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    Clinical Trial Results:
    COMBI-AD: A phase III randomized double blind study of dabrafenib (GSK2118436) in COMBInation with trametinib (GSK1120212) versus two placebos in the ADjuvant treatment of high-risk BRAF V600 mutation-positive melanoma after surgical resection

    Summary
    EudraCT number
    		 2012-001266-15
    Trial protocol
    		 BE   SE   CZ   DE   NO   GB   AT   GR   IT   NL   DK   ES  
    Global end of trial date
    31 Jul 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Jul 2024
    First version publication date
    25 Jul 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    115532
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01682083
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 legacy GSK code: BRF115532, Novartis: CDRB436F2301
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    Novartis Campus, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@Novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@Novartis.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    31 Jul 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Jul 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to evaluate the efficacy of dabrafenib and trametinib combination therapy compared to two placebos with respect to Relapse Free Survival (RFS) in patients with completely resected, histologically confirmed, BRAF V600E/K high-risk, stage III cutaneous melanoma.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    08 Jan 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 5
    Country: Number of subjects enrolled
    Australia: 103
    Country: Number of subjects enrolled
    Austria: 11
    Country: Number of subjects enrolled
    Belgium: 21
    Country: Number of subjects enrolled
    Brazil: 3
    Country: Number of subjects enrolled
    Canada: 27
    Country: Number of subjects enrolled
    Czechia: 15
    Country: Number of subjects enrolled
    Denmark: 19
    Country: Number of subjects enrolled
    France: 109
    Country: Number of subjects enrolled
    Germany: 90
    Country: Number of subjects enrolled
    United Kingdom: 86
    Country: Number of subjects enrolled
    Greece: 13
    Country: Number of subjects enrolled
    Israel: 12
    Country: Number of subjects enrolled
    Italy: 97
    Country: Number of subjects enrolled
    Japan: 5
    Country: Number of subjects enrolled
    Netherlands: 21
    Country: Number of subjects enrolled
    New Zealand: 4
    Country: Number of subjects enrolled
    Norway: 19
    Country: Number of subjects enrolled
    Poland: 22
    Country: Number of subjects enrolled
    Russian Federation: 29
    Country: Number of subjects enrolled
    Spain: 41
    Country: Number of subjects enrolled
    Sweden: 27
    Country: Number of subjects enrolled
    Switzerland: 18
    Country: Number of subjects enrolled
    Taiwan: 4
    Country: Number of subjects enrolled
    United States: 69
    Worldwide total number of subjects
    870
    EEA total number of subjects
    505
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    712
    From 65 to 84 years
    156
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted in 169 centers across 25 countries.

    Pre-assignment
    Screening details
    		 Patients were planned to be randomized in a 1:1 ratio, stratified by BRAF mutation status (V600E, V600K) and stage of disease (Stage IIIa, IIIb, IIIc).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Dabrafenib and Trametinib combination therapy
    Arm description
    		 Subjects received dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) orally for 12 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dabrafenib
    Investigational medicinal product code
    Other name
    GSK2118436
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dabrafenib, 150 mg twice daily (bid) + trametinib, 2 mg (once daily). Dabrafenib was provided as 50 mg and 75 mg capsules. Each capsule contained 50 mg or 75 mg of free base (present as the mesylate salt).

    Investigational medicinal product name
    Trametinib
    Investigational medicinal product code
    Other name
    GSK1120212
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dabrafenib, 150 mg twice daily (bid) + trametinib, 2 mg (once daily). Trametinib study treatment was provided as 0.5 mg and 2 mg tablets. Each tablet contained 0.5 mg or 2 mg of trametinib parent (present as the dimethyl sulfoxide solvate).

    Arm title
    		 Dabrafenib and Trametinib placebos
    Arm description
    		 Subjects received matching placebos orally for 12 months
    Arm type
    		 Placebo

    Investigational medicinal product name
    Matching placebo capsules for dabrafenib, 150 mg (bid) + placebo tablets for trametinib, 2 mg (once daily)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The placebo capsules/tablets contained the same inactive ingredients and film coatings as the dabrafenib and trametinib study treatment.

    Number of subjects in period 1
    		Dabrafenib and Trametinib combination therapy Dabrafenib and Trametinib placebos
    Started
    438
    432
    Untreated
    3
    0
    Safety Population
    435
    432
    Completed
    0
    0
    Not completed
    438
    432
         Adverse event, serious fatal
    125
    136
         Physician decision
    11
    8
         Consent withdrawn by subject
    50
    53
         Study closed by sponsor
    225
    192
         Lost to follow-up
    27
    43

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Dabrafenib and Trametinib combination therapy
    Reporting group description
    		 Subjects received dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) orally for 12 months.

