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    Clinical Trial Results:
    An Open-Label, Multicenter Study to Assess the Safety of RO5185426 (Vemurafenib) in Patients with Metastatic Melanoma

    Summary
    EudraCT number
    2010-023526-21
    Trial protocol
    ES   AT   SE   NL   SI   GR   DE   GB   CZ   HU   SK   BE   BG   NO   PT   LV   FI   IT   DK   EE   LT   IE  
    Global end of trial date
    24 Feb 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    06 Aug 2017
    First version publication date
    06 Aug 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MO25515
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01307397
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Hoffmann-La Roche
    Sponsor organisation address
    Grenzacherstrasse, 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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    14 Mar 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Feb 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the safety and tolerability of vemurafenib in participants with metastatic melanoma (surgically incurable and unresectable Stage IIIC or Stage IV, American Joint Committee on Cancer [AJCC]), harboring the BRAF V600 mutation (identified by the cobas® 4800 BRAF V600 Mutation Test)
    Protection of trial subjects
    The study was conducted in accordance with the principles of the “Declaration of Helsinki” and Good Clinical Practice (GCP) according to the regulations and procedures described in the protocol. Approval from the Ethics Committee (EC)/Institutional Review Board (IRB) was obtained before study start. Roche also obtained approval from the relevant Competent Authority prior to starting the study. No modifications were made to the protocol after receipt of the EC/IRB approval.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    01 Mar 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Albania: 12
    Country: Number of subjects enrolled
    Argentina: 19
    Country: Number of subjects enrolled
    Australia: 158
    Country: Number of subjects enrolled
    Austria: 59
    Country: Number of subjects enrolled
    Belgium: 66
    Country: Number of subjects enrolled
    Bosnia and Herzegovina: 27
    Country: Number of subjects enrolled
    Brazil: 53
    Country: Number of subjects enrolled
    Bulgaria: 42
    Country: Number of subjects enrolled
    Canada: 145
    Country: Number of subjects enrolled
    Colombia: 17
    Country: Number of subjects enrolled
    Croatia: 21
    Country: Number of subjects enrolled
    Czech Republic: 137
    Country: Number of subjects enrolled
    Denmark: 28
    Country: Number of subjects enrolled
    Ecuador: 1
    Country: Number of subjects enrolled
    Estonia: 8
    Country: Number of subjects enrolled
    Finland: 18
    Country: Number of subjects enrolled
    Germany: 389
    Country: Number of subjects enrolled
    Greece: 55
    Country: Number of subjects enrolled
    Hungary: 55
    Country: Number of subjects enrolled
    India: 3
    Country: Number of subjects enrolled
    Ireland: 12
    Country: Number of subjects enrolled
    Israel: 73
    Country: Number of subjects enrolled
    Italy: 383
    Country: Number of subjects enrolled
    Korea, Republic of: 41
    Country: Number of subjects enrolled
    Latvia: 12
    Country: Number of subjects enrolled
    Lithuania: 13
    Country: Number of subjects enrolled
    Macedonia, the former Yugoslav Republic of: 20
    Country: Number of subjects enrolled
    Mexico: 10
    Country: Number of subjects enrolled
    Netherlands: 234
    Country: Number of subjects enrolled
    Norway: 47
    Country: Number of subjects enrolled
    Peru: 5
    Country: Number of subjects enrolled
    Poland: 75
    Country: Number of subjects enrolled
    Portugal: 21
    Country: Number of subjects enrolled
    Romania: 29
    Country: Number of subjects enrolled
    Russian Federation: 60
    Country: Number of subjects enrolled
    Serbia: 28
    Country: Number of subjects enrolled
    Slovakia: 18
    Country: Number of subjects enrolled
    Slovenia: 21
    Country: Number of subjects enrolled
    South Africa: 34
    Country: Number of subjects enrolled
    Spain: 300
    Country: Number of subjects enrolled
    Sweden: 77
    Country: Number of subjects enrolled
    Switzerland: 36
    Country: Number of subjects enrolled
    Turkey: 111
    Country: Number of subjects enrolled
    United Kingdom: 246
    Worldwide total number of subjects
    3219
    EEA total number of subjects
    2366
    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)
    3
    Adults (18-64 years)
    2371
    From 65 to 84 years
    825
    85 years and over
    20

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    A total of 7495 participants were screened; 3224 participants were enrolled and 3219 participants received at least 1 dose of vemurafenib. Further 38 participants were screened at a site in Austria and 29 of these participants were enrolled and treated; however, they were not included in analysis populations due to critical audit findings.

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

    Arms
    Arm title
    Vemurafenib
    Arm description
    Participants received continuous oral doses of vemurafenib 960 milligrams (mg) (four 240 mg tablets) twice daily in each 28-day treatment cycle until the development of progressive disease, unacceptable toxicity, consent withdrawal, protocol violations endangering participant’s safety, death or study termination by the Sponsor.
    Arm type
    Experimental

    Investigational medicinal product name
    Vemurafenib
    Investigational medicinal product code
    Other name
    RO5185426, Zelboraf
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received continuous oral doses of vemurafenib 960 mg (four 240 mg tablets) twice daily in each 28-day treatment cycle until the development of progressive disease, unacceptable toxicity, consent withdrawal, protocol violations endangering participant’s safety, death or study termination by the Sponsor.

    Number of subjects in period 1
    Vemurafenib
    Started
    3219
    Completed
    0
    Not completed
    3219
         Protocol deviation
    6
         Death
    120
         Missing
    4
         Investigator's Decision
    62
         Refused Treatment
    66
         Administrative/Other
    226
         Progressive Disease
    2414
         Consent withdrawn by subject
    62
         Adverse Events
    225
         Lost to follow-up
    34

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Vemurafenib
    Reporting group description
    Participants received continuous oral doses of vemurafenib 960 milligrams (mg) (four 240 mg tablets) twice daily in each 28-day treatment cycle until the development of progressive disease, unacceptable toxicity, consent withdrawal, protocol violations endangering participant’s safety, death or study termination by the Sponsor.

