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    Clinical Trial Results:
    A Phase II, open-label study to assess the safety and efficacy of oral MEK162 in adults with locally advanced and unresectable or metastatic malignant cutaneous melanoma, harboring BRAFV600 or NRAS mutations

    Summary
    EudraCT number
    		 2010-023412-13
    Trial protocol
    		 NL   DE   IT  
    Global end of trial date
    06 Feb 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Feb 2024
    First version publication date
    07 Feb 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CMEK162X2201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01320085
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 CMEK162X2201: Other Study ID
    Sponsors
    Sponsor organisation name
    Pfizer Inc.
    Sponsor organisation address
    235 E 42nd Street, New York, United States, NY 10017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    30 May 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Feb 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To estimate the objective response rates (ORRs) of MEK162 when administered orally as 45 milligram (mg) twice daily (BID), to adult subjects with advanced, unresectable cutaneous malignant melanoma, i)harboring BRAFV600 or ii) harboring NRAS mutations and iii) when administered orally as 60 mg BID, to adult subjects with advanced, unresectable cutaneous malignant melanoma, harboring BRAFV600 mutations.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Council for Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trials subjects were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    24 Mar 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Switzerland: 20
    Country: Number of subjects enrolled
    Germany: 53
    Country: Number of subjects enrolled
    Italy: 46
    Country: Number of subjects enrolled
    Netherlands: 40
    Country: Number of subjects enrolled
    United States: 24
    Worldwide total number of subjects
    183
    EEA total number of subjects
    139
    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)
    120
    From 65 to 84 years
    63
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 This study included only those subjects for whom the presence of a v-raf murine sarcoma viral oncogene homolog B1 (BRAFV600) or Neuroblastoma RAS viral oncogene homolog (NRAS) gene mutation in the tumor tissue was determined.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Binimetinib 45 mg BRAF
    Arm description
    		 Subjects with BRAF mutations received an oral dose of 45 milligrams (mg) of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Subjects were followed up to 30 days after last dose of study drug.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Binimetinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral dose of 45 mg binimetinib twice daily

    Arm title
    		 Binimetinib 45 mg NRAS
    Arm description
    		 Subjects with NRAS mutations received an oral dose of 45 mg of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Subjects were followed up to 30 days after last dose of study drug.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Binimetinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral dose of 45 mg binimetinib twice daily

    Arm title
    		 Binimetinib 60 mg BRAF
    Arm description
    		 Subjects with BRAF mutations received an oral dose of 60 mg of binimetinib (4 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Subjects were followed up to 30 days after last dose of study drug.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Binimetinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral dose of 60 mg binimetinib twice daily

    Number of subjects in period 1
    		Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF
    Started
    41
    117
    25
    Completed
    0
    0
    0
    Not completed
    41
    117
    25
         Consent withdrawn by subject
    2
    4
    1
         Adverse events
    12
    20
    5
         Protocol Deviation
    1
    -
    1
         Administrative problems
    -
    -
    1
         Disease Progression
    26
    93
    17

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Binimetinib 45 mg BRAF
    Reporting group description
    		 Subjects with BRAF mutations received an oral dose of 45 milligrams (mg) of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Subjects were followed up to 30 days after last dose of study drug.

    Reporting group title
    Binimetinib 45 mg NRAS
    Reporting group description
    		 Subjects with NRAS mutations received an oral dose of 45 mg of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Subjects were followed up to 30 days after last dose of study drug.

    Reporting group title
    Binimetinib 60 mg BRAF
    Reporting group description
    		 Subjects with BRAF mutations received an oral dose of 60 mg of binimetinib (4 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Subjects were followed up to 30 days after last dose of study drug.

    Reporting group values
    		 Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF Total
    Number of subjects
    		 41 117 25 183
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 30 67 23 120
        From 65-84 years
    		 11 50 2 63
        85 years and over
    		 0 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 53.7 ( 14.59 ) 59.6 ( 13.74 ) 51.3 ( 9.81 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 19 33 17 69
        Male
    		 22 84 8 114
    Race/Ethnicity, Customized
    Units: Subjects
        Caucasian
    		 41 117 25 183
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 0 10 0 10
        Other
    		 41 107 25 173

    End points

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    End points reporting groups
    Reporting group title
    Binimetinib 45 mg BRAF
    Reporting group description
    		 Subjects with BRAF mutations received an oral dose of 45 milligrams (mg) of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Subjects were followed up to 30 days after last dose of study drug.

    Reporting group title
    Binimetinib 45 mg NRAS
    Reporting group description
    		 Subjects with NRAS mutations received an oral dose of 45 mg of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Subjects were followed up to 30 days after last dose of study drug.