    Reporting group title
    Dabrafenib and Trametinib placebos
    Reporting group description
    		 Subjects received matching placebos orally for 12 months

    Reporting group values
    		 Dabrafenib and Trametinib combination therapy Dabrafenib and Trametinib placebos Total
    Number of subjects
    		 438 432 870
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 353 359 712
        From 65-84 years
    		 84 72 156
        85 years and over
    		 1 1 2
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 50.4 ( 14.17 ) 50.5 ( 13.14 ) -
    Sex: Female, Male
    Units: participants
        Female
    		 195 193 388
        Male
    		 243 239 482
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 432 427 859
        Asian
    		 6 5 11

    End points

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    End points reporting groups
    Reporting group title
    Dabrafenib and Trametinib combination therapy
    Reporting group description
    		 Subjects received dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) orally for 12 months.

    Reporting group title
    Dabrafenib and Trametinib placebos
    Reporting group description
    		 Subjects received matching placebos orally for 12 months

    Primary: Percentage of Participants with Relapse-free survival (RFS) events

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    End point title
    		 Percentage of Participants with Relapse-free survival (RFS) events [1]
    End point description
    Patients with no event by the time of the analysis cut-off date (30-Jun-2017) were censored at the date of the last efficacy assessment (i.e., either radiological or non-radiological) prior to the analysis cut-off. Patients lost to follow-up prior to disease recurrence were censored. Patients who started subsequent anti-cancer therapy prior to disease recurrence were censored at the date of last efficacy assessment (either radiological or non-radiological) before the initiation of subsequent anti-cancer therapy. Patients for whom an event occurred after a period of extended lost-to-follow-up were censored.
    End point type
    Primary
    End point timeframe
    Approximately 3.5 years
    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: Only descriptive statistics performed
    End point values
    		 Dabrafenib and Trametinib combination therapy Dabrafenib and Trametinib placebos
    Number of subjects analysed
    438
    432
    Units: Participants
        Relapsed (event)
    163
    247
        Died (event)
    3
    1
        Censored, follow-up ended at Primary Completion
    43
    35
        Censored, follow-up ongoing at Primary Completion
    229
    149
    No statistical analyses for this end point

    Primary: Relapse-free survival (RFS)

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    End point title
    		 Relapse-free survival (RFS)
    End point description
    Recurrence-free survival was defined as the time from randomization to disease recurrence (local recurrence, distant recurrence, second primary melanoma), or death from any cause. Patients with no event by the time of the analysis cut-off date (30-Jun-2017) were censored at the date of the last efficacy assessment (i.e., either radiological or non-radiological) prior to the analysis cut-off. Patients lost to follow-up prior to disease recurrence were censored. Patients who started subsequent anti-cancer therapy prior to disease recurrence were censored at the date of last efficacy assessment (either radiological or non-radiological) before the initiation of subsequent anti-cancer therapy. Patients for whom an event occurred after a period of extended lost-to-follow-up were censored.
    End point type
    Primary
    End point timeframe
    Approximately 3.5 years
    End point values
    		 Dabrafenib and Trametinib combination therapy Dabrafenib and Trametinib placebos
    Number of subjects analysed
    438
    432
    Units: Months
        median (full range (min-max))
    999 (44.5 to 999)
    16.6 (12.7 to 22.1)
    Statistical analysis title
    		 Relapse-free survival (RFS)
    Statistical analysis description
    The null hypothesis, H0: λ = 1 or reject it in favor of the alternative hypothesis, HA: λ ≠ 1, where λ is the hazard ratio (HR) of combination therapy relative to placebo.
    Comparison groups
    Dabrafenib and Trametinib combination therapy v Dabrafenib and Trametinib placebos
    Number of subjects included in analysis
    870
    Analysis specification
    Pre-specified
    Analysis type
    		 [2]
    P-value
    		 < 0.0001
    Method
    		 Logrank
    Parameter type
    		 Log hazard ratio
    Point estimate
    0.47
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.39
         upper limit
    		 0.58
    Notes
    [2] - Hazard ratio is obtained from the stratified Pike estimator. A hazard ratio <1 indicates a lower risk with Dabrafenib + Trametinib compared with Placebo.

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    Overall Survival (OS) was defined as the interval from randomization to the date of death, irrespective of the cause of death. Censoring was performed using the date of last known contact for those who were alive at the time of analysis.
    End point type
    Secondary
    End point timeframe
    Approximately 10 years
    End point values
    		 Dabrafenib and Trametinib combination therapy Dabrafenib and Trametinib placebos
    Number of subjects analysed
    438
    432
    Units: Months
        median (full range (min-max))
    999 (120.7 to 999)
    999 (999 to 999)
    Statistical analysis title
    		 Overall Survival (OS)
    Statistical analysis description
    Hazard ratio is obtained from the stratified Pike estimator.
    Comparison groups
    Dabrafenib and Trametinib combination therapy v Dabrafenib and Trametinib placebos
    Number of subjects included in analysis
    870
    Analysis specification
    Pre-specified
    Analysis type
    		 [3]
    P-value
    		 = 0.063
    Method
    		 Logrank
    Parameter type
    		 Log hazard ratio
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.62
         upper limit
    		 1.01
    Notes
    [3] - A hazard ratio <1 indicates a lower risk with dabrafenib + trametinib compared with Placebo.

