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    Clinical Trial Results:
    A phase II, open-label, multicenter study of Dabrafenib plus Trametinib in subjects with BRAF Mutation- positive melanoma that has metastasized to the brain. 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/CtrdWeb/home.novfor complete trial results.

    Summary
    EudraCT number
    		 2013-003452-21
    Trial protocol
    		 ES   DE   IT  
    Global end of trial date
    14 Feb 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Feb 2019
    First version publication date
    15 Feb 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    117277
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02039947
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharmaceutical
    Sponsor organisation address
    CH-4002, Basel, Swaziland,
    Public contact
    Clinical Disclosure Office, Novartis Pharmaceutical, 41 613241111,
    Scientific contact
    Clinical Disclosure Office, Novartis Pharmaceutical, 41 613241111,
    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
    14 Feb 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Feb 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the intracranial response (IR) of subjects with locally confirmed BRAF V600E cutaneous melanoma with metastases to the brain confirmed by MRI, asymptomatic, without prior local therapy and ECOG score of 0 or 1 (cohort A). IR was defined as the proportion of subjects with a confirmed intracranial complete response (CR) or partial response (PR) by investigator assessment using modified RECIST 1.1 guidelines
    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
    21 Feb 2014
    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
    Australia: 5
    Country: Number of subjects enrolled
    Canada: 11
    Country: Number of subjects enrolled
    France: 55
    Country: Number of subjects enrolled
    Germany: 6
    Country: Number of subjects enrolled
    Italy: 14
    Country: Number of subjects enrolled
    Spain: 22
    Country: Number of subjects enrolled
    United States: 12
    Worldwide total number of subjects
    125
    EEA total number of subjects
    97
    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)
    97
    From 65 to 84 years
    28
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A subject was considered to have completed the study if the subject died during the study treatment or follow-up period or (for subject in Cohort A) had at least 3 years follow-up from the date of first dose of study treatment at the end of the study. All subjects achieved that definition and then the study ended.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort A
    Arm description
    		 Subjects will receive dabrafenib 150 milligram (mg) twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dabrafenib Trametinib
    Investigational medicinal product code
    Other name
    Dabrafenib Trametinib
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Dabrafenib- 50 mg and 75 mg capsules Trametinib- 0.5 mg and 2.0 mg tablets

    Investigational medicinal product name
    Dabrafenib Trametinib
    Investigational medicinal product code
    Other name
    Dabrafenib Trametinib
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Dabrafenib- 50 mg and 75 mg capsules Trametinib- 0.5 mg and 2.0 mg tablets

    Arm title
    		 Cohort B
    Arm description
    		 Subjects will receive dabrafenib 150 mg twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dabrafenib Trametinib
    Investigational medicinal product code
    Other name
    Dabrafenib Trametinib
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Dabrafenib- 50 mg and 75 mg capsules Trametinib- 0.5 mg and 2.0 mg tablets

    Arm title
    		 Cohort C
    Arm description
    		 Subjects will receive dabrafenib 150 mg twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dabrafenib Trametinibets
    Investigational medicinal product code
    Other name
    Dabrafenib Trametinibets
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Dabrafenib- 50 mg and 75 mg capsules Trametinib- 0.5 mg and 2.0 mg tablets

    Arm title
    		 Cohort D
    Arm description
    		 Subjects will receive dabrafenib 150 mg twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dabrafenib Trametinib
    Investigational medicinal product code
    Other name
    Dabrafenib Trametinib
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Dabrafenib-50 mg and 75 mg capsules Trametinib-0.5 mg and 2.0 mg tablets

    Number of subjects in period 1
    		Cohort A Cohort B Cohort C Cohort D
    Started
    76
    16
    16
    17
    Completed
    76
    16
    16
    17

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort A
    Reporting group description
    		 Subjects will receive dabrafenib 150 milligram (mg) twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity.

    Reporting group title
    Cohort B
    Reporting group description
    		 Subjects will receive dabrafenib 150 mg twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity

    Reporting group title
    Cohort C
    Reporting group description
    		 Subjects will receive dabrafenib 150 mg twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity

    Reporting group title
    Cohort D
    Reporting group description
    		 Subjects will receive dabrafenib 150 mg twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity

    Reporting group values
    		 Cohort A Cohort B Cohort C Cohort D Total
    Number of subjects
    		 76 16 16 17 125
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0
        Adults (18-64 years)
    		 60 12 9 16 97
        From 65-84 years
    		 16 4 7 1 28
        85 years and over
    		 0 0 0 0 0
    Age Continuous
    Units: Years
        median (standard deviation)
    		 53.2 ± 14.69 55.1 ± 11.05 65.6 ± 10.40 47.5 ± 13.01 -
    Sex: Female, Male
    Units: Subjects
        Female
    		 36 6 5 6 53
        Male
    		 40 10 11 11 72
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0 0
        Asian
    		 0 0 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0
        Black or African American
    		 0 0 0 0 0
        White
    		 76 16 16 17 125
        More than one race
    		 0 0 0 0 0
        Unknown or Not Reported
    		 0 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Cohort A
    Reporting group description
    		 Subjects will receive dabrafenib 150 milligram (mg) twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity.

    Reporting group title
    Cohort B
    Reporting group description
    		 Subjects will receive dabrafenib 150 mg twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity

    Reporting group title
    Cohort C
    Reporting group description
    		 Subjects will receive dabrafenib 150 mg twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity

    Reporting group title
    Cohort D
    Reporting group description
    		 Subjects will receive dabrafenib 150 mg twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity

    Subject analysis set title
    All treated population
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All subjects who receive at least one dose of study medication are comprised the All Treated subjects (ATS) population.

    Primary: Intracranial response (IR) rate

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    End point title
    		 Intracranial response (IR) rate [1] [2]
    End point description
    The intracranial response rate is defined as the percentage of subjects achieving a confirmed intracranial CR or PR. This is based on investigator-assessed best intracranial response.
    End point type
    Primary
    End point timeframe
    From the start of treatment until disease progression or the start of new anti-cancer therapy
    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: “because only Cohort A is considered for primary efficacy analysis”
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No hypothesis testing completed for cohort B,C and D
    End point values
    		 Cohort A
    Number of subjects analysed
    76
    Units: Number of participants
    45
    No statistical analyses for this end point

    Secondary: Intracranial response rate of cohorts B, C and D

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    End point title
    		 Intracranial response rate of cohorts B, C and D [3]
    End point description
    The intracranial response rate is defined as the percentage of subjects achieving a confirmed intracranial CR or PR. This is based on investigator-assessed best intracranial response. No hypothesis testing completed for cohort B,C and D
    End point type
    Secondary
    End point timeframe
    Approximately 2 years
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No hypothesis testing completed for cohort B,C and D
    End point values
    		 Cohort B Cohort C Cohort D
    Number of subjects analysed
    16
    16
    17
    Units: Number of participants
    9
    7
    10
    No statistical analyses for this end point