    Reporting group values
    Vemurafenib Total
    Number of subjects
    3219 3219
    Age categorical
    Units: Subjects
    Age Continuous
    The safety population included all participants who received at least one dose of study medication
    Units: years
        arithmetic mean (standard deviation)
    54.5 ± 14.06 -
    Gender, Male/Female
    Units: Subjects
        Female
    1397 1397
        Male
    1822 1822

    End points

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    End points reporting groups
    Reporting group title
    Vemurafenib
    Reporting group description
    Participants received continuous oral doses of vemurafenib 960 milligrams (mg) (four 240 mg tablets) twice daily in each 28-day treatment cycle until the development of progressive disease, unacceptable toxicity, consent withdrawal, protocol violations endangering participant’s safety, death or study termination by the Sponsor.

    Primary: Percentage of Participants Experiencing Any Grade 3 or 4 Adverse Events (AEs) as determined by National Cancer Institute-Common Toxicity Criteria for Adverse Events (NCI-CTCAE) Version 4.0

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    End point title
    Percentage of Participants Experiencing Any Grade 3 or 4 Adverse Events (AEs) as determined by National Cancer Institute-Common Toxicity Criteria for Adverse Events (NCI-CTCAE) Version 4.0 [1]
    End point description
    The intensity of AEs were graded on a 5-point scale (Grade 1 to 5) according to the NCI-CTCAE version 4.0, where Grade 1 indicates "Mild" severity and Grade 5 indicates "Death". The CTCAE defines Grades 3 and 4 as follows: Grade 3 means "Severe"; Inability to work or perform normal daily activity; treatment or medical intervention is indicated in order to improve the overall wellbeing or symptoms; delaying the onset of treatment is not putting the survival of the participant at direct risk. Grade 4 means "Life-threatening, Disabling"; based on extreme limitation in activity; significant medical intervention/therapy required; and hospitalization probable. Analysis was performed on the safety population (all participants who received at least one dose of study medication).
    End point type
    Primary
    End point timeframe
    Baseline up to 28 days post end of treatment (maximum up to 46 months)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No hypothesis testing was done in this single arm Safety study. All results presented are descriptive only.
    End point values
    Vemurafenib
    Number of subjects analysed
    3219
    Units: Percentage of participants
        number (not applicable)
    52.8
    No statistical analyses for this end point

    Primary: Percentage of Participants With at Least 1 AE Leading to Study Drug Interruption or Drug Discontinuation

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    End point title
    Percentage of Participants With at Least 1 AE Leading to Study Drug Interruption or Drug Discontinuation [2]
    End point description
    An AE was considered as any unfavorable and unintended sign, symptom, or disease associated with the use of the study drug, whether or not considered related to the study drug. Pre existing conditions that worsened during the study and laboratory or clinical tests that resulted in a change in treatment or discontinuation from study drug were reported as adverse events. Percentage of participants with dose interruption or discontinuation due to AE was presented. Analysis was performed on the safety population.
    End point type
    Primary
    End point timeframe
    Baseline up to 28 days post end of treatment (maximum up to 46 months)
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No hypothesis testing was done in this single arm Safety study. All results presented are descriptive only.
    End point values
    Vemurafenib
    Number of subjects analysed
    3219
    Units: Percentage of participants
    number (not applicable)
        AE Leading to Drug Discontinuation
    7
        AE Leading to Study Drug Interruption
    34
    No statistical analyses for this end point

    Primary: Percentage of Participants with AEs of Special Interest

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    End point title
    Percentage of Participants with AEs of Special Interest [3]
    End point description
    AEs of special interest included cutaneous squamous cell carcinoma (SCC), rash, photosensitivity, liver injury, arthralgia, fatigue, gastrointestinal (GI) polyps, pancreatitis, Potentiation of radiation toxicity, prolongation of cardiac repolarization or arrhythmia, non-cutaneous SCC and other primary malignancies (other than cutaneous SCC or new primary melanoma). Analysis was performed on the safety population.
    End point type
    Primary
    End point timeframe
    Baseline up to 28 days post end of treatment (maximum up to 46 months)
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No hypothesis testing was done in this single arm Safety study. All results presented are descriptive only.
    End point values
    Vemurafenib
    Number of subjects analysed
    3219
    Units: Percentage of participants
    number (not applicable)
        Arthralgia
    42.3
        Rash
    47.9
        Photosensitivity
    28.4
        Fatigue
    36.8
        Cutaneous SCC
    14.6
        Non Cutaneous SCC
    0.1
        New Primary Melanoma
    1.7
        GI Polyps
    0.03
        Pancreatitis
    0.2
        Potentiation of radiation toxicity
    1.4
        Prolongation of Cardiac Repolarization/ Arrhythmia
    17
        Other primary malignancy
    3.2
        Liver Injury
    14.1
    No statistical analyses for this end point

    Primary: Mean Cumulative Dose of Vemurafenib

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    End point title
    Mean Cumulative Dose of Vemurafenib [4]
    End point description
    Analysis was performed on the safety population.
    End point type
    Primary
    End point timeframe
    Baseline up to end of treatment or death (maximum up to 46 months)
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No hypothesis testing was done in this single arm Safety study. All results presented are descriptive only.
    End point values
    Vemurafenib
    Number of subjects analysed
    3219
    Units: Grams
        arithmetic mean (standard deviation)
    501.283 ± 510.9121
    No statistical analyses for this end point

    Primary: Duration of Vemurafenib Treatment

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    End point title
    Duration of Vemurafenib Treatment [5]
    End point description
    Exposure excluding treatment interruptions: Duration during which participants actually took vemurafenib. Any time without dose taken due to adverse events, noncompliance or any other reasons was not counted. Exposure including treatment interruptions: date of last dose date of first dose + 1; duration during which participants actually took vemurafenib as well as duration on which medication was not taken were included in this calculation. Analysis was performed on the safety population.
    End point type
    Primary
    End point timeframe
    Baseline up to end of treatment or death (maximum up to 46 months)
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No hypothesis testing was done in this single arm Safety study. All results presented are descriptive only.
    End point values
    Vemurafenib
    Number of subjects analysed
    3219
    Units: Months
    arithmetic mean (standard deviation)
        Exposure excluding interruptions
    9.383 ± 9.6755
        Exposure including interruptions
    9.724 ± 9.9072
    No statistical analyses for this end point