    Secondary: Percentage of Participants with Overall Survival (OS) events

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    End point title
    		 Percentage of Participants with Overall Survival (OS) events
    End point description
    Censoring was performed using the date of last known contact for those who were alive at the time of analysis.
    End point type
    Secondary
    End point timeframe
    Approximately 10 years
    End point values
    		 Dabrafenib and Trametinib combination therapy Dabrafenib and Trametinib placebos
    Number of subjects analysed
    438
    432
    Units: Participants
        Died (event)
    125
    136
        Censored, follow-up ended
    313
    296
        Censored, follow-up ongoing
    0
    0
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Distant metastasis-free survival (DMFS) events

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    End point title
    		 Percentage of Participants with Distant metastasis-free survival (DMFS) events
    End point description
    The first appearance of distant metastasis or all-cause mortality were used as events. Censoring was performed using the date of the last assessment for those who were alive without distant metastasis at the time of analysis.
    End point type
    Secondary
    End point timeframe
    Approximately 3.5 years
    End point values
    		 Dabrafenib and Trametinib combination therapy Dabrafenib and Trametinib placebos
    Number of subjects analysed
    438
    432
    Units: Participants
        Relapsed (event)
    106
    150
        Died (event)
    4
    2
        Censored, follow-up ended at Primary Completion
    99
    131
        Censored, follow-up ongoing at Primary Completion
    229
    149
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Freedom from relapse (FFR) events

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    End point title
    		 Percentage of Participants with Freedom from relapse (FFR) events
    End point description
    The first appearance of local/distant metastasis or mortality due to disease recurrence or toxicity were used as events. Censoring was performed using the date of last assessment for those who were alive without local/distant metastasis or new primary melanoma at the time of analysis. FFR was censored if patients died from causes other than melanoma or treatment-related toxicity at the date of death.
    End point type
    Secondary
    End point timeframe
    Approximately 3.5 years
    End point values
    		 Dabrafenib and Trametinib combination therapy Dabrafenib and Trametinib placebos
    Number of subjects analysed
    438
    432
    Units: Participants
        Relapsed (event)
    163
    247
        Died (event)
    2
    0
        Censored, follow-up ended at Primary Completion
    44
    36
        Censored, follow-up ongoing at Primary Completion
    229
    149
    No statistical analyses for this end point

    Secondary: Distant metastasis-free survival (DMFS)

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    End point title
    		 Distant metastasis-free survival (DMFS)
    End point description
    Distant metastasis-free survival (DMFS) was defined as the interval from randomization to the date of first distant metastasis or date of death, whichever occurred first. The first appearance of distant metastasis or all-cause mortality were used as events. Censoring was performed using the date of the last assessment for those who were alive without distant metastasis at the time of analysis.
    End point type
    Secondary
    End point timeframe
    Approximately 3.5 years
    End point values
    		 Dabrafenib and Trametinib combination therapy Dabrafenib and Trametinib placebos
    Number of subjects analysed
    438
    432
    Units: Months
        median (full range (min-max))
    999 (999 to 999)
    999 (41.2 to 999)
    Statistical analysis title
    		 Distant metastasis-free survival (DMFS)
    Statistical analysis description
    Hazard ratio is estimated using Pike estimator.
    Comparison groups
    Dabrafenib and Trametinib combination therapy v Dabrafenib and Trametinib placebos
    Number of subjects included in analysis
    870
    Analysis specification
    Pre-specified
    Analysis type
    		 [4]
    P-value
    		 < 0.001
    Method
    		 Logrank
    Parameter type
    		 Log hazard ratio
    Point estimate
    0.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4
         upper limit
    		 0.65
    Notes
    [4] - A hazard ratio <1 indicates a lower risk with Dabrafenib + Trametinib compared with Placebo.