    Secondary: Disease Control for intracranial, extracranial and overall response for each cohort

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    End point title
    		 Disease Control for intracranial, extracranial and overall response for each cohort
    End point description
    Disease Control rate is defined as the percentage of subjects achieving a confirmed intracranial/extracranial/overall CR or PR or SD or Non-CR/Non-PD. This is based on investigator-assessed response. No hypothesis testing completed for cohort B,C and D
    End point type
    Secondary
    End point timeframe
    Approximately 2 years
    End point values
    		 Cohort A Cohort B Cohort C Cohort D
    Number of subjects analysed
    76
    16
    16
    17
    Units: Number of participants
        Intracranial Response
    59
    14
    12
    15
        Extracranial Response
    60
    11
    15
    11
        Overall Response
    60
    14
    12
    15
    No statistical analyses for this end point

    Secondary: Extracranial response rate (ER) for each cohort

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    End point title
    		 Extracranial response rate (ER) for each cohort
    End point description
    Disease Control rate is defined as the percentage of subjects achieving a confirmed intracranial/extracranial/overall CR or PR or SD or Non-CR/Non-PD. This is based on investigator-assessed response. No hypothesis testing completed for cohort B,C and D
    End point type
    Secondary
    End point timeframe
    Approximately 2 years
    End point values
    		 Cohort A Cohort B Cohort C Cohort D
    Number of subjects analysed
    76
    16
    16
    17
    Units: Number of participants
    42
    7
    12
    7
    No statistical analyses for this end point

    Secondary: Overall response (OR) for each cohort

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    End point title
    		 Overall response (OR) for each cohort
    End point description
    Disease Control rate is defined as the percentage of subjects achieving a confirmed intracranial/extracranial/overall CR or PR or SD or Non-CR/Non-PD. This is based on investigator-assessed response. No hypothesis testing completed for cohort B,C and D
    End point type
    Secondary
    End point timeframe
    Approximately 2 years
    End point values
    		 Cohort A Cohort B Cohort C Cohort D
    Number of subjects analysed
    76
    16
    16
    17
    Units: Number of participants
    45
    9
    7
    11
    No statistical analyses for this end point

    Secondary: Duration of intracranial, extracranial and overall response for each cohort

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    End point title
    		 Duration of intracranial, extracranial and overall response for each cohort
    End point description
    Duration of intracranial, extracranial and overall response, are defined as the time from first documented evidence of CR or PR until time of first documented intracranial, extracranial, or overall disease progression. No hypothesis testing completed for cohort B,C and D
    End point type
    Secondary
    End point timeframe
    From first documented evidence of CR or PR until time of first documented intracranial, extracranial, or overall disease progression
    End point values
    		 Cohort A Cohort B Cohort C Cohort D
    Number of subjects analysed
    76
    16
    16
    17
    Units: Month
    median (confidence interval 95%)
        Duration of intracranial
    6.5 (4.9 to 8.6)
    7.3 (3.6 to 12.6)
    8.3 (1.3 to 15.0)
    4.5 (2.8 to 5.9)
        Duration of extracranial
    10.2 (5.8 to 9999)
    9999 (9999 to 9999)
    4.9 (3.0 to 22.4)
    5.9 (1.8 to 9999)
        Duration of Overall Response
    6.2 (4.9 to 8.3)
    12.5 (5.3 to 9999)
    6.6 (1.3 to 16.3)
    4.5 (2.8 to 11.2)
    No statistical analyses for this end point

    Secondary: Progression-free survival (PFS) for each cohort Based on investigator assessment

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    End point title
    		 Progression-free survival (PFS) for each cohort Based on investigator assessment
    End point description
    PFS is defined as the interval between first dose and the earliest date of disease progression or death due to any cause. No hypothesis testing completed for cohort B,C and D
    End point type
    Secondary
    End point timeframe
    From the first dose to the earliest date of disease progression or death
    End point values
    		 Cohort A Cohort B Cohort C Cohort D
    Number of subjects analysed
    76
    16
    16
    17
    Units: Month
        median (confidence interval 95%)
    5.7 (5.3 to 7.3)
    7.2 (4.7 to 14.6)
    3.7 (1.7 to 6.5)
    5.5 (3.7 to 11.6)
    No statistical analyses for this end point

    Secondary: Overall survival (OS) for each cohort

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    End point title
    		 Overall survival (OS) for each cohort
    End point description
    Overall survival (OS) is defined as the time from the first dose until death due to any cause. No hypothesis testing completed for cohort B,C and D
    End point type
    Secondary
    End point timeframe
    From the first dose to death
    End point values
    		 Cohort A Cohort B Cohort C Cohort D
    Number of subjects analysed
    76
    16
    16
    17
    Units: Month
        median (confidence interval 95%)
    10.8 (8.7 to 17.9)
    24.3 (7.9 to 9999)
    10.1 (4.6 to 17.6)
    11.5 (6.8 to 22.4)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All adverse events reported in this record are from date of First Patient First Treatment until Last Patient Last Visit
    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
    19.0
    Reporting groups
    Reporting group title
    Cohort A
    Reporting group description
    		 Cohort A

    Reporting group title
    Cohort B
    Reporting group description
    		 Cohort B

    Reporting group title
    Cohort C
    Reporting group description
    		 Cohort C

    Reporting group title
    Cohort D
    Reporting group description
    		 Cohort D