    Primary: Mean Total Vemurafenib Dose Per Day

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    End point title
    Mean Total Vemurafenib Dose Per Day [6]
    End point description
    Exposure excluding treatment interruptions: Duration during which participants actually took vemurafenib. Any time without dose taken due to adverse events, noncompliance or any other reasons was not counted. Exposure including treatment interruptions: date of last dose date of first dose + 1; duration during which participants actually took vemurafenib as well as duration on which medication was not taken were included in this calculation. Average total dose per day: total actual dose taken divided by total actual days on treatment. Analysis was performed on the safety population.
    End point type
    Primary
    End point timeframe
    Baseline up to end of treatment or death (maximum up to 46 months)
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No hypothesis testing was done in this single arm Safety study. All results presented are descriptive only.
    End point values
    Vemurafenib
    Number of subjects analysed
    3219
    Units: Grams
    arithmetic mean (standard deviation)
        Average Total Dose Per Day Excluding Interruptions
    1.802 ± 0.2314
        Average Total Dose Per Day Including Interruptions
    1.732 ± 0.2874
    No statistical analyses for this end point

    Primary: Dose Intensity of vemurafenib

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    End point title
    Dose Intensity of vemurafenib [7]
    End point description
    Dose intensity was defined as (total actual doses taken/total planned doses) *100, where total planned doses = prescribed doses * planned days on treatment, where planned days on treatment were defined as the interval between date of first dose and date of last dose. Analysis was performed on the safety population.
    End point type
    Primary
    End point timeframe
    Baseline up to end of treatment or death (maximum up to 46 months)
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No hypothesis testing was done in this single arm Safety study. All results presented are descriptive only.
    End point values
    Vemurafenib
    Number of subjects analysed
    3219
    Units: Percentage of planned dose
        arithmetic mean (standard deviation)
    90.21 ± 14.966
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Improvement in Eastern Cooperative Group (ECOG) Performance Status

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    End point title
    Percentage of Participants With Improvement in Eastern Cooperative Group (ECOG) Performance Status
    End point description
    ECOG Performance Status was measured on therapy assessed participant's performance status on 5 point scale: 0 = fully active/able to carry on all pre disease activities without restriction; 1=restricted in physically strenuous activity, ambulatory/able to carry out light or sedentary work; 2=ambulatory (greater than [>] 50% of waking hours [hrs]), capable of all self care, unable to carry out any work activities; 3=capable of only limited self care, confined to bed/chair >50% of waking hrs; 4=completely disabled, cannot carry on any self care, totally confined to bed/chair; 5=dead. Percentage of participants who had at least one point improvement from baseline at any assessment visit as well as at last study visit was reported. Analysis was performed on the safety population.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 1 of each 28 day cycle up to end of treatment (up to 46 months)
    End point values
    Vemurafenib
    Number of subjects analysed
    3219
    Units: Percentage of Participants
    number (not applicable)
        At Least 1 Point Improvement at Any Visit
    24.7
        At Least 1 Point Improvement at Last Visit
    9.9
    No statistical analyses for this end point

    Secondary: Percentage of Participants who Received any Concomitant Medications

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    End point title
    Percentage of Participants who Received any Concomitant Medications
    End point description
    Concomitant medications were all medications taken during the study, including those started before but ongoing at first dose. No medications for Melanoma were included. Percentage of participants who received at least one concomitant medication was reported. Analysis was performed on the safety population.
    End point type
    Secondary
    End point timeframe
    Baseline up to 46 months
    End point values
    Vemurafenib
    Number of subjects analysed
    3219
    Units: Percentage of Participants
        number (not applicable)
    93.8
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Best Overall Response (BOR) of Confirmed Complete Response or Partial Response, as per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)

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    End point title
    Percentage of Participants With Best Overall Response (BOR) of Confirmed Complete Response or Partial Response, as per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)
    End point description
    BOR was assessed by the investigator according to RECIST v1.1. BOR was defined as having confirmed CR or PR. CR: disappearance of all target and non-target lesions and no new lesions, all pathological lymph nodes must have decreased to less than (<) 10 millimeter (mm) in short axis; PR: at least a 30% decrease in the sum of diameters of target lesions (taking as reference the baseline sum diameters), no progression in non-target lesion, and no new lesions. Confirmed responses were those that persisted on repeat imaging greater than or equal to (>=) 4 weeks after initial response. Analysis was performed on the safety population. Number of subjects analyzed = participants with measurable disease at baseline
    End point type
    Secondary
    End point timeframe
    Baseline until first documentation of confirmed CR or PR (assessed at baseline, at Weeks 8, 16, as per institution standard of care thereafter but a minimum every 16 weeks thereafter until the end of the study [up to 46 months])
    End point values
    Vemurafenib
    Number of subjects analysed
    2982
    Units: Percentage of Participants
        number (confidence interval 95%)
    33.4 (31.7 to 35.1)
    No statistical analyses for this end point

    Secondary: Duration of Response

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    End point title
    Duration of Response
    End point description
    The duration of response was defined as the time between the date of first confirmed CR or PR and date of first progression of disease (PD), or death, from any cause. Responses were assessed as per RECIST v1.1. CR: disappearance of all target and non-target lesions and no new lesions, all pathological lymph nodes must have decreased to < 10 mm in short axis; PR: at least a 30% decrease in the sum of diameters of target lesions (taking as reference the baseline sum diameters), no progression in non-target lesion, and no new lesions. Confirmed responses were those that persisted on repeat imaging >= 4 weeks after initial response. PD: at least 20% increase in the sum of diameters of target lesions compared to smallest sum of diameters on study and absolute increase of at least 5 mm, progression of existing non target lesions, or presence of new lesion. Analysis was performed on the safety population. Number of subjects analyzed=participants who achieved CR or PR.
    End point type
    Secondary
    End point timeframe
    From 1st documentation of confirmed CR or PR to PD or death, whichever occurred first (assessed at baseline, at Weeks 8, 16, as per institution standard of care thereafter but a minimum every 16 weeks thereafter until end of the study [up to 46 months])
    End point values
    Vemurafenib
    Number of subjects analysed
    996
    Units: Months
        median (confidence interval 95%)
    7.4 (7.1 to 8.3)
    No statistical analyses for this end point