    Secondary: Freedom from relapse (FFR)

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    End point title
    		 Freedom from relapse (FFR)
    End point description
    Freedom from relapse (FFR) was defined as the interval from randomization to local or distant recurrence with censoring of patients dying from causes other than melanoma or treatment -related toxicity at the date of death. The first appearance of local/distant metastasis or mortality due to disease recurrence or toxicity were used as events. Censoring was performed using the date of last assessment for those who were alive without local/distant metastasis or new primary melanoma at the time of analysis. FFR was censored if patients died from causes other than melanoma or treatment-related toxicity at the date of death.
    End point type
    Secondary
    End point timeframe
    Approximately 3.5 years
    End point values
    		 Dabrafenib and Trametinib combination therapy Dabrafenib and Trametinib placebos
    Number of subjects analysed
    438
    432
    Units: Months
        median (full range (min-max))
    999 (44.5 to 999)
    16.6 (12.7 to 22.3)
    Statistical analysis title
    		 Freedom from relapse (FFR)
    Statistical analysis description
    Hazard ratio is estimated using Pike estimator.
    Comparison groups
    Dabrafenib and Trametinib combination therapy v Dabrafenib and Trametinib placebos
    Number of subjects included in analysis
    870
    Analysis specification
    Pre-specified
    Analysis type
    		 [5]
    P-value
    		 < 0.001
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.47
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.39
         upper limit
    		 0.57
    Notes
    [5] - A hazard ratio <1 indicates a lower risk with Dabrafenib + Trametinib compared with Placebo.

    Post-hoc: All collected deaths

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    End point title
    		 All collected deaths
    End point description
    Pre-treatment deaths were collected from day of participant’s informed consent to the day before first dose of study medication. On-treatment deaths were collected from first dose of study treatment to 30 days after last dose of study medication (on-treatment), up to approximately 12 months. ​ Deaths were collected in the post treatment survival follow up from 31 days after last dose of study medication until the end of the study, up to approximately 126 months. These are not considered AEs​
    End point type
    Post-hoc
    End point timeframe
    Pre-treatment deaths: Up to 28 days prior to treatment. On-treatment deaths: Up to approximately 12 months. Post-treatment deaths: Up to approximately 126 months
    End point values
    		 Dabrafenib and Trametinib combination therapy Dabrafenib and Trametinib placebos
    Number of subjects analysed
    438
    432
    Units: Participants
        Pre-treatment deaths
    0
    0
        On-treatment deaths
    4
    1
        Post-treatment deaths
    121
    135
        All deaths
    125
    136
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from first dose of study treatment to 30 days after last dose of study medication (on-treatment), up to approximately 12 months. ​
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    Dabrafenib + @Trametinib
    Reporting group description
    		 Dabrafenib + @Trametinib