    Reporting group title
    Total
    Reporting group description
    		 Total

    Serious adverse events
    		 Cohort A Cohort B Cohort C Cohort D Total
    Total subjects affected by serious adverse events
         subjects affected / exposed
    26 / 76 (34.21%)
    5 / 16 (31.25%)
    4 / 16 (25.00%)
    9 / 17 (52.94%)
    44 / 125 (35.20%)
         number of deaths (all causes)
    54
    10
    15
    13
    92
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Intracranial tumour haemorrhage
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    2 / 125 (1.60%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pelvic venous thrombosis
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    1 / 17 (5.88%)
    2 / 125 (1.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    2 / 125 (1.60%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    4 / 76 (5.26%)
    1 / 16 (6.25%)
    2 / 16 (12.50%)
    2 / 17 (11.76%)
    9 / 125 (7.20%)
         occurrences causally related to treatment / all
    5 / 5
    1 / 1
    2 / 2
    2 / 2
    9 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    2 / 125 (1.60%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Ejection fraction decreased
         subjects affected / exposed
    2 / 76 (2.63%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    2 / 17 (11.76%)
    5 / 125 (4.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    1 / 1
    2 / 2
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Troponin T increased
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    2 / 76 (2.63%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    2 / 125 (1.60%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocarditis
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tachyarrhythmia
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    2 / 125 (1.60%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    2 / 76 (2.63%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    2 / 125 (1.60%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    2 / 76 (2.63%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    3 / 125 (2.40%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 0
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 76 (2.63%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    2 / 125 (1.60%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Detachment of retinal pigment epithelium
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Macular detachment
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vision blurred
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    2 / 125 (1.60%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Lumbar spinal stenosis
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Erysipelas
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia infection
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia pneumococcal
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    2 / 125 (1.60%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cohort A Cohort B Cohort C Cohort D Total
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    74 / 76 (97.37%)
    16 / 16 (100.00%)
    16 / 16 (100.00%)
    17 / 17 (100.00%)
    123 / 125 (98.40%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 16 (6.25%)
    2 / 16 (12.50%)
    0 / 17 (0.00%)
    3 / 125 (2.40%)
         occurrences all number
    0
    1
    2
    0
    1
    Lipoma
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    2 / 125 (1.60%)
         occurrences all number
    2
    0
    1
    0
    3
    Papilloma
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    1 / 125 (0.80%)
         occurrences all number
    0
    0
    0
    1
    0
    Seborrhoeic keratosis
         subjects affected / exposed
    1 / 76 (1.32%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    3 / 125 (2.40%)
         occurrences all number
    1
    1
    1
    0
    3
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    1 / 125 (0.80%)
         occurrences all number
    0
    0
    0
    1
    1
    Flushing
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 16 (0.00%)
    2 / 16 (12.50%)
    0 / 17 (0.00%)
    3 / 125 (2.40%)
         occurrences all number
    1
    0
    2
    0
    1
    Hot flush
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    2 / 125 (1.60%)
         occurrences all number
    0
    1
    0
    1
    2
    Hypertension
         subjects affected / exposed
    6 / 76 (7.89%)
    3 / 16 (18.75%)
    3 / 16 (18.75%)
    0 / 17 (0.00%)
    12 / 125 (9.60%)
         occurrences all number
    6
    3
    4
    0
    14
    Hypotension
         subjects affected / exposed
    1 / 76 (1.32%)
    2 / 16 (12.50%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    4 / 125 (3.20%)
         occurrences all number
    1
    2
    0
    3
    4
    Lymphoedema
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    2 / 125 (1.60%)
         occurrences all number
    0
    1
    0
    1
    2
    Peripheral venous disease
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences all number
    0
    0
    1
    0
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    28 / 76 (36.84%)
    5 / 16 (31.25%)
    3 / 16 (18.75%)
    5 / 17 (29.41%)
    41 / 125 (32.80%)
         occurrences all number
    33
    6
    5
    7
    58
    Chest pain
         subjects affected / exposed
    3 / 76 (3.95%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    4 / 125 (3.20%)
         occurrences all number
    5
    0
    1
    0
    4
    Chills
         subjects affected / exposed
    18 / 76 (23.68%)
    6 / 16 (37.50%)
    7 / 16 (43.75%)
    6 / 17 (35.29%)
    37 / 125 (29.60%)
         occurrences all number
    33
    13
    8
    10
    52
    Face oedema
         subjects affected / exposed
    2 / 76 (2.63%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    3 / 125 (2.40%)
         occurrences all number
    2
    0
    0
    1
    2
    Fatigue
         subjects affected / exposed
    7 / 76 (9.21%)
    4 / 16 (25.00%)
    8 / 16 (50.00%)
    3 / 17 (17.65%)
    22 / 125 (17.60%)
         occurrences all number
    7
    5
    9
    4
    26
    Gait disturbance
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences all number
    0
    0
    1
    0
    1
    General physical health deterioration
         subjects affected / exposed
    2 / 76 (2.63%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    3 / 125 (2.40%)
         occurrences all number
    2
    1
    0
    0
    3
    Ill-defined disorder
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences all number
    0
    0
    1
    0
    1
    Influenza like illness
         subjects affected / exposed
    5 / 76 (6.58%)
    2 / 16 (12.50%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    8 / 125 (6.40%)
         occurrences all number
    5
    3
    1
    0
    9
    Mucosal inflammation
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences all number
    0
    0
    1
    0
    1
    Oedema peripheral
         subjects affected / exposed
    11 / 76 (14.47%)
    2 / 16 (12.50%)
    2 / 16 (12.50%)
    3 / 17 (17.65%)
    18 / 125 (14.40%)
         occurrences all number
    14
    2
    4
    3
    23
    Pain
         subjects affected / exposed
    2 / 76 (2.63%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    4 / 125 (3.20%)
         occurrences all number
    2
    1
    0
    1
    4
    Pyrexia
         subjects affected / exposed
    45 / 76 (59.21%)
    7 / 16 (43.75%)
    8 / 16 (50.00%)
    8 / 17 (47.06%)
    68 / 125 (54.40%)
         occurrences all number
    133
    13
    19
    30
    161
    Temperature regulation disorder
         subjects affected / exposed
    1 / 76 (1.32%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    2 / 125 (1.60%)
         occurrences all number
    2
    1
    0
    0
    3
    Thirst
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences all number
    0
    0
    1
    0
    1
    Xerosis
         subjects affected / exposed
    3 / 76 (3.95%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    4 / 125 (3.20%)
         occurrences all number
    4
    0
    0
    1
    5
    Reproductive system and breast disorders
    Metrorrhagia
