
         occurrences all number
    22
    45
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    43 / 246 (17.48%)
    46 / 247 (18.62%)
         occurrences all number
    47
    66
    Chills
         subjects affected / exposed
    13 / 246 (5.28%)
    25 / 247 (10.12%)
         occurrences all number
    16
    28
    Fatigue
         subjects affected / exposed
    82 / 246 (33.33%)
    91 / 247 (36.84%)
         occurrences all number
    99
    128
    Oedema peripheral
         subjects affected / exposed
    28 / 246 (11.38%)
    34 / 247 (13.77%)
         occurrences all number
    32
    44
    Pyrexia
         subjects affected / exposed
    57 / 246 (23.17%)
    69 / 247 (27.94%)
         occurrences all number
    71
    104
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    31 / 246 (12.60%)
    23 / 247 (9.31%)
         occurrences all number
    35
    28
    Dyspnoea
         subjects affected / exposed
    18 / 246 (7.32%)
    19 / 247 (7.69%)
         occurrences all number
    19
    24
    Oropharyngeal pain
         subjects affected / exposed
    21 / 246 (8.54%)
    18 / 247 (7.29%)
         occurrences all number
    27
    19
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    10 / 246 (4.07%)
    13 / 247 (5.26%)
         occurrences all number
    11
    14
    Insomnia
         subjects affected / exposed
    24 / 246 (9.76%)
    17 / 247 (6.88%)
         occurrences all number
    26
    22
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    43 / 246 (17.48%)
    62 / 247 (25.10%)
         occurrences all number
    47
    87
    Aspartate aminotransferase increased
         subjects affected / exposed
    29 / 246 (11.79%)
    58 / 247 (23.48%)
         occurrences all number
    29
    78
    Blood alkaline phosphatase increased
         subjects affected / exposed
    24 / 246 (9.76%)
    41 / 247 (16.60%)
         occurrences all number
    28
    55
    Blood bilirubin increased
         subjects affected / exposed
    17 / 246 (6.91%)
    19 / 247 (7.69%)
         occurrences all number
    22
    21
    Blood cholesterol increased
         subjects affected / exposed
    10 / 246 (4.07%)
    16 / 247 (6.48%)
         occurrences all number
    10
    16
    Blood creatine phosphokinase increased
         subjects affected / exposed
    7 / 246 (2.85%)
    86 / 247 (34.82%)
         occurrences all number
    8
    134
    Blood creatinine increased
         subjects affected / exposed
    20 / 246 (8.13%)
    37 / 247 (14.98%)
         occurrences all number
    23
    48
    Ejection fraction decreased
         subjects affected / exposed
    12 / 246 (4.88%)
    28 / 247 (11.34%)
         occurrences all number
    14
    38
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    44 / 246 (17.89%)
    52 / 247 (21.05%)
         occurrences all number
    60
    72
    Weight decreased
         subjects affected / exposed
    13 / 246 (5.28%)
    16 / 247 (6.48%)
         occurrences all number
    15
    18
    Injury, poisoning and procedural complications
    Sunburn
         subjects affected / exposed
    45 / 246 (18.29%)
    37 / 247 (14.98%)
         occurrences all number
    66
    57
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    8 / 246 (3.25%)
    15 / 247 (6.07%)
         occurrences all number
    8
    15
    Dysgeusia
         subjects affected / exposed
    25 / 246 (10.16%)
    38 / 247 (15.38%)
         occurrences all number
    26
    42
    Headache
         subjects affected / exposed
    39 / 246 (15.85%)
    44 / 247 (17.81%)
         occurrences all number
    46
    64
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    20 / 246 (8.13%)
    39 / 247 (15.79%)
         occurrences all number
    24
    50
    Eye disorders
    Chorioretinopathy
         subjects affected / exposed
    1 / 246 (0.41%)
    29 / 247 (11.74%)
         occurrences all number
    2
    34
    Retinal detachment
         subjects affected / exposed
    1 / 246 (0.41%)
    19 / 247 (7.69%)
         occurrences all number
    1
    21
    Vision blurred
         subjects affected / exposed