    Reporting group title
    Total
    Reporting group description
    		 Total

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Serious adverse events
    		 Dabrafenib + @Trametinib Total Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    155 / 435 (35.63%)
    199 / 867 (22.95%)
    44 / 432 (10.19%)
         number of deaths (all causes)
    4
    5
    1
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bowen's disease
         subjects affected / exposed
    2 / 435 (0.46%)
    4 / 867 (0.46%)
    2 / 432 (0.46%)
         occurrences causally related to treatment / all
    0 / 5
    1 / 7
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bladder transitional cell carcinoma
         subjects affected / exposed
    0 / 435 (0.00%)
    1 / 867 (0.12%)
    1 / 432 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    0 / 435 (0.00%)
    1 / 867 (0.12%)
    1 / 432 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    B-cell lymphoma
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acanthoma
         subjects affected / exposed
    0 / 435 (0.00%)
    1 / 867 (0.12%)
    1 / 432 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    1 / 435 (0.23%)
    2 / 867 (0.23%)
    1 / 432 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    3 / 435 (0.69%)
    6 / 867 (0.69%)
    3 / 432 (0.69%)
         occurrences causally related to treatment / all
    5 / 5
    8 / 9
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Salivary gland adenoma
         subjects affected / exposed
    0 / 435 (0.00%)
    1 / 867 (0.12%)
    1 / 432 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal cancer
         subjects affected / exposed
    0 / 435 (0.00%)
    1 / 867 (0.12%)
    1 / 432 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma in situ
         subjects affected / exposed
    0 / 435 (0.00%)
    1 / 867 (0.12%)
    1 / 432 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    1 / 435 (0.23%)
    4 / 867 (0.46%)
    3 / 432 (0.69%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 4
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lentigo maligna
         subjects affected / exposed
    0 / 435 (0.00%)
    1 / 867 (0.12%)
    1 / 432 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Keratoacanthoma
         subjects affected / exposed
    1 / 435 (0.23%)
    2 / 867 (0.23%)
    1 / 432 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Focal nodular hyperplasia
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endometrial adenocarcinoma
         subjects affected / exposed
    2 / 435 (0.46%)
    2 / 867 (0.23%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colorectal adenoma
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Embolism
         subjects affected / exposed
    0 / 435 (0.00%)
    1 / 867 (0.12%)
    1 / 432 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    6 / 435 (1.38%)
    6 / 867 (0.69%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    4 / 6
    4 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphoedema
         subjects affected / exposed
    0 / 435 (0.00%)
    1 / 867 (0.12%)
    1 / 432 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular occlusion
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Influenza like illness
         subjects affected / exposed
    3 / 435 (0.69%)
    3 / 867 (0.35%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    2 / 435 (0.46%)
    2 / 867 (0.23%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    13 / 435 (2.99%)
    13 / 867 (1.50%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    18 / 18
    18 / 18
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    67 / 435 (15.40%)
    71 / 867 (8.19%)
    4 / 432 (0.93%)
         occurrences causally related to treatment / all
    84 / 85
    85 / 89
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Testicular mass
         subjects affected / exposed
    0 / 435 (0.00%)
    1 / 867 (0.12%)
    1 / 432 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Priapism
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    3 / 435 (0.69%)
    4 / 867 (0.46%)
    1 / 432 (0.23%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Obsessive-compulsive disorder
         subjects affected / exposed
    0 / 435 (0.00%)
    1 / 867 (0.12%)
    1 / 432 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 435 (0.69%)
    3 / 867 (0.35%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 435 (0.46%)
    2 / 867 (0.23%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ejection fraction decreased
         subjects affected / exposed
    13 / 435 (2.99%)
    18 / 867 (2.08%)
    5 / 432 (1.16%)
         occurrences causally related to treatment / all
    14 / 14
    19 / 19
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Right ventricular systolic pressure increased
         subjects affected / exposed
    0 / 435 (0.00%)
    1 / 867 (0.12%)
    1 / 432 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Troponin increased
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Limb injury
         subjects affected / exposed
    0 / 435 (0.00%)
    1 / 867 (0.12%)
    1 / 432 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 435 (0.00%)
    1 / 867 (0.12%)
    1 / 432 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seroma
         subjects affected / exposed
    1 / 435 (0.23%)
    2 / 867 (0.23%)
    1 / 432 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    0 / 435 (0.00%)
    1 / 867 (0.12%)
    1 / 432 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrioventricular block second degree
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac ventricular thrombosis
         subjects affected / exposed
    0 / 435 (0.00%)
    1 / 867 (0.12%)
    1 / 432 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 435 (0.00%)
    1 / 867 (0.12%)
    1 / 432 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Amyotrophic lateral sclerosis
         subjects affected / exposed
    0 / 435 (0.00%)
    1 / 867 (0.12%)
    1 / 432 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Carpal tunnel syndrome
         subjects affected / exposed
    0 / 435 (0.00%)
    1 / 867 (0.12%)
    1 / 432 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Demyelinating polyneuropathy
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    2 / 435 (0.46%)
    2 / 867 (0.23%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    2 / 435 (0.46%)
    2 / 867 (0.23%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral sensorimotor neuropathy
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    1 / 435 (0.23%)
    2 / 867 (0.23%)
    1 / 432 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meningoradiculitis
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    4 / 435 (0.92%)