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    2 / 125 (1.60%)
         occurrences all number
    1
    0
    0
    2
    2
    Prostatomegaly
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences all number
    0
    1
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences all number
    0
    0
    1
    0
    1
    Cough
         subjects affected / exposed
    10 / 76 (13.16%)
    2 / 16 (12.50%)
    1 / 16 (6.25%)
    3 / 17 (17.65%)
    16 / 125 (12.80%)
         occurrences all number
    12
    2
    1
    3
    18
    Dry throat
         subjects affected / exposed
    1 / 76 (1.32%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    2 / 125 (1.60%)
         occurrences all number
    1
    1
    0
    0
    2
    Dyspnoea
         subjects affected / exposed
    5 / 76 (6.58%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    6 / 125 (4.80%)
         occurrences all number
    5
    0
    0
    1
    6
    Epistaxis
         subjects affected / exposed
    2 / 76 (2.63%)
    3 / 16 (18.75%)
    1 / 16 (6.25%)
    2 / 17 (11.76%)
    8 / 125 (6.40%)
         occurrences all number
    3
    3
    1
    2
    7
    Nasal congestion
         subjects affected / exposed
    2 / 76 (2.63%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    3 / 125 (2.40%)
         occurrences all number
    2
    0
    0
    1
    3
    Productive cough
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    1 / 17 (5.88%)
    3 / 125 (2.40%)
         occurrences all number
    1
    0
    1
    1
    3
    Wheezing
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences all number
    0
    0
    1
    0
    1
    Rhinitis allergic
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    2 / 125 (1.60%)
         occurrences all number
    1
    0
    0
    1
    2
    Psychiatric disorders
    Affective disorder
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences all number
    0
    0
    1
    0
    1
    Agitation
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    1 / 125 (0.80%)
         occurrences all number
    0
    0
    0
    1
    1
    Anxiety
         subjects affected / exposed
    2 / 76 (2.63%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    4 / 125 (3.20%)
         occurrences all number
    2
    1
    0
    1
    4
    Apathy
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences all number
    0
    1
    0
    0
    1
    Confusional state
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    1 / 17 (5.88%)
    3 / 125 (2.40%)
         occurrences all number
    1
    0
    1
    2
    4
    Delirium
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences all number
    0
    1
    0
    0
    1
    Insomnia
         subjects affected / exposed
    6 / 76 (7.89%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    2 / 17 (11.76%)
    8 / 125 (6.40%)
         occurrences all number
    6
    0
    0
    2
    7
    Depression
         subjects affected / exposed
    2 / 76 (2.63%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    3 / 125 (2.40%)
         occurrences all number
    2
    1
    0
    0
    3
    Sleep disorder
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    1 / 125 (0.80%)
         occurrences all number
    0
    0
    0
    1
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    9 / 76 (11.84%)
    2 / 16 (12.50%)
    1 / 16 (6.25%)
    3 / 17 (17.65%)
    15 / 125 (12.00%)
         occurrences all number
    9
    7
    1
    3
    20
    Amylase increased
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    1 / 125 (0.80%)
         occurrences all number
    0
    0
    0
    1
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    12 / 76 (15.79%)
    3 / 16 (18.75%)
    2 / 16 (12.50%)
    3 / 17 (17.65%)
    20 / 125 (16.00%)
         occurrences all number
    13
    3
    2
    3
    21
    Blood alkaline phosphatase increased
         subjects affected / exposed
    6 / 76 (7.89%)
    1 / 16 (6.25%)
    2 / 16 (12.50%)
    3 / 17 (17.65%)
    12 / 125 (9.60%)
         occurrences all number
    6
    1
    2
    3
    12
    Blood cholesterol increased
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    1 / 125 (0.80%)
         occurrences all number
    0
    0
    0
    2
    2
    Blood creatine phosphokinase increased
         subjects affected / exposed
    7 / 76 (9.21%)
    3 / 16 (18.75%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    10 / 125 (8.00%)
         occurrences all number
    11
    4
    0
    0
    17
    Blood creatinine increased
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    2 / 125 (1.60%)
         occurrences all number
    1
    0
    0
    1
    2
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    6 / 76 (7.89%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    8 / 125 (6.40%)
         occurrences all number
    6
    1
    1
    0
    8
    Blood phosphorus decreased
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences all number
    0
    1
    0
    0
    1
    Blood potassium decreased
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    1 / 125 (0.80%)
         occurrences all number
    0
    0
    0
    1
    1
    Blood pressure increased
         subjects affected / exposed
    1 / 76 (1.32%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    2 / 125 (1.60%)
         occurrences all number
    1
    1
    0
    0
    0
    Blood sodium increased
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    1 / 125 (0.80%)
         occurrences all number
    0
    0
    0
    1
    1
    C-reactive protein increased
         subjects affected / exposed
    4 / 76 (5.26%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    5 / 125 (4.00%)
         occurrences all number
    4
    1
    0
    0
    6
    Ejection fraction decreased
         subjects affected / exposed
    4 / 76 (5.26%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 17 (5.88%)
    7 / 125 (5.60%)
         occurrences all number
    6
    1
    1
    1
    9
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences all number
    0
    0
    1
    0
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    7 / 76 (9.21%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    4 / 17 (23.53%)
    13 / 125 (10.40%)
         occurrences all number
    7
    1
    1
    4
    17
    Lipase increased
         subjects affected / exposed
    3 / 76 (3.95%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    4 / 125 (3.20%)
         occurrences all number
    5
    0
    0
    1
    6
    Neutrophil count decreased
         subjects affected / exposed
    4 / 76 (5.26%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    1 / 17 (5.88%)
    6 / 125 (4.80%)
         occurrences all number
    6
    0
    1
    1
    8
    Neutrophil count increased
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences all number
    0
    1
    0
    0
    1
    Platelet count decreased
         subjects affected / exposed
    2 / 76 (2.63%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    3 / 125 (2.40%)
         occurrences all number
    2
    0
    1
    0
    3
    Weight decreased
         subjects affected / exposed
    4 / 76 (5.26%)
    2 / 16 (12.50%)
    3 / 16 (18.75%)
    3 / 17 (17.65%)
    12 / 125 (9.60%)
         occurrences all number
    4
    2
    4
    3
    13
    Weight increased
         subjects affected / exposed
    4 / 76 (5.26%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    2 / 17 (11.76%)
    6 / 125 (4.80%)
         occurrences all number
    4
    0
    0
    2
    6
    White blood cell count decreased
         subjects affected / exposed
    2 / 76 (2.63%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    3 / 125 (2.40%)
         occurrences all number
    2
    0
    1
    0
    3
    Injury, poisoning and procedural complications
    Animal bite
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences all number
    0
    1
    0
    0
    1
    Contusion
         subjects affected / exposed
    1 / 76 (1.32%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    2 / 125 (1.60%)
         occurrences all number
    1
    1
    0
    0
    2
    Fall
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    2 / 125 (1.60%)
         occurrences all number