    6 / 246 (2.44%)
    28 / 247 (11.34%)
         occurrences all number
    6
    28
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    18 / 246 (7.32%)
    26 / 247 (10.53%)
         occurrences all number
    19
    31
    Abdominal pain upper
         subjects affected / exposed
    17 / 246 (6.91%)
    12 / 247 (4.86%)
         occurrences all number
    19
    13
    Constipation
         subjects affected / exposed
    28 / 246 (11.38%)
    26 / 247 (10.53%)
         occurrences all number
    30
    33
    Diarrhoea
         subjects affected / exposed
    82 / 246 (33.33%)
    149 / 247 (60.32%)
         occurrences all number
    136
    275
    Dyspepsia
         subjects affected / exposed
    14 / 246 (5.69%)
    19 / 247 (7.69%)
         occurrences all number
    14
    22
    Nausea
         subjects affected / exposed
    64 / 246 (26.02%)
    105 / 247 (42.51%)
         occurrences all number
    78
    166
    Stomatitis
         subjects affected / exposed
    3 / 246 (1.22%)
    15 / 247 (6.07%)
         occurrences all number
    3
    23
    Vomiting
         subjects affected / exposed
    33 / 246 (13.41%)
    63 / 247 (25.51%)
         occurrences all number
    41
    97
    Skin and subcutaneous tissue disorders
    Actinic keratosis
         subjects affected / exposed
    25 / 246 (10.16%)
    13 / 247 (5.26%)
         occurrences all number
    29
    31
    Alopecia
         subjects affected / exposed
    75 / 246 (30.49%)
    41 / 247 (16.60%)
         occurrences all number
    78
    43
    Dermatitis acneiform
         subjects affected / exposed
    22 / 246 (8.94%)
    34 / 247 (13.77%)
         occurrences all number
    26
    42
    Dry skin
         subjects affected / exposed
    41 / 246 (16.67%)
    38 / 247 (15.38%)
         occurrences all number
    44
    41
    Erythema
         subjects affected / exposed
    33 / 246 (13.41%)
    26 / 247 (10.53%)
         occurrences all number
    49
    46
    Hyperkeratosis
         subjects affected / exposed
    66 / 246 (26.83%)
    25 / 247 (10.12%)
         occurrences all number
    113
    33
    Keratosis pilaris
         subjects affected / exposed
    26 / 246 (10.57%)
    9 / 247 (3.64%)
         occurrences all number
    29
    10
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    9 / 246 (3.66%)
    17 / 247 (6.88%)
         occurrences all number
    10
    21
    Palmoplantar keratoderma
         subjects affected / exposed
    20 / 246 (8.13%)
    5 / 247 (2.02%)
         occurrences all number
    21
    6
    Photosensitivity reaction
         subjects affected / exposed
    48 / 246 (19.51%)
    84 / 247 (34.01%)
         occurrences all number
    56
    115
    Pruritus
         subjects affected / exposed
    47 / 246 (19.11%)
    49 / 247 (19.84%)
         occurrences all number
    52
    75
    Rash
         subjects affected / exposed
    94 / 246 (38.21%)
    98 / 247 (39.68%)
         occurrences all number
    117
    151
    Rash maculo-papular
         subjects affected / exposed
    37 / 246 (15.04%)
    36 / 247 (14.57%)
         occurrences all number
    47
    60
    Solar dermatitis
         subjects affected / exposed
    13 / 246 (5.28%)
    15 / 247 (6.07%)
         occurrences all number
    22
    22
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    103 / 246 (41.87%)
    94 / 247 (38.06%)
         occurrences all number
    168
    150
    Back pain
         subjects affected / exposed
    14 / 246 (5.69%)
    19 / 247 (7.69%)
         occurrences all number
    14
    23
    Musculoskeletal pain
         subjects affected / exposed
    16 / 246 (6.50%)
    11 / 247 (4.45%)
         occurrences all number
    18
    12
    Myalgia
         subjects affected / exposed
    31 / 246 (12.60%)
    36 / 247 (14.57%)
         occurrences all number
    34
    47
    Pain in extremity
         subjects affected / exposed
    39 / 246 (15.85%)
    29 / 247 (11.74%)
         occurrences all number
    50
    45
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    5 / 246 (2.03%)
    16 / 247 (6.48%)
         occurrences all number