    4 / 867 (0.46%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Facial paralysis
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Blood loss anaemia
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    2 / 435 (0.46%)
    2 / 867 (0.23%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Visual impairment
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uveitis
         subjects affected / exposed
    2 / 435 (0.46%)
    2 / 867 (0.23%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    2 / 435 (0.46%)
    2 / 867 (0.23%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Macular oedema
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Iritis
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Central serous chorioretinopathy
         subjects affected / exposed
    4 / 435 (0.92%)
    4 / 867 (0.46%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chorioretinopathy
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 435 (0.00%)
    1 / 867 (0.12%)
    1 / 432 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Obstructive pancreatitis
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    4 / 435 (0.92%)
    4 / 867 (0.46%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retroperitoneal haematoma
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Proctalgia
         subjects affected / exposed
    0 / 435 (0.00%)
    1 / 867 (0.12%)
    1 / 432 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatic toxicity
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatotoxicity
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic haemorrhage
         subjects affected / exposed
    0 / 435 (0.00%)
    1 / 867 (0.12%)
    1 / 432 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Panniculitis
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Erythema nodosum
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 435 (0.46%)
    2 / 867 (0.23%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Calculus urinary
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephrotic syndrome
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Inappropriate antidiuretic hormone secretion
         subjects affected / exposed
    0 / 435 (0.00%)
    1 / 867 (0.12%)
    1 / 432 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ovarian dysfunction
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Rhabdomyolysis
         subjects affected / exposed
    2 / 435 (0.46%)
    2 / 867 (0.23%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myopathy
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abscess jaw
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Parvovirus infection
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    3 / 435 (0.69%)
    3 / 867 (0.35%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    2 / 435 (0.46%)
    2 / 867 (0.23%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 435 (0.00%)
    1 / 867 (0.12%)
    1 / 432 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Groin infection
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Groin abscess
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile infection
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    8 / 435 (1.84%)
    9 / 867 (1.04%)
    1 / 432 (0.23%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 13
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epstein-Barr virus infection
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis infective
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    5 / 435 (1.15%)
    6 / 867 (0.69%)
    1 / 432 (0.23%)
         occurrences causally related to treatment / all
    1 / 7
    1 / 8
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 435 (0.00%)
    1 / 867 (0.12%)
    1 / 432 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vulval abscess
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    0 / 435 (0.00%)
    1 / 867 (0.12%)
    1 / 432 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 435 (0.00%)
    1 / 867 (0.12%)
    1 / 432 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    4 / 435 (0.92%)
    4 / 867 (0.46%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Salpingitis
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retinitis
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rash pustular
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural infection
         subjects affected / exposed
    0 / 435 (0.00%)
    1 / 867 (0.12%)
    1 / 432 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 435 (0.69%)
    3 / 867 (0.35%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    0 / 435 (0.00%)
    1 / 867 (0.12%)
    1 / 432 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    4 / 435 (0.92%)
    4 / 867 (0.46%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 435 (0.00%)
    1 / 867 (0.12%)
    1 / 432 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 435 (0.23%)
    1 / 867 (0.12%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    2 / 435 (0.46%)
    2 / 867 (0.23%)
    0 / 432 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Dabrafenib + @Trametinib Total Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    414 / 435 (95.17%)
    757 / 867 (87.31%)
    343 / 432 (79.40%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    64 / 435 (14.71%)
    70 / 867 (8.07%)
    6 / 432 (1.39%)
         occurrences all number
    78
    88
    10
    Aspartate aminotransferase increased
         subjects affected / exposed
    61 / 435 (14.02%)
    68 / 867 (7.84%)
    7 / 432 (1.62%)
         occurrences all number
    72
    81
    9
    Blood alkaline phosphatase increased
         subjects affected / exposed
    31 / 435 (7.13%)
    32 / 867 (3.69%)
    1 / 432 (0.23%)
         occurrences all number
    35
    36
    1
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    22 / 435 (5.06%)
    23 / 867 (2.65%)
    1 / 432 (0.23%)
         occurrences all number
    26
    27
    1
    Vascular disorders
    Lymphoedema
         subjects affected / exposed
    34 / 435 (7.82%)
    58 / 867 (6.69%)
    24 / 432 (5.56%)
         occurrences all number
    37
    65
    28
    Hypertension
         subjects affected / exposed
    49 / 435 (11.26%)
    85 / 867 (9.80%)
    36 / 432 (8.33%)
         occurrences all number
    57
    95
    38
    Nervous system disorders
    Headache
         subjects affected / exposed
    170 / 435 (39.08%)
    272 / 867 (31.37%)
    102 / 432 (23.61%)
         occurrences all number
    317
    494
    177
    Dizziness
         subjects affected / exposed
    34 / 435 (7.82%)
    67 / 867 (7.73%)
    33 / 432 (7.64%)
         occurrences all number
    45
    86
    41
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    34 / 435 (7.82%)
    38 / 867 (4.38%)
    4 / 432 (0.93%)
         occurrences all number
    53