    1
    0
    1
    0
    0
    Ligament sprain
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    2 / 125 (1.60%)
         occurrences all number
    0
    1
    0
    1
    2
    Muscle strain
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    2 / 125 (1.60%)
         occurrences all number
    1
    0
    1
    0
    2
    Procedural pain
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences all number
    0
    1
    0
    0
    0
    Cardiac disorders
    Cyanosis
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences all number
    0
    0
    1
    0
    1
    Nervous system disorders
    Amnesia
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    1 / 17 (5.88%)
    2 / 125 (1.60%)
         occurrences all number
    0
    0
    1
    1
    2
    Aphasia
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    3 / 17 (17.65%)
    4 / 125 (3.20%)
         occurrences all number
    1
    0
    0
    3
    4
    Aphonia
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences all number
    0
    1
    0
    0
    1
    Cerebellar syndrome
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences all number
    0
    1
    0
    0
    1
    Dizziness
         subjects affected / exposed
    5 / 76 (6.58%)
    5 / 16 (31.25%)
    0 / 16 (0.00%)
    3 / 17 (17.65%)
    13 / 125 (10.40%)
         occurrences all number
    7
    7
    0
    3
    14
    Dysarthria
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    2 / 125 (1.60%)
         occurrences all number
    1
    0
    0
    1
    2
    Dysgeusia
         subjects affected / exposed
    2 / 76 (2.63%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    4 / 125 (3.20%)
         occurrences all number
    2
    1
    1
    0
    4
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    2 / 125 (1.60%)
         occurrences all number
    1
    0
    1
    0
    2
    Headache
         subjects affected / exposed
    28 / 76 (36.84%)
    5 / 16 (31.25%)
    6 / 16 (37.50%)
    8 / 17 (47.06%)
    47 / 125 (37.60%)
         occurrences all number
    47
    9
    9
    13
    70
    Hemianopia
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences all number
    0
    1
    0
    0
    1
    Motor dysfunction
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    1 / 125 (0.80%)
         occurrences all number
    0
    0
    0
    1
    1
    Neuropathy peripheral
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences all number
    0
    0
    1
    0
    1
    Paraesthesia
         subjects affected / exposed
    5 / 76 (6.58%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    2 / 17 (11.76%)
    8 / 125 (6.40%)
         occurrences all number
    5
    1
    0
    2
    8
    Paresis
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    1 / 125 (0.80%)
         occurrences all number
    0
    0
    0
    1
    1
    Partial seizures
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    2 / 17 (11.76%)
    2 / 125 (1.60%)
         occurrences all number
    0
    0
    0
    2
    1
    Peripheral motor neuropathy
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences all number
    0
    0
    1
    0
    1
    Presyncope
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    2 / 125 (1.60%)
         occurrences all number
    1
    0
    1
    0
    1
    Restless legs syndrome
         subjects affected / exposed
    0 / 76 (0.00%)
    2 / 16 (12.50%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    2 / 125 (1.60%)
         occurrences all number
    0
    2
    0
    0
    2
    Seizure
         subjects affected / exposed
    2 / 76 (2.63%)
    1 / 16 (6.25%)
    3 / 16 (18.75%)
    3 / 17 (17.65%)
    9 / 125 (7.20%)
         occurrences all number
    4
    1
    3
    3
    6
    Syncope
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    2 / 125 (1.60%)
         occurrences all number
    0
    1
    1
    0
    0
    Temporal lobe epilepsy
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    1 / 125 (0.80%)
         occurrences all number
    0
    0
    0
    1
    1
    Tongue paralysis
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences all number
    0
    1
    0
    0
    1
    Tonic clonic movements
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    1 / 125 (0.80%)
         occurrences all number
    0
    0
    0
    1
    1
    Tremor
         subjects affected / exposed
    3 / 76 (3.95%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    4 / 125 (3.20%)
         occurrences all number
    3
    0
    2
    0
    5
    Visual field defect
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    1 / 125 (0.80%)
         occurrences all number
    0
    0
    0
    1
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 76 (5.26%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    2 / 17 (11.76%)
    6 / 125 (4.80%)
         occurrences all number
    4
    0
    0
    2
    10
    Lymphopenia
         subjects affected / exposed
    4 / 76 (5.26%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    4 / 125 (3.20%)
         occurrences all number
    4
    0
    0
    0
    4
    Neutropenia
         subjects affected / exposed
    11 / 76 (14.47%)
    2 / 16 (12.50%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    14 / 125 (11.20%)
         occurrences all number
    12
    2
    1
    0
    18
    Thrombocytopenia
         subjects affected / exposed
    4 / 76 (5.26%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    2 / 17 (11.76%)
    7 / 125 (5.60%)
         occurrences all number
    4
    0
    1
    2
    7
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 76 (0.00%)
    2 / 16 (12.50%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    2 / 125 (1.60%)
         occurrences all number
    0
    3
    0
    0
    3
    Hypoacusis
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    2 / 125 (1.60%)
         occurrences all number
    1
    0
    1
    0
    2
    Vertigo
         subjects affected / exposed
    3 / 76 (3.95%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    4 / 125 (3.20%)
         occurrences all number
    3
    0
    1
    0
    3
    Eye disorders
    Asthenopia
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences all number
    0
    0
    1
    0
    1
    Cataract
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences all number
    0
    1
    0
    0
    1
    Conjunctival irritation
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    1 / 125 (0.80%)
         occurrences all number
    0
    0
    0
    1
    1
    Diplopia
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    1 / 17 (5.88%)
    3 / 125 (2.40%)
         occurrences all number
    1
    0
    1
    1
    3
    Dry eye
         subjects affected / exposed
    2 / 76 (2.63%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    3 / 125 (2.40%)
         occurrences all number
    2
    0
    0
    1
    3
    Eye pain
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences all number
    0
    0
    1
    0
    1
    Eye pruritus
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    1 / 125 (0.80%)
         occurrences all number
    0
    0
    0
    2
    2
    Eyelid oedema
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    2 / 17 (11.76%)
    3 / 125 (2.40%)
         occurrences all number
    0
    1
    0
    3
    4
    Lacrimation increased
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    2 / 125 (1.60%)
         occurrences all number
    1
    0
    1
    0
    2
    Posterior capsule opacification
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences all number
    0
    0
    1
    0
    1
    Punctate keratitis
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    1 / 125 (0.80%)
         occurrences all number
    0
    0
    0
    1
    1
    Retinopathy
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences all number
    0
    0
    1
    0
    1
    Vision blurred
         subjects affected / exposed
    3 / 76 (3.95%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 17 (5.88%)
    6 / 125 (4.80%)
         occurrences all number
    3
    1
    1
    1
    5
    Visual acuity reduced
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    1 / 125 (0.80%)