    5
    17
    Folliculitis
         subjects affected / exposed
    12 / 246 (4.88%)
    18 / 247 (7.29%)
         occurrences all number
    15
    19
    Nasopharyngitis
         subjects affected / exposed
    14 / 246 (5.69%)
    20 / 247 (8.10%)
         occurrences all number
    16
    24
    Urinary tract infection
         subjects affected / exposed
    10 / 246 (4.07%)
    15 / 247 (6.07%)
         occurrences all number
    12
    18
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    50 / 246 (20.33%)
    50 / 247 (20.24%)
         occurrences all number
    55
    62
    Hyponatraemia
         subjects affected / exposed
    3 / 246 (1.22%)
    13 / 247 (5.26%)
         occurrences all number
    3
    19

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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.
    24 Feb 2015
    Version 5 of the protocol included the following changes: updated safety information on vemurafenib to include information on progression of cancers associated with RAS mutations, panniculitis, radiation recall/sensitization, and pancreatitis; updated risks associated with cobimetinib following the final efficacy analysis of this study and updates to the cobimetinib Investigator’s Brochure (IB, Version 7). Following the final efficacy analysis and extensive evaluation of safety data, quarterly Data Safety and Monitoring Board review of unblinded safety data will no longer occur. Following the final efficacy analysis, quality of life assessments will no longer be conducted. Tumor assessments will be conducted in accordance with local standard of care. Central collection and review of tumor scans will no longer be required. The analysis plan for overall survival (OS) was revised, with final OS analysis to be performed at approximately 250 deaths without further interim analyses. Following the final efficacy analysis and evaluation of electrocardiogram (ECG) data, ECG monitoring requirements were revised. The Medical Monitor was changed.
    20 Oct 2015
    Version 6 of the protocol included the following changes: following the final overall survival analysis, there was a reduction of the schedule of dermatological, physical, anal, and gynecological exams, to align with the Investigator’s Brochure for vemurafenib. Addition of high-level summary of results of the primary and final analyses of Study GO28141. Removal of the background pharmacokinetic data from Study NO25395. Allowance for participants to cross over to treatment with vemurafenib / cobimetinib. Provision of a description of commercially available tablets and allowance for participants to switch to commercial supplies of study drug, when available. Change to the Medical Monitor contact information. Clarification that the source of Reference Safety Information for vemurafenib is the Investigator's Brochure and update of the safety data cutoff, where appropriate. Update of dose-modification guidelines modified to reflect practices to be applied during the course of standard clinical care.
    30 Mar 2016
    Version 7 of the protocol included the following changes: addition of safety information for vemurafenib related to acute kidney injury. Revision of safety information for cobimetinib, including the addition of the potential risk of rhabdomyolysis and/or Grade 4 increased creatine phosphokinase (CPK) and reorganization of risk section into Identified/Potential/Other risks associated with cobimetinib. Provision of further clarity for the crossover of treatment from placebo to cobimetinib, including the schedule for performing ophthalmologic examinations and evaluations of left ventricular function. Provision of further clarity around performance of safety assessments. Images for left ventricular function no longer were to be sent for central review. Reversion of dose modification language to Protocol Version 5, to remain consistent with usual practice. Removal of GDC-0973 from the protocol text and the use of cobimetinib throughout.

    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
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