    59
    6
    General disorders and administration site conditions
    Influenza like illness
         subjects affected / exposed
    66 / 435 (15.17%)
    95 / 867 (10.96%)
    29 / 432 (6.71%)
         occurrences all number
    113
    150
    37
    Oedema peripheral
         subjects affected / exposed
    58 / 435 (13.33%)
    77 / 867 (8.88%)
    19 / 432 (4.40%)
         occurrences all number
    76
    100
    24
    Pyrexia
         subjects affected / exposed
    248 / 435 (57.01%)
    293 / 867 (33.79%)
    45 / 432 (10.42%)
         occurrences all number
    852
    914
    62
    Fatigue
         subjects affected / exposed
    204 / 435 (46.90%)
    326 / 867 (37.60%)
    122 / 432 (28.24%)
         occurrences all number
    298
    457
    159
    Chills
         subjects affected / exposed
    158 / 435 (36.32%)
    177 / 867 (20.42%)
    19 / 432 (4.40%)
         occurrences all number
    384
    406
    22
    Asthenia
         subjects affected / exposed
    58 / 435 (13.33%)
    100 / 867 (11.53%)
    42 / 432 (9.72%)
         occurrences all number
    74
    120
    46
    Eye disorders
    Dry eye
         subjects affected / exposed
    22 / 435 (5.06%)
    35 / 867 (4.04%)
    13 / 432 (3.01%)
         occurrences all number
    23
    38
    15
    Vision blurred
         subjects affected / exposed
    27 / 435 (6.21%)
    43 / 867 (4.96%)
    16 / 432 (3.70%)
         occurrences all number
    30
    47
    17
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    143 / 435 (32.87%)
    208 / 867 (23.99%)
    65 / 432 (15.05%)
         occurrences all number
    206
    310
    104
    Constipation
         subjects affected / exposed
    51 / 435 (11.72%)
    78 / 867 (9.00%)
    27 / 432 (6.25%)
         occurrences all number
    59
    92
    33
    Abdominal pain upper
         subjects affected / exposed
    31 / 435 (7.13%)
    58 / 867 (6.69%)
    27 / 432 (6.25%)
         occurrences all number
    37
    75
    38
    Abdominal pain
         subjects affected / exposed
    33 / 435 (7.59%)
    56 / 867 (6.46%)
    23 / 432 (5.32%)
         occurrences all number
    45
    73
    28
    Vomiting
         subjects affected / exposed
    120 / 435 (27.59%)
    163 / 867 (18.80%)
    43 / 432 (9.95%)
         occurrences all number
    208
    267
    59
    Nausea
         subjects affected / exposed
    173 / 435 (39.77%)
    261 / 867 (30.10%)
    88 / 432 (20.37%)
         occurrences all number
    284
    413
    129
    Dyspepsia
         subjects affected / exposed
    23 / 435 (5.29%)
    49 / 867 (5.65%)
    26 / 432 (6.02%)
         occurrences all number
    25
    68
    43
    Dry mouth
         subjects affected / exposed
    41 / 435 (9.43%)
    56 / 867 (6.46%)
    15 / 432 (3.47%)
         occurrences all number
    52
    71
    19
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    73 / 435 (16.78%)
    106 / 867 (12.23%)
    33 / 432 (7.64%)
         occurrences all number
    82
    121
    39
    Dyspnoea
         subjects affected / exposed
    30 / 435 (6.90%)
    47 / 867 (5.42%)
    17 / 432 (3.94%)
         occurrences all number
    32
    51
    19
    Epistaxis
         subjects affected / exposed
    41 / 435 (9.43%)
    43 / 867 (4.96%)
    2 / 432 (0.46%)
         occurrences all number
    71
    74
    3
    Oropharyngeal pain
         subjects affected / exposed
    39 / 435 (8.97%)
    54 / 867 (6.23%)
    15 / 432 (3.47%)
         occurrences all number
    52
    68
    16
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    24 / 435 (5.52%)
    42 / 867 (4.84%)
    18 / 432 (4.17%)
         occurrences all number
    26
    45
    19
    Dermatitis acneiform
         subjects affected / exposed
    54 / 435 (12.41%)
    64 / 867 (7.38%)
    10 / 432 (2.31%)
         occurrences all number
    75
    86
    11
    Dry skin
         subjects affected / exposed
    55 / 435 (12.64%)
    87 / 867 (10.03%)
    32 / 432 (7.41%)
         occurrences all number
    67
    99
    32
    Erythema
         subjects affected / exposed
    53 / 435 (12.18%)
    68 / 867 (7.84%)
    15 / 432 (3.47%)
         occurrences all number
    63
    78
    15
    Hyperhidrosis
         subjects affected / exposed
    30 / 435 (6.90%)
    37 / 867 (4.27%)
    7 / 432 (1.62%)
         occurrences all number
    58
    65
    7
    Night sweats
         subjects affected / exposed
    23 / 435 (5.29%)
    34 / 867 (3.92%)
    11 / 432 (2.55%)
         occurrences all number
    29
    42
    13
    Rash maculo-papular
         subjects affected / exposed
    31 / 435 (7.13%)
    42 / 867 (4.84%)
    11 / 432 (2.55%)
         occurrences all number
    35
    48
    13
    Rash
         subjects affected / exposed
    112 / 435 (25.75%)
    166 / 867 (19.15%)
    54 / 432 (12.50%)
         occurrences all number
    175
    241
    66
    Pruritus
         subjects affected / exposed
    47 / 435 (10.80%)
    92 / 867 (10.61%)
    45 / 432 (10.42%)
         occurrences all number
    61
    120
    59
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    24 / 435 (5.52%)
    30 / 867 (3.46%)
    6 / 432 (1.39%)
         occurrences all number
    27
    33
    6
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    70 / 435 (16.09%)
    110 / 867 (12.69%)
    40 / 432 (9.26%)
         occurrences all number
    100
    145
    45
    Muscle spasms
         subjects affected / exposed
    40 / 435 (9.20%)
    53 / 867 (6.11%)
    13 / 432 (3.01%)
         occurrences all number
    55
    71
    16
    Back pain
         subjects affected / exposed
    38 / 435 (8.74%)
    72 / 867 (8.30%)
    34 / 432 (7.87%)
         occurrences all number
    45
    109
    64
    Arthralgia
         subjects affected / exposed
    122 / 435 (28.05%)
    190 / 867 (21.91%)
    68 / 432 (15.74%)
         occurrences all number
    194
    284
    90
    Pain in extremity
         subjects affected / exposed
    60 / 435 (13.79%)
    98 / 867 (11.30%)
    38 / 432 (8.80%)
         occurrences all number
    93
    140
    47
    Infections and infestations
    Folliculitis
         subjects affected / exposed
    24 / 435 (5.52%)
    33 / 867 (3.81%)
    9 / 432 (2.08%)
         occurrences all number
    27
    39
    12
    Nasopharyngitis
         subjects affected / exposed
    41 / 435 (9.43%)
    89 / 867 (10.27%)
    48 / 432 (11.11%)
         occurrences all number
    54
    117
    63
    Urinary tract infection
         subjects affected / exposed
    26 / 435 (5.98%)
    34 / 867 (3.92%)
    8 / 432 (1.85%)
         occurrences all number
    41
    50
    9
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    47 / 435 (10.80%)
    72 / 867 (8.30%)
    25 / 432 (5.79%)
         occurrences all number
    56
    83
    27