         occurrences all number
    0
    0
    0
    1
    1
    Visual impairment
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    2 / 17 (11.76%)
    3 / 125 (2.40%)
         occurrences all number
    1
    0
    0
    2
    2
    Vitreous detachment
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    1 / 125 (0.80%)
         occurrences all number
    0
    0
    0
    1
    1
    Vitreous floaters
         subjects affected / exposed
    3 / 76 (3.95%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    4 / 125 (3.20%)
         occurrences all number
    3
    1
    0
    0
    4
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences all number
    0
    1
    0
    0
    1
    Abdominal pain
         subjects affected / exposed
    8 / 76 (10.53%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    5 / 17 (29.41%)
    14 / 125 (11.20%)
         occurrences all number
    11
    1
    0
    8
    18
    Abdominal pain lower
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    1 / 125 (0.80%)
         occurrences all number
    0
    0
    0
    1
    1
    Abdominal pain upper
         subjects affected / exposed
    5 / 76 (6.58%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    7 / 125 (5.60%)
         occurrences all number
    6
    1
    0
    4
    10
    Constipation
         subjects affected / exposed
    8 / 76 (10.53%)
    1 / 16 (6.25%)
    4 / 16 (25.00%)
    6 / 17 (35.29%)
    19 / 125 (15.20%)
         occurrences all number
    9
    1
    4
    9
    23
    Diarrhoea
         subjects affected / exposed
    24 / 76 (31.58%)
    8 / 16 (50.00%)
    3 / 16 (18.75%)
    7 / 17 (41.18%)
    42 / 125 (33.60%)
         occurrences all number
    30
    15
    4
    11
    54
    Dry mouth
         subjects affected / exposed
    5 / 76 (6.58%)
    2 / 16 (12.50%)
    1 / 16 (6.25%)
    3 / 17 (17.65%)
    11 / 125 (8.80%)
         occurrences all number
    5
    2
    1
    3
    12
    Dyspepsia
         subjects affected / exposed
    5 / 76 (6.58%)
    2 / 16 (12.50%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    8 / 125 (6.40%)
         occurrences all number
    5
    2
    1
    0
    8
    Faecalith
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences all number
    0
    0
    1
    0
    1
    Faeces soft
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    1 / 125 (0.80%)
         occurrences all number
    0
    0
    0
    1
    1
    Gastrointestinal disorder
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    1 / 125 (0.80%)
         occurrences all number
    0
    0
    0
    1
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 76 (1.32%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    3 / 125 (2.40%)
         occurrences all number
    1
    1
    0
    1
    3
    Gingival bleeding
         subjects affected / exposed
    1 / 76 (1.32%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    3 / 125 (2.40%)
         occurrences all number
    1
    1
    1
    0
    3
    Nausea
         subjects affected / exposed
    24 / 76 (31.58%)
    7 / 16 (43.75%)
    4 / 16 (25.00%)
    6 / 17 (35.29%)
    41 / 125 (32.80%)
         occurrences all number
    42
    9
    5
    9
    49
    Rectal haemorrhage
         subjects affected / exposed
    2 / 76 (2.63%)
    2 / 16 (12.50%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    4 / 125 (3.20%)
         occurrences all number
    2
    4
    0
    0
    5
    Retching
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences all number
    0
    0
    1
    0
    0
    Stomatitis
         subjects affected / exposed
    3 / 76 (3.95%)
    1 / 16 (6.25%)
    2 / 16 (12.50%)
    0 / 17 (0.00%)
    6 / 125 (4.80%)
         occurrences all number
    3
    1
    3
    0
    7
    Tongue discolouration
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences all number
    0
    1
    0
    0
    1
    Vomiting
         subjects affected / exposed
    24 / 76 (31.58%)
    2 / 16 (12.50%)
    2 / 16 (12.50%)
    6 / 17 (35.29%)
    34 / 125 (27.20%)
         occurrences all number
    32
    3
    2
    10
    32
    Hepatobiliary disorders
    Hepatocellular injury
         subjects affected / exposed
    2 / 76 (2.63%)
    2 / 16 (12.50%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    4 / 125 (3.20%)
         occurrences all number
    3
    2
    0
    0
    6
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    5 / 76 (6.58%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    6 / 125 (4.80%)
         occurrences all number
    5
    0
    1
    0
    6
    Actinic elastosis
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences all number
    0
    1
    0
    0
    1
    Actinic keratosis
         subjects affected / exposed
    0 / 76 (0.00%)
    2 / 16 (12.50%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    3 / 125 (2.40%)
         occurrences all number
    0
    3
    1
    0
    2
    Alopecia
         subjects affected / exposed
    7 / 76 (9.21%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    2 / 17 (11.76%)
    10 / 125 (8.00%)
         occurrences all number
    7
    0
    1
    2
    10
    Aquagenic wrinkling of palms
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    1 / 125 (0.80%)
         occurrences all number
    0
    0
    0
    1
    1
    Dermatitis acneiform
         subjects affected / exposed
    3 / 76 (3.95%)
    1 / 16 (6.25%)
    3 / 16 (18.75%)
    1 / 17 (5.88%)
    8 / 125 (6.40%)
         occurrences all number
    4
    1
    3
    1
    9
    Dry skin
         subjects affected / exposed
    7 / 76 (9.21%)
    2 / 16 (12.50%)
    3 / 16 (18.75%)
    3 / 17 (17.65%)
    15 / 125 (12.00%)
         occurrences all number
    9
    2
    3
    4
    17
    Ecchymosis
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences all number
    0
    0
    1
    0
    1
    Eczema
         subjects affected / exposed
    2 / 76 (2.63%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    3 / 125 (2.40%)
         occurrences all number
    2
    0
    3
    0
    5
    Erythema
         subjects affected / exposed
    5 / 76 (6.58%)
    0 / 16 (0.00%)
    4 / 16 (25.00%)
    1 / 17 (5.88%)
    10 / 125 (8.00%)
         occurrences all number
    7
    0
    5
    2
    14
    Erythema multiforme
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences all number
    0
    0
    1
    0
    1
    Generalised erythema
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    1 / 17 (5.88%)
    2 / 125 (1.60%)
         occurrences all number
    0
    0
    1
    1
    2
    Hyperhidrosis
         subjects affected / exposed
    4 / 76 (5.26%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    1 / 17 (5.88%)
    6 / 125 (4.80%)
         occurrences all number
    4
    0
    1
    1
    6
    Hyperkeratosis
         subjects affected / exposed
    7 / 76 (9.21%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    8 / 125 (6.40%)
         occurrences all number
    7
    1
    0
    0
    6
    Intertrigo
         subjects affected / exposed
    4 / 76 (5.26%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    5 / 125 (4.00%)
         occurrences all number
    4
    0
    0
    1
    5
    Nail disorder
         subjects affected / exposed
    1 / 76 (1.32%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    2 / 125 (1.60%)
         occurrences all number
    1
    1
    0
    0
    2
    Night sweats
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    2 / 125 (1.60%)
         occurrences all number
    1
    0
    0
    1
    1
    Onycholysis
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    2 / 125 (1.60%)
         occurrences all number
    1
    0
    1
    0
    2
    Pain of skin
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    2 / 125 (1.60%)
         occurrences all number
    1
    0
    0
    1
    2
    Palmar erythema
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences all number
    0
    0
    1
    0
    1
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 16 (0.00%)
    3 / 16 (18.75%)
    0 / 17 (0.00%)
    4 / 125 (3.20%)
         occurrences all number
    1
    0
    3
    0
    4
    Palmoplantar keratoderma