    Secondary: Time to Response

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    End point title
    Time to Response
    End point description
    Time to response was defined as the time between the date of first treatment and date of first confirmed CR or PR (assessed as per RECIST v1.1). CR: disappearance of all target and non-target lesions and no new lesions, all pathological lymph nodes must have decreased to < 10 mm in short axis; PR: at least a 30% decrease in the sum of diameters of target lesions (taking as reference the baseline sum diameters), no progression in non-target lesion, and no new lesions. Confirmed responses were those that persisted on repeat imaging >= 4 weeks after initial response. Analysis was performed on the safety population. Number of subjects analyzed = participants with measurable disease at baseline.
    End point type
    Secondary
    End point timeframe
    Baseline until first documentation of confirmed CR or PR, whichever occurred first (assessed at baseline, at Weeks 8, 16, as per institution standard of care thereafter but a minimum every 16 weeks thereafter until the end of the study [up to 46 months])
    End point values
    Vemurafenib
    Number of subjects analysed
    2982
    Units: Months
        median (full range (min-max))
    1.84 (0.8 to 26.7)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With PD Assessed According to RECIST v1.1 or Death

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    End point title
    Percentage of Participants With PD Assessed According to RECIST v1.1 or Death
    End point description
    PD was assessed according to RECIST v1.1. PD was defined as at least 20% increase in the sum of diameters of target lesions compared to smallest sum of diameters on study and absolute increase of at least 5 mm, progression of existing non-target lesions, or presence of new lesion. Analysis was performed on the safety population.
    End point type
    Secondary
    End point timeframe
    Baseline until PD or death, whichever occurred first (assessed at baseline, at Weeks 8, 16, as per institution standard of care thereafter but a minimum every 16 weeks thereafter until the end of the study [up to 46 months])
    End point values
    Vemurafenib
    Number of subjects analysed
    3219
    Units: Percentage of Participants
        number (not applicable)
    87.3
    No statistical analyses for this end point

    Secondary: Progression Free Survival (PFS)

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    End point title
    Progression Free Survival (PFS)
    End point description
    PFS was defined as the time between the date of the first treatment and the date of first progression or death from any cause. PD was assessed according to RECIST v1.1. PD was defined as at least 20% increase in the sum of diameters of target lesions compared to smallest sum of diameters on study and absolute increase of at least 5 mm, progression of existing non-target lesions, or presence of new lesion. Analysis was performed on the safety population.
    End point type
    Secondary
    End point timeframe
    Baseline until PD or death, whichever occurred first (assessed at baseline, at Weeks 8, 16, as per institution standard of care thereafter but a minimum every 16 weeks thereafter until the end of the study [up to 46 months])
    End point values
    Vemurafenib
    Number of subjects analysed
    3219
    Units: Months
        median (confidence interval 95%)
    5.6 (5.5 to 5.8)
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Died

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    End point title
    Percentage of Participants Who Died
    End point description
    Analysis was performed on the safety population.
    End point type
    Secondary
    End point timeframe
    Baseline until death (maximum up to 46 months)
    End point values
    Vemurafenib
    Number of subjects analysed
    3219
    Units: Percentage of participants
        number (not applicable)
    63.8
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    Overall Survival (OS)
    End point description
    Overall Survival was defined as the time from the date of first treatment to the date of death, regardless of the cause of death. Analysis was performed on the safety population.
    End point type
    Secondary
    End point timeframe
    Baseline until death (maximum up to 46 months)
    End point values
    Vemurafenib
    Number of subjects analysed
    3219
    Units: Months
        median (confidence interval 95%)
    12.1 (11.5 to 12.7)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to 28 days post end of treatment (maximum up to 46 months)
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Vemurafenib
    Reporting group description
    Participants received continuous oral doses of vemurafenib 960 mg (four 240 mg tablets) twice daily in each 28-day treatment cycle until the development of progressive disease, unacceptable toxicity, consent withdrawal, protocol violations endangering participant’s safety, death or study termination by the Sponsor.