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Oct 2012
    Amendment 1: • Updated RFS and OS analysis and study completion definitions; • Deleted the formal interim efficacy analysis; • Added details of randomization capping and interim analysis for OS at the time of the RFS analysis; • Updated male contraception requirements to align with current standard for dabrafenib and trametinib; • Revised Dose Modification Guidelines for Pyrexia, Visual Changes, and LVEF; • Added table showing statistical power scenario for OS analysis; • Minor changes for clarification and consistency throughout the protocol
    12 Nov 2012
    Amendment 2: • Country specific amendment for France to include tables for the management and dose modification for hypertension and renal insufficiency in response to a request from the French regulatory agency
    13 Dec 2012
    Amendment 3: • Added CT/MRI assessment at Month 21; • Included 80% power calculation for OS; • Provided the rationale for use of the Pike estimator of the treatment hazard ratio; • Updated male and female contraception requirements
    17 Jan 2013
    Amendment 4: • Country specific amendment for Sweden to include Risk/Benefit Assessment in Section 1 at the request of the Swedish regulatory agency
    24 Oct 2013
    Amendment 5: • Clarifications and updates to eligibility criteria; • Deleted exclusion for glucose-6-phosphate dehydrogenase (G6PD) deficiency; • Clarified follow-up assessments required for subjects that discontinue treatment prior to Month 12 without evidence of disease recurrence; • Updated dosing instructions; • Updated dose modification guidelines for visual changes; • Updated guidance for symptomatic decreased LVEF; • Updated guidelines for QTc prolongation; • Updated prohibited and cautionary medications; • Clarifications and updates to the Time and Events tables; • Clarified imaging requirements for efficacy assessments; • Added collection of new malignancy information; • Added Appendix 15 to address request by French Regulatory Authority for additional monitoring following discontinuation of dabrafenib (applied only to subjects enrolled in France)
    05 Oct 2016
    Amendment 6: • Deleted or replaced references to GSK or its staff with that of Novartis/Novartis and its authorized agents and administrative changes to align with Novartis processes and procedures
    31 May 2017
    Amendment 7: • Updated Sponsor contact information; • Added language to state the primary analysis of RFS can be performed using a data cut-off at approximately 2.5 years after Last patient First Dose. Updated data-cut-off date for final RFS analysis and provided related updated statistical assumptions; • Clarified that the primary analysis for RFS was the first interim analysis for Overall Survival and added a second interim analysis for survival after approximately 299 events
    21 Dec 2018
    Amendment 8: • Updated the Final OS analysis to occur after 50% of OS events rather than at 70% and addressed statistical considerations in the relevant sections; • Statistical assumptions updated for Statistical Power Scenarios for Overall Survival (Additional analyses added for 5-year and study completion RFS rates / Additional descriptive analysis added for post-recurrence antineoplastic treatment); • Updates made to the Time and events Schedule to reduce the number of assessments for both pre-and post-recurrence after patients have been on study for more than 60 months
    05 Nov 2021
    Amendment 9: • Ceased central imaging collection; • Disruption proof language has been added in the event of a public health emergency how the site should proceed if the subject could not attend study visits at site; • Clarification provided, PK samples for ocular events were no longer required for subjects that discontinued study treatment; • Updates made in Prompt reporting of SAEs and other events for Novartis section based on feedback from the Federal Institute for Drugs and Medical Devices (BfArM) in Germany to require prompt SAE follow up reporting
    08 Feb 2023
    Amendment 10: • Updated the Final OS analysis to occur when approximately 260 events occurred (or by the end of Jul-2023, whichever comes first); • All remaining alpha was spent for this final OS analysis by taking into account alpha spent at the first interim analysis; • Updated number of OS events and updated the percentage (%) of statistical power for 255, 260 and 299 events. Additional text regarding statistical power added

    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.
    Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com for complete trial results.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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