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences all number
    0
    1
    0
    0
    1
    Panniculitis
         subjects affected / exposed
    4 / 76 (5.26%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    4 / 125 (3.20%)
         occurrences all number
    5
    0
    0
    0
    4
    Papule
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    2 / 125 (1.60%)
         occurrences all number
    1
    0
    0
    1
    2
    Pruritus
         subjects affected / exposed
    5 / 76 (6.58%)
    0 / 16 (0.00%)
    2 / 16 (12.50%)
    2 / 17 (11.76%)
    9 / 125 (7.20%)
         occurrences all number
    5
    0
    2
    2
    8
    Pruritus generalised
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    2 / 125 (1.60%)
         occurrences all number
    1
    0
    0
    1
    2
    Rash
         subjects affected / exposed
    9 / 76 (11.84%)
    7 / 16 (43.75%)
    3 / 16 (18.75%)
    3 / 17 (17.65%)
    22 / 125 (17.60%)
         occurrences all number
    10
    8
    3
    4
    26
    Rash erythematous
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences all number
    0
    0
    1
    0
    1
    Rash generalised
         subjects affected / exposed
    5 / 76 (6.58%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    5 / 125 (4.00%)
         occurrences all number
    5
    0
    0
    0
    5
    Rash maculo-papular
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    2 / 125 (1.60%)
         occurrences all number
    0
    1
    1
    0
    2
    Seborrhoeic dermatitis
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences all number
    0
    0
    1
    0
    1
    Skin exfoliation
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    1 / 125 (0.80%)
         occurrences all number
    0
    0
    0
    1
    1
    Skin fissures
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences all number
    0
    0
    1
    0
    1
    Skin hyperplasia
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences all number
    0
    0
    1
    0
    1
    Skin lesion
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    1 / 17 (5.88%)
    3 / 125 (2.40%)
         occurrences all number
    1
    0
    1
    2
    4
    Skin mass
         subjects affected / exposed
    1 / 76 (1.32%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    2 / 125 (1.60%)
         occurrences all number
    1
    1
    0
    0
    2
    Skin striae
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    1 / 125 (0.80%)
         occurrences all number
    0
    0
    0
    1
    1
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    2 / 76 (2.63%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    3 / 125 (2.40%)
         occurrences all number
    2
    0
    1
    0
    3
    Nocturia
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    2 / 125 (1.60%)
         occurrences all number
    1
    0
    1
    0
    2
    Pollakiuria
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    2 / 125 (1.60%)
         occurrences all number
    0
    1
    1
    0
    2
    Urinary incontinence
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences all number
    0
    0
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    15 / 76 (19.74%)
    3 / 16 (18.75%)
    2 / 16 (12.50%)
    6 / 17 (35.29%)
    26 / 125 (20.80%)
         occurrences all number
    22
    5
    2
    11
    39
    Back pain
         subjects affected / exposed
    11 / 76 (14.47%)
    1 / 16 (6.25%)
    3 / 16 (18.75%)
    2 / 17 (11.76%)
    17 / 125 (13.60%)
         occurrences all number
    11
    1
    3
    3
    15
    Bone pain
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences all number
    0
    0
    1
    0
    1
    Flank pain
         subjects affected / exposed
    2 / 76 (2.63%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    3 / 125 (2.40%)
         occurrences all number
    2
    0
    1
    0
    1
    Joint range of motion decreased
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    1 / 125 (0.80%)
         occurrences all number
    0
    0
    0
    1
    1
    Muscle spasms
         subjects affected / exposed
    7 / 76 (9.21%)
    0 / 16 (0.00%)
    4 / 16 (25.00%)
    1 / 17 (5.88%)
    12 / 125 (9.60%)
         occurrences all number
    9
    0
    4
    1
    13
    Muscular weakness
         subjects affected / exposed
    3 / 76 (3.95%)
    1 / 16 (6.25%)
    2 / 16 (12.50%)
    3 / 17 (17.65%)
    9 / 125 (7.20%)
         occurrences all number
    5
    1
    2
    5
    12
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 76 (1.32%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    3 / 125 (2.40%)
         occurrences all number
    1
    1
    0
    1
    3
    Musculoskeletal pain
         subjects affected / exposed
    4 / 76 (5.26%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    5 / 125 (4.00%)
         occurrences all number
    4
    0
    0
    1
    5
    Musculoskeletal stiffness
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences all number
    0
    1
    0
    0
    1
    Myalgia
         subjects affected / exposed
    13 / 76 (17.11%)
    5 / 16 (31.25%)
    2 / 16 (12.50%)
    6 / 17 (35.29%)
    26 / 125 (20.80%)
         occurrences all number
    17
    10
    3
    7
    39
    Neck pain
         subjects affected / exposed
    3 / 76 (3.95%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    1 / 17 (5.88%)
    5 / 125 (4.00%)
         occurrences all number
    3
    0
    1
    1
    5
    Osteoarthritis
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences all number
    0
    0
    1
    0
    1
    Pain in extremity
         subjects affected / exposed
    8 / 76 (10.53%)
    3 / 16 (18.75%)
    3 / 16 (18.75%)
    2 / 17 (11.76%)
    16 / 125 (12.80%)
         occurrences all number
    13
    3
    5
    2
    23
    Rhabdomyolysis
         subjects affected / exposed
    1 / 76 (1.32%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    2 / 125 (1.60%)
         occurrences all number
    1
    1
    0
    0
    2
    Synovial cyst
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences all number
    0
    1
    0
    0
    1
    Tendonitis
         subjects affected / exposed
    2 / 76 (2.63%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    3 / 125 (2.40%)
         occurrences all number
    2
    0
    0
    1
    3
    Infections and infestations
    Angular cheilitis
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences all number
    0
    1
    0
    0
    1
    Bronchitis
         subjects affected / exposed
    4 / 76 (5.26%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    5 / 125 (4.00%)
         occurrences all number
    4
    0
    0
    2
    6
    Cellulitis
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    1 / 125 (0.80%)
         occurrences all number
    0
    0
    0
    1
    1
    Folliculitis
         subjects affected / exposed
    4 / 76 (5.26%)
    2 / 16 (12.50%)
    0 / 16 (0.00%)
    4 / 17 (23.53%)
    10 / 125 (8.00%)
         occurrences all number
    4
    2
    0
    4
    10
    Fungal skin infection
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences all number
    0
    1
    0
    0
    1
    Herpes zoster
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    2 / 125 (1.60%)
         occurrences all number
    1
    0
    0
    1
    2
    Influenza
         subjects affected / exposed
    7 / 76 (9.21%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    7 / 125 (5.60%)
         occurrences all number
    8
    0
    0
    0
    8
    Laryngitis
         subjects affected / exposed
    1 / 76 (1.32%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    2 / 125 (1.60%)
         occurrences all number
    1
    1
    0
    0
    2
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences all number
    0
    0
    1
    0
    0
    Lung infection
         subjects affected / exposed
    2 / 76 (2.63%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    3 / 125 (2.40%)
         occurrences all number
    2
    0
    0
    1
    3
    Nasopharyngitis
         subjects affected / exposed
    7 / 76 (9.21%)
    2 / 16 (12.50%)
    2 / 16 (12.50%)
    0 / 17 (0.00%)
    11 / 125 (8.80%)
         occurrences all number
    7
    3
    2