    Serious adverse events
    Vemurafenib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1114 / 3219 (34.61%)
         number of deaths (all causes)
    2054
         number of deaths resulting from adverse events
    Vascular disorders
    Intermittent Claudication
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Extremity necrosis
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Hypotension
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    thrombophlebitis
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Circulatory Collapse
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Deep vein thrombosis
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Haematoma
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypertension
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Hypertensive Crisis
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    68 / 3219 (2.11%)
         occurrences causally related to treatment / all
    68 / 79
         deaths causally related to treatment / all
    0 / 0
    Chronic lymphocytic leukaemia
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Fibrous histiocytoma
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Intracranial tumour haemorrhage
         subjects affected / exposed
    7 / 3219 (0.22%)
         occurrences causally related to treatment / all
    4 / 7
         deaths causally related to treatment / all
    2 / 3
    Keratoacanthoma
         subjects affected / exposed
    260 / 3219 (8.08%)
         occurrences causally related to treatment / all
    359 / 361
         deaths causally related to treatment / all
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    43 / 3219 (1.34%)
         occurrences causally related to treatment / all
    36 / 46
         deaths causally related to treatment / all
    0 / 0
    Malignant melanoma in situ
         subjects affected / exposed
    10 / 3219 (0.31%)
         occurrences causally related to treatment / all
    8 / 10
         deaths causally related to treatment / all
    0 / 0
    Melanocytic naevus
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Mycosis Fungoides
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Papilloma
         subjects affected / exposed
    4 / 3219 (0.12%)
         occurrences causally related to treatment / all
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    259 / 3219 (8.05%)
         occurrences causally related to treatment / all
    348 / 352
         deaths causally related to treatment / all
    0 / 0
    Skin papilloma
         subjects affected / exposed
    3 / 3219 (0.09%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Tumour Ulceration
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Tumour necrosis
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Acanthoma
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Adrenocarcinoma of Colon
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Bowen's Disease
         subjects affected / exposed
    5 / 3219 (0.16%)
         occurrences causally related to treatment / all
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    Benign Neoplasm of Skin
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Breast Cancer
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Carcinoma In Situ of Skin
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Cervix Carcinoma Stage 0
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cholesteatoma
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Chondrosarcoma
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Ependymoma
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Eye Naevus
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infected Neoplasm
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Invasive Ductal Breast Carcinoma
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intraductal Proliferative Breast Lesion
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Kaposi's Sarcoma
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lymphoma
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Myxoid Liposarcoma
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Neoplasm
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Neuroendocrine Carcinoma
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Neuroendocrine Carcinoma of the Skin
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Neuroendocrine Tumour
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pancreatic Carcinoma
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Oral Papilloma
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Rectal Cancer
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Seborrhoeic Keratosis
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin Neoplasm Bleeding
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Squamous Cell Carcinoma of the Oral Cavity
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Squamous Cell Carcinoma of the Vulva
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Superficial Spreading Melanoma Stage Unspecified
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Synovial Sarcoma
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Transitional Cell Carcinoma
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Tumour Associated Fever
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lentigo Maligna
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Food allergy
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    3 / 3219 (0.09%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Chills
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Chronic fatigue syndrome
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Death
         subjects affected / exposed
    7 / 3219 (0.22%)
         occurrences causally related to treatment / all
    1 / 7
         deaths causally related to treatment / all
    1 / 7
    Drug Dislocation
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Drug interaction
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Fatigue
         subjects affected / exposed
    6 / 3219 (0.19%)
         occurrences causally related to treatment / all
    5 / 8
         deaths causally related to treatment / all
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    9 / 3219 (0.28%)
         occurrences causally related to treatment / all
    4 / 9
         deaths causally related to treatment / all
    2 / 5
    Malaise
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Multi-organ disorder
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Multi-organ failure
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    2 / 2
    Oedema
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyrexia
         subjects affected / exposed
    32 / 3219 (0.99%)
         occurrences causally related to treatment / all
    17 / 34
         deaths causally related to treatment / all
    0 / 0
    Sudden cardiac death
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Asthenia
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Generalised Oedema
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Impaired Healing
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Surgical Failure
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Visceral Pain
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Euthanasia
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    3 / 3219 (0.09%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Completed suicide
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    Confusional state
         subjects affected / exposed
    5 / 3219 (0.16%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Bipolar Disorder
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Delirium
         subjects affected / exposed
    3 / 3219 (0.09%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Mania
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Mood Altered
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Cervical polyp
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Uterine Haemorrhage
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Adnexal Torsion
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Endometrial Hyperplasia
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metrorrhagia
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Peyronie's Disease
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Uterine cervical erosion
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Alcohol Poisoning
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Fall
         subjects affected / exposed
    4 / 3219 (0.12%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    3 / 3219 (0.09%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Over dose
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Radiation injury
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Respiratory fume inhalation disorder
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Spinal fracture
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cystitis Radiation
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Facial Bone Fracture
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Femur Fracture
         subjects affected / exposed
    4 / 3219 (0.12%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Fracture
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Head Injury
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Fracture Displacement
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Humerus Fracture
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lumbar Vertrebral Fracture
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Multiple Injuries
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Patella Fracture
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Radiation Necrosis
         subjects affected / exposed
    4 / 3219 (0.12%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Radius Fracture
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Road Traffic Accident
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Spinal Compression Fracture
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Splenic Rupture
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Subdural Haematoma
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sunburn
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Tendon Injury
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tibia Fracture
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Toxicity to Various Agents
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    7 / 3219 (0.22%)
         occurrences causally related to treatment / all
    3 / 7
         deaths causally related to treatment / all
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gamma glutamyltransferase increased
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Lipase increased
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    3 / 3219 (0.09%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Blood glucose increased
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    3 / 3219 (0.09%)
         occurrences causally related to treatment / all
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    10 / 3219 (0.31%)
         occurrences causally related to treatment / all
    1 / 10
         deaths causally related to treatment / all
    1 / 4
    Angina pectoris
         subjects affected / exposed
    5 / 3219 (0.16%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Arrhythmia
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    15 / 3219 (0.47%)
         occurrences causally related to treatment / all
    6 / 15
         deaths causally related to treatment / all
    0 / 0
    Atrial flutter
         subjects affected / exposed
    4 / 3219 (0.12%)
         occurrences causally related to treatment / all
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    Cardiac failure
         subjects affected / exposed
    6 / 3219 (0.19%)
         occurrences causally related to treatment / all
    3 / 6
         deaths causally related to treatment / all
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    3 / 3219 (0.09%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 1
    Left ventricular dysfunction
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    7 / 3219 (0.22%)
         occurrences causally related to treatment / all
    1 / 8
         deaths causally related to treatment / all
    0 / 2
    Pericardial effusion
         subjects affected / exposed
    7 / 3219 (0.22%)
         occurrences causally related to treatment / all
    4 / 7
         deaths causally related to treatment / all
    0 / 0
    Pericardial haemorrhage
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pericarditis
         subjects affected / exposed
    7 / 3219 (0.22%)
         occurrences causally related to treatment / all
    7 / 8
         deaths causally related to treatment / all
    0 / 0
    Torsade de pointes
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Tachycardia
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Acute Coronary Syndrome
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Atrioventricular Block
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Angina Unstable
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Cardiac Arrest
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    Cardiac Failure Acute
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Cardiac Faiure Congestive
         subjects affected / exposed
    3 / 3219 (0.09%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Cardiogenic Shock
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Cardiomyopathy
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Coronary Artery Stenosis