    0
    11
    Onychomycosis
         subjects affected / exposed
    2 / 76 (2.63%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    1 / 17 (5.88%)
    4 / 125 (3.20%)
         occurrences all number
    2
    0
    1
    1
    4
    Oral candidiasis
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    2 / 125 (1.60%)
         occurrences all number
    1
    0
    1
    0
    2
    Oral herpes
         subjects affected / exposed
    3 / 76 (3.95%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    4 / 125 (3.20%)
         occurrences all number
    3
    3
    0
    0
    6
    Paronychia
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    2 / 125 (1.60%)
         occurrences all number
    2
    0
    1
    0
    3
    Pharyngitis streptococcal
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences all number
    0
    2
    0
    0
    2
    Pneumonia
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences all number
    0
    0
    1
    0
    1
    Postoperative wound infection
         subjects affected / exposed
    1 / 76 (1.32%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    2 / 125 (1.60%)
         occurrences all number
    1
    1
    0
    0
    2
    Pulpitis dental
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences all number
    0
    1
    0
    0
    1
    Rash pustular
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    2 / 125 (1.60%)
         occurrences all number
    1
    0
    0
    1
    2
    Respiratory tract infection
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    2 / 125 (1.60%)
         occurrences all number
    1
    0
    0
    1
    2
    Rhinitis
         subjects affected / exposed
    4 / 76 (5.26%)
    0 / 16 (0.00%)
    2 / 16 (12.50%)
    0 / 17 (0.00%)
    6 / 125 (4.80%)
         occurrences all number
    4
    0
    2
    0
    6
    Sialoadenitis
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences all number
    0
    1
    0
    0
    1
    Skin infection
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
    1 / 125 (0.80%)
         occurrences all number
    0
    0
    0
    1
    1
    Tonsillitis
         subjects affected / exposed
    2 / 76 (2.63%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    3 / 125 (2.40%)
         occurrences all number
    2
    1
    0
    0
    2
    Tooth infection
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences all number
    0
    1
    0
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 76 (1.32%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
    2 / 125 (1.60%)
         occurrences all number
    1
    1
    0
    0
    2
    Urinary tract infection
         subjects affected / exposed
    3 / 76 (3.95%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    2 / 17 (11.76%)
    6 / 125 (4.80%)
         occurrences all number
    3
    0
    1
    2
    6
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    9 / 76 (11.84%)
    4 / 16 (25.00%)
    7 / 16 (43.75%)
    3 / 17 (17.65%)
    23 / 125 (18.40%)
         occurrences all number
    10
    5
    7
    3
    28
    Dehydration
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    1 / 17 (5.88%)
    2 / 125 (1.60%)
         occurrences all number
    0
    0
    1
    1
    2
    Diabetes mellitus
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences all number
    0
    0
    1
    0
    1
    Gout
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    1 / 125 (0.80%)
         occurrences all number
    0
    0
    1
    0
    1
    Hyperglycaemia
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
    2 / 125 (1.60%)
         occurrences all number
    1
    0
    1
    0
    2
    Hypocalcaemia
         subjects affected / exposed
    3 / 76 (3.95%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    2 / 17 (11.76%)
    5 / 125 (4.00%)
         occurrences all number
    3
    0
    0
    2
    5
    Hypokalaemia
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    2 / 17 (11.76%)
    3 / 125 (2.40%)
         occurrences all number
    0
    1
    0
    4
    5
    Hypomagnesaemia
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    1 / 17 (5.88%)
    3 / 125 (2.40%)
         occurrences all number
    1
    0
    1
    1
    3
    Hyponatraemia
         subjects affected / exposed
    2 / 76 (2.63%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 17 (5.88%)
    5 / 125 (4.00%)
         occurrences all number
    2
    1
    1
    2
    6
    Hypophosphataemia
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    2 / 17 (11.76%)
    2 / 125 (1.60%)
         occurrences all number
    0
    0
    0
    2
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Apr 2014
    ● Survival follow-up period has been extended in order to collect additional long-term overall survival data. ● Addition of secondary objective of long-term (particularly 5-year) OS. ● Additional information available: Dabrafenib, another small molecule BRAF- inhibitor received FDA-approval in May 2013 and EMA approval in August 2013. ● Reference to abstaining to any food or drink containing grapefruit and grapefruit juice, Seville oranges, or pomelos was removed. ● Additional information available: In Jan-2014 the combination of dabrafenib and trametinib received FDA approval, and in February 2014 the combination received approval in Australia.
    20 Aug 2014
    A country-specific amendment as requested by the French regulatory agency
    16 Mar 2015
    ●Study design revised for clarity around treatment discontinuation and follow up of subjects. ● Exclusion HIV removed per March 2014 updates to Inc/Exc (combination). ● Permanent discontinuation from study treatment revised for clarity around treatment discontinuation and follow up of subjects. ● Dosage and administration section revised based on combination dosage and administration March 2014
    06 Dec 2015
    ● Study Objectives: 1. Primary endpoint amended to allow for locally confirmed BRAF V600E (followed by central confirmation as with all other cohorts) and 2. Secondary endpoint number 9 OS changed from 5 to 3 year. ● Cohort A subject population updated to allow for locally confirmed BRAF V600E (followed by central confirmation as with all other cohorts). And definition of study closure updated from “where all subjects still in follow up have had at least 5 years follow up…” to “where all subjects still in follow up have had at least 3 years follow up…” ● Discussion of Design – primary efficacy objective endpoint amended to allow for locally confirmed BRAF V600E (followed by central confirmation as with all other cohorts)
    13 Jul 2016
    ●Delete or replace references to GSK or its staff with that of Novartis/Novartis and its authorized agents. ● Make administrative changes to align with Novartis processes and procedures
    16 May 2017
    Amendment 6 did not incorporate amendment 5, as it was only for submission in countries that had not submitted GSK to Novartis sponsorship change ● Study design section amended to define study close as when 70% of Cohort A subjects are lost to follow up or completed or when all Cohort A subjects have been followed up for 3 years, whichever is earlier. ● Section 10.5 – Study closure definition amended from 70% of all enrolled study population to 70% of primary efficacy population (Cohort A) and addition of at least three years follow up for all Cohort A subjects Estimation
    21 Jun 2017
    Amendment 7 did incorporate amendment 5, as it was for submission in countries that had already submitted GSK to Novartis sponsorship change ● Study design section amended to define study close as when 70% of Cohort A subjects are lost to follow up or completed or when all Cohort A subjects have been followed up for 3 years, whichever is earlier. ● Section 10.5 – Study closure definition amended from 70% of all enrolled study population to 70% of primary efficacy population (Cohort A) and addition of at least three years follow up for all Cohort A subjects. Estimation of study length amended to approximately 5 years from study start

    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/CtrdWeb/home.novfor 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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