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sinus Node Dysfunction
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Supraventricular Tachycardia
         subjects affected / exposed
    3 / 3219 (0.09%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    4 / 3219 (0.12%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    0 / 1
    Acute respiratory failure
         subjects affected / exposed
    4 / 3219 (0.12%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    Dyspnoea
         subjects affected / exposed
    4 / 3219 (0.12%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    1 / 1
    Epistaxis
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haemoptysis
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pleural effusion
         subjects affected / exposed
    6 / 3219 (0.19%)
         occurrences causally related to treatment / all
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    13 / 3219 (0.40%)
         occurrences causally related to treatment / all
    3 / 13
         deaths causally related to treatment / all
    0 / 3
    Respiratory failure
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bronchial Haemorrhage
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Acute Pulmonary Oedema
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    hydrothorax
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pleurisy
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pleuritic Pain
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary Toxicity
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    1 / 1
    Vocal Cord Leukoplakia
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    22 / 3219 (0.68%)
         occurrences causally related to treatment / all
    7 / 25
         deaths causally related to treatment / all
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    1 / 2
    Eosinophilia
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neutropenia
         subjects affected / exposed
    3 / 3219 (0.09%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Agranulocytosis
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Febrile Neutropenia
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Lymph Node Pain
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Microcytic Anaemia
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Brain oedema
         subjects affected / exposed
    3 / 3219 (0.09%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Cerebral haematoma
         subjects affected / exposed
    3 / 3219 (0.09%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    1 / 1
    Cerebral haemorrhage
         subjects affected / exposed
    14 / 3219 (0.43%)
         occurrences causally related to treatment / all
    4 / 14
         deaths causally related to treatment / all
    3 / 8
    Cerebrovascular accident
         subjects affected / exposed
    10 / 3219 (0.31%)
         occurrences causally related to treatment / all
    1 / 10
         deaths causally related to treatment / all
    0 / 5
    Cognitive disorder
         subjects affected / exposed
    3 / 3219 (0.09%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Depressed Level of Consicousness
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Dizziness
         subjects affected / exposed
    3 / 3219 (0.09%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Dysarthria
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Epilepsy
         subjects affected / exposed
    10 / 3219 (0.31%)
         occurrences causally related to treatment / all
    1 / 14
         deaths causally related to treatment / all
    0 / 0
    Generalised Tonic Clonic Seizure
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Facial paresis
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    3 / 3219 (0.09%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    Haemorrhagic stroke
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Headache
         subjects affected / exposed
    3 / 3219 (0.09%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Intracranial Pressure Increased
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Ischaemic stroke
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorder
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neuralgia
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Sciatica
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Stupor
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Tremor
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    VIIth nerve paralysis
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Aphasia
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Balance Disorder
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cerebral Disorder
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Carpal Tunnel Syndrome
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cerebrospinal Fluid Leakage
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Facial Nerve Disorder
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolic Encephalopathy
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Migraine
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Monoplegia
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neurotoxicity
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Partial Seizures
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Peripheral Sensorimotor Neuropathy
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Polyneuropathy
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Seizure
         subjects affected / exposed
    12 / 3219 (0.37%)
         occurrences causally related to treatment / all
    0 / 13
         deaths causally related to treatment / all
    0 / 0
    Simple Partial Seizure
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Spinal Cord Compression
         subjects affected / exposed
    3 / 3219 (0.09%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Status Epilepticus
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Subarachanoid Haemorrhage
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vasogenic Cerebral Oedema
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cerebellar Infarction
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Eye disorders
    Neovascular Age-related macular degeneration
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diplopia
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Iridocyclitis
         subjects affected / exposed
    3 / 3219 (0.09%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Uveitis
         subjects affected / exposed
    6 / 3219 (0.19%)
         occurrences causally related to treatment / all
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    Vitreous haemorrhage
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Cataract
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Macular Oedema
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Glaucoma
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Papilloedema
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Retinal Artery occlusion
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Retinal Detachment
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Retinopathy
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Iritis
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Ear and labyrinth disorders
    Deafness
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Vertigo
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hearnig Impaired
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Abdominal pain
         subjects affected / exposed
    4 / 3219 (0.12%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    Abdominal pain lower
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Constipation
         subjects affected / exposed
    6 / 3219 (0.19%)
         occurrences causally related to treatment / all
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea
         subjects affected / exposed
    16 / 3219 (0.50%)
         occurrences causally related to treatment / all
    9 / 16
         deaths causally related to treatment / all
    0 / 0
    Diverticular perforation
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Duodenal ulcer
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    3 / 3219 (0.09%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Heamatemesis
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ileus
         subjects affected / exposed
    3 / 3219 (0.09%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    3 / 3219 (0.09%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    3 / 3219 (0.09%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Jejunal perforation
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Nausea
         subjects affected / exposed
    13 / 3219 (0.40%)
         occurrences causally related to treatment / all
    11 / 15
         deaths causally related to treatment / all
    0 / 0
    Oesophagitis
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pancreatitis
         subjects affected / exposed
    4 / 3219 (0.12%)
         occurrences causally related to treatment / all
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    3 / 3219 (0.09%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Vomiting
         subjects affected / exposed
    17 / 3219 (0.53%)
         occurrences causally related to treatment / all
    9 / 18
         deaths causally related to treatment / all
    0 / 0
    Anal Fistula
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Anal skin Tags
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Colitis
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Dyspepsia
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Enteroocolitis
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Faeces Pale
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Food Poisoning
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastric Haemorrhagic
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal Necrosis
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Gastrointestinal Toxicity
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intestinal Ischaemia
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Intussusception
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Leukoplakia oral
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Mouth Ulceration
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Paraesthesia oral
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rectal Haemorrhage
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Retroperitoneal haematoma
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Calculus ureteric
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Glomerulonephritis minimal lesion
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Haematuria
         subjects affected / exposed
    3 / 3219 (0.09%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Renal Colic
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Urinary tract disorder
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Acute Kidney Injury
         subjects affected / exposed
    8 / 3219 (0.25%)
         occurrences causally related to treatment / all
    4 / 9
         deaths causally related to treatment / all
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Nephropathy
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Nephhropathy Toxic
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Tubulointerstitial Nephritis
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary Fistula
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    4 / 3219 (0.12%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    4 / 3219 (0.12%)
         occurrences causally related to treatment / all
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatitis
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    3 / 3219 (0.09%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Cholangitis
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cholecystitis
         subjects affected / exposed
    3 / 3219 (0.09%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Hepatic Failure
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatitis Toxic
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Acanthosis
         subjects affected / exposed
    4 / 3219 (0.12%)
         occurrences causally related to treatment / all
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    Angioedema
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Actinic keratosis
         subjects affected / exposed
    9 / 3219 (0.28%)
         occurrences causally related to treatment / all
    10 / 10
         deaths causally related to treatment / all
    0 / 0
    Dermatitis exfoliative
         subjects affected / exposed
    3 / 3219 (0.09%)
         occurrences causally related to treatment / all
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    Hypersensitivity Vasculitis
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Photosensitivity reaction
         subjects affected / exposed
    5 / 3219 (0.16%)
         occurrences causally related to treatment / all
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    Rash
         subjects affected / exposed
    5 / 3219 (0.16%)
         occurrences causally related to treatment / all
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    7 / 3219 (0.22%)
         occurrences causally related to treatment / all
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    Rash pruritic
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin Mass
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Toxic epidermal necrolysis
         subjects affected / exposed
    3 / 3219 (0.09%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    1 / 1
    Lichenoid Keratosis
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Dermal Cyst
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Dermatitis exfoliative Generalised
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Drug eruption
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Drug reaction with eosinophilia and systemic symptoms
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Hyperkeratosis
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Erythema Nodosum
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Panniculitis
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Rash Erythematous
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Rash Follicular
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Rash Generalised
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Rash Macular
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Rash Papular
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Steven Johnson Syndrome
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    12 / 3219 (0.37%)
         occurrences causally related to treatment / all
    11 / 13
         deaths causally related to treatment / all
    0 / 0
    Back pain
         subjects affected / exposed
    6 / 3219 (0.19%)
         occurrences causally related to treatment / all
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    Bursitis
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Muscular weakness
         subjects affected / exposed
    3 / 3219 (0.09%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    3 / 3219 (0.09%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Arthritis
         subjects affected / exposed
    3 / 3219 (0.09%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Myalgia
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Neck pain
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Osteoporosis
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pathological fracture
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dupuytren's Contracture
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Osteitis
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Spinal Pain
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Endocrine disorders
    Hyperadrenalism
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Dehydration
         subjects affected / exposed
    4 / 3219 (0.12%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    4 / 3219 (0.12%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Hyperuricaemia
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    4 / 3219 (0.12%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Decreased Appetite
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    4 / 3219 (0.12%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    Type 2 Diabestes Mellitus
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Electrolyte Imbalance
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypertriglyceridaemia
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Abscess Limb
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Anal abscess
         subjects affected / exposed
    5 / 3219 (0.16%)
         occurrences causally related to treatment / all
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    Blastocystis infection
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cellulitis
         subjects affected / exposed
    5 / 3219 (0.16%)
         occurrences causally related to treatment / all
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Device related infection
         subjects affected / exposed
    4 / 3219 (0.12%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Diverticulitis
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Erysipelas
         subjects affected / exposed
    9 / 3219 (0.28%)
         occurrences causally related to treatment / all
    1 / 10
         deaths causally related to treatment / all
    0 / 0
    Escherichia bacteraemia
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    Gastroenteritis
         subjects affected / exposed
    4 / 3219 (0.12%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    Groin abscess
         subjects affected / exposed
    5 / 3219 (0.16%)
         occurrences causally related to treatment / all
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    Herpes zoster
         subjects affected / exposed
    3 / 3219 (0.09%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    H1N1 Influenza
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infection
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    7 / 3219 (0.22%)
         occurrences causally related to treatment / all
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    Lung infection
         subjects affected / exposed
    6 / 3219 (0.19%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    Oesophageal candidiasis
         subjects affected / exposed
    3 / 3219 (0.09%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Oral candidiasis
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Otitis externa
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pilonidal cyst
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Pharyngotonsillitis
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumocystis jiroveci pneumonia
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Pneumonia
         subjects affected / exposed
    31 / 3219 (0.96%)
         occurrences causally related to treatment / all
    4 / 39
         deaths causally related to treatment / all
    1 / 3
    Postoperative Wound Infection
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Rash pustular
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    7 / 3219 (0.22%)
         occurrences causally related to treatment / all
    0 / 7
         deaths causally related to treatment / all
    0 / 2
    Sepsis
         subjects affected / exposed
    7 / 3219 (0.22%)
         occurrences causally related to treatment / all
    1 / 7
         deaths causally related to treatment / all
    1 / 3
    Salmonella sepsis
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin infection
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 3219 (0.12%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    11 / 3219 (0.34%)
         occurrences causally related to treatment / all
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Viral infection
         subjects affected / exposed
    3 / 3219 (0.09%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    Vulvitis
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Wound infection
         subjects affected / exposed
    4 / 3219 (0.12%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Wound infection staphylococcal
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Acinetobacter Infection
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Appendicitis Perforated
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Arthritis Bacterial
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Brain Abscess
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Atypical Pneumonia
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cholecystitis Infective
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Colonic Abscess
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal Infection
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis Viral
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypopyon
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infected Dermal Cyst
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infectious Pleural Effusion
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Localised Infection
         subjects affected / exposed
    2 / 3219 (0.06%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Lymph Gland Infection
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ophthalmic Herpes Zoster
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin Bacterial Infection
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Perineal Abscess
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Soft Tissue Infection
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Subdiaphragmatic Abscess
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Tonsillitis
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tooth Abscess
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tooth Infection
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Clostridium Colitis
         subjects affected / exposed
    1 / 3219 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Vemurafenib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2956 / 3219 (91.83%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    264 / 3219 (8.20%)
         occurrences all number
    348
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin papilloma
         subjects affected / exposed
    621 / 3219 (19.29%)
         occurrences all number
    953
    Melanocytic Naevus
         subjects affected / exposed
    227 / 3219 (7.05%)
         occurrences all number
    332
    Seborrhoeic Keratosis
         subjects affected / exposed
    266 / 3219 (8.26%)
         occurrences all number
    333
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    363 / 3219 (11.28%)
         occurrences all number
    484
    Fatigue
         subjects affected / exposed
    834 / 3219 (25.91%)
         occurrences all number
    1129
    Asthenia
         subjects affected / exposed
    382 / 3219 (11.87%)
         occurrences all number
    535
    Oedema Peripheral
         subjects affected / exposed
    238 / 3219 (7.39%)
         occurrences all number
    274
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    163 / 3219 (5.06%)
         occurrences all number
    175
    Injury, poisoning and procedural complications
    Sunburn
         subjects affected / exposed
    318 / 3219 (9.88%)
         occurrences all number
    522
    Investigations
    Weight decreased
         subjects affected / exposed
    414 / 3219 (12.86%)
         occurrences all number
    485
    Electrocardiogram QT prolonged
         subjects affected / exposed
    521 / 3219 (16.19%)
         occurrences all number
    753
    Blood and lymphatic system disorders
    Anaenia
         subjects affected / exposed
    215 / 3219 (6.68%)
         occurrences all number
    316
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    191 / 3219 (5.93%)
         occurrences all number
    215
    Nervous system disorders
    Headache
         subjects affected / exposed
    458 / 3219 (14.23%)
         occurrences all number
    637
    Dysgeusia
         subjects affected / exposed
    191 / 3219 (5.93%)
         occurrences all number
    205
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    584 / 3219 (18.14%)
         occurrences all number
    866
    Nausea
         subjects affected / exposed
    718 / 3219 (22.31%)
         occurrences all number
    965
    Vomiting
         subjects affected / exposed
    449 / 3219 (13.95%)
         occurrences all number
    635
    Constipation
         subjects affected / exposed
    196 / 3219 (6.09%)
         occurrences all number
    211
    Abdominal Pain
         subjects affected / exposed
    170 / 3219 (5.28%)
         occurrences all number
    214
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    873 / 3219 (27.12%)
         occurrences all number
    942
    Dry skin
         subjects affected / exposed
    538 / 3219 (16.71%)
         occurrences all number
    597
    Erythema
         subjects affected / exposed
    327 / 3219 (10.16%)
         occurrences all number
    415
    Hyperkeratosis
         subjects affected / exposed
    830 / 3219 (25.78%)
         occurrences all number
    1201
    Photosensitivity reaction
         subjects affected / exposed
    678 / 3219 (21.06%)
         occurrences all number
    891
    Rash
         subjects affected / exposed
    556 / 3219 (17.27%)
         occurrences all number
    709
    Pruritus
         subjects affected / exposed
    320 / 3219 (9.94%)
         occurrences all number
    370
    Actinic Keratosis
         subjects affected / exposed
    246 / 3219 (7.64%)
         occurrences all number
    405
    Palmar Plantar Erythrodysaesthesia syndrome
         subjects affected / exposed
    193 / 3219 (6.00%)
         occurrences all number
    253
    Rash Erythematous
         subjects affected / exposed
    195 / 3219 (6.06%)
         occurrences all number
    246
    Rash Maculo- Papular
         subjects affected / exposed
    179 / 3219 (5.56%)
         occurrences all number
    240
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1357 / 3219 (42.16%)
         occurrences all number
    2178
    Myalgia
         subjects affected / exposed
    308 / 3219 (9.57%)
         occurrences all number
    402
    Back Pain
         subjects affected / exposed
    191 / 3219 (5.93%)
         occurrences all number
    214
    Muscloskeletal Pain
         subjects affected / exposed
    222 / 3219 (6.90%)
         occurrences all number
    277
    Pain in Extremity
         subjects affected / exposed
    276 / 3219 (8.57%)
         occurrences all number
    343
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    482 / 3219 (14.97%)
         occurrences all number
    603
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    170 / 3219 (5.28%)
         occurrences all number
    199
    Nasopharyngitis
         subjects affected / exposed
    171 / 3219 (5.31%)
         occurrences all number
    223

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Apr 2011
    • Based on result of a different study similar participant population was allowed to be enrolled in this study and therefore participants with surgically incurable and unresectable Stage IIIC or Stage IV (AJCC) and participants who had not received prior treatment for metastatic melanoma were allowed into the study (in addition to participants who had received prior treatment). • Included participants at least 16 years of age due to the assumed similarities between the biological/physiological and pharmacokinetic/pharmacodynamic characteristics of 16 to 18-year-old participants. • Excluded participants with a known hypersensitivity to vemurafenib or another BRAF inhibitor. • Excluded participants with congenital long QT syndrome considering the recent data of effect of vemurafenib on the QT interval. • Clarified the type of concomitant medication that was prohibited or must be used with caution. • Included ECG monitoring to be 28 days after starting treatment with vemurafenib, every 4 weeks for the following 3 months, every 12 weeks thereafter and at the end of study/follow-up visit, following the new safety information. • Clarified the definition of the date at which the Screening Period started to be the date at which the first archival tumor tissue sample was sent to the central testing laboratory for BRAF mutation testing, except when a study procedure was performed prior to sending the tumor sample to the testing laboratory, when this date was recorded as the date of the start of Screening. • Clarified the reporting of SCC to allow for the proper coding to the preferred term cutaneous SCC and clarified that SCC should be reported as an serious AE only if it meets the definition of an serious AE.
    30 Nov 2011
    • Included a long term follow-up safety phase for 24 months after the last participant enrolled. • Added information to the study background. • Included tolerability as part of the primary objective of the study, together with safety. • Clearly defined the end of treatment visit and the 28 day follow-up visit after discontinuation of vemurafenib and updated the sections referring to visits. • Increased the number of participants to be screened and enrolled. • Clarified that only a protocol violation that endangered a participant’s safety would mandate discontinuation of study treatment. • Added the option for participants who developed disease progression but who in the opinion of the investigator would still benefit from continuing vemurafenib treatment, could do so after discussion with the Sponsor. • Included that for participants who developed any other suspicious lesions (in addition to SCC), tissue from the lesions was also to be provided for confirmation of diagnosis by a designated central pathology laboratory. • Clarified when the study enrolment would end in relation to local regulatory approval and reimbursement of vemurafenib for the treatment of metastatic melanoma. • Increased the number of study centers. • Clarified the exclusion criteria • Clarified the use of limited field radiotherapy to include all palliative reasons if the limited field radiotherapy was not considered a target lesion for the RECIST assessments. • Increased the follow-up of chest CT for evaluation of non cutaneous SCC. • Clarified that the participants with known or suspected bone metastases should undergo radionuclide bone scan or PET scan at baseline if clinically indicated. • Clarified the definition of AE and SAEs. • Amended the statistical analyses.
    15 Aug 2012
    • Added that participant recruitment has been higher than expected with additional countries and sites than originally planned being included. The protocol has been updated to reflect the higher number of participant and revised statistical assumptions. It was estimated that approximately 7400 participants will be screened and approximately 3300 participants with the BRAF V600 mutation will be enrolled in the study and receive treatment with vemurafenib. • Increased the visit window to +/- 5 days to allow flexibility and to be more realistic to clinical routine, and the follow-up visit to after 28 days. • Included an additional head and neck examination for monitoring of non cutaneous SCCs to align with the monitoring guidance of the Zelboraf® (marketed name of vemurafenib) Summary of Product Characteristics, to the Long Term Safety Follow-up Phase, to be performed at 6 months following study drug discontinuation or until initiation of another neo plastic therapy. • Added a dermatological evaluation at 6 months following study drug discontinuation or until initiation of another anti neoplastic therapy for monitoring of cutaneous SCCs to align with the monitoring guidance of the vemurafenib Summary of Product Characteristics • Included for consistency throughout the protocol that as well as cutaneous SCC, BCC and keratoacanthoma and other second primary malignancies were defined as events requiring close monitoring.

    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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