    Reporting group title
    Binimetinib 60 mg BRAF
    Reporting group description
    		 Subjects with BRAF mutations received an oral dose of 60 mg of binimetinib (4 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by participant refusal or investigator's decision whichever occurred first. Subjects were followed up to 30 days after last dose of study drug.

    Primary: Percentage of Subjects With Objective Response (OR)

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    End point title
    		 Percentage of Subjects With Objective Response (OR) [1]
    End point description
    Objective response as assessed by the investigator per Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.0, was defined as subjects with a best overall response of complete response (CR) or partial response (PR), were recorded from date of randomization or date of start of treatment until date of first documentation of progressive disease (PD) or death due to any cause. CR was defined as complete disappearance of all target and non-target lesions, and sustained for at least 4 weeks apart before progression. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (<) 10 millimeter (mm). PR defined as at least 30 percent (%) decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. The full analysis set included all subjects who received at least one dose of study drug.
    End point type
    Primary
    End point timeframe
    From date of start of treatment until date of first documentation of PD or death due to any cause, whichever occurred first (maximum duration of up to 33 months).
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive analysis was planned for this endpoint.
    End point values
    		 Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF
    Number of subjects analysed
    41
    117
    25
    Units: Percentage of subjects
        number (confidence interval 95%)
    4.9 (0.6 to 16.5)
    14.5 (8.7 to 22.2)
    12.0 (2.5 to 31.2)
    No statistical analyses for this end point

    Secondary: Progression-Free Survival (PFS)

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    End point title
    		 Progression-Free Survival (PFS)
    End point description
    PFS as assessed by investigator per RECIST v1.0, was defined as time (in months) from the date of start of treatment to first documentation of PD or date of death due to any cause or data censoring date, whichever occurred first. PD for target disease=at least a 20% increase in sum of longest diameters of all measured target lesions, taking as reference smallest sum on study (including baseline sum if it was smallest on study),sum also demonstrated absolute increase of greater than or equal to (>=) 5 millimeter (mm),or appearance of >=1 new lesions. For non-target disease:PD = unequivocal progression of pre-existing lesions and if overall tumor burden increased sufficiently to merit discontinuation of therapy; appearance of any new unequivocal malignant lesion was also considered PD. If a subject did not have an event, data censoring was done at date of last adequate tumor assessment. Analysis: Kaplan-Meier method. Full analysis set was used.
    End point type
    Secondary
    End point timeframe
    From date of start of treatment until date of first documentation of PD or date of death due to any cause or date of data censoring, whichever occurred first (maximum duration of up to 33 months)
    End point values
    		 Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF
    Number of subjects analysed
    41
    117
    25
    Units: months
        median (confidence interval 95%)
    3.5 (1.9 to 3.8)
    3.6 (2.6 to 3.8)
    1.8 (1.5 to 3.7)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    Overall survival was defined as the time (in months) from the date of start of treatment to the date of death due to any cause or data censoring date, whichever occurred first. Subjects last known to be alive were censored at date of last contact. Analysis was performed using Kaplan-Meier method. Here 99999 indicates data could not be estimated due to less number of subjects with event. The full analysis set included all subjects who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    From date of start of treatment to date of death due to any cause or date of censoring, whichever occurred first (maximum duration of up to 33 months)
    End point values
    		 Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF
    Number of subjects analysed
    41
    117
    25
    Units: months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    16.6 (4.9 to 99999)
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR)

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    End point title
    		 Duration of Response (DOR)
    End point description
    DOR:time from first documentation of OR(confirmed CR/PR) to first documentation of PD/death due to any cause/data censoring date,whichever occurred first.RECIST v1.0,CR:disappearance of all target(T),Non-T lesions sustained=>4 weeks.Any pathological lymph nodes(T/non-T) reduced in short axis to <10mm. PR:>=30% decrease in sum of diameters(SOD) of T lesions,taking reference baseline SOD.PD (T lesions):at least 20% increase SOD, taking as reference smallest sum on study treatment, with absolute increase of >=5 mm/appearance of >=1 new lesions. PD (Non-T lesions)unequivocal progression of pre-existing lesions/increase in overall tumor burden leading to discontinuation of therapy/appearance of new unequivocal malignant lesion. 99999=data not estimated as less number of subjects with event. Full analysis set was evaluated. Number of subjects analyzed=subjects evaluable for endpoint.
    End point type
    Secondary
    End point timeframe
    From first documentation of CR or PR until first documentation of tumor progression or death due to any cause or data censoring date, whichever occurred first (maximum duration of up to 33 months)
    End point values
    		 Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF
    Number of subjects analysed
    2
    17
    3
    Units: months
        median (confidence interval 95%)
    3.6 (3.6 to 3.7)
    4.0 (3.7 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Time to Response (TTR)

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    End point title
    		 Time to Response (TTR)
    End point description
    TTR as assessed by investigator according to RECIST v1.0, was defined as the time (in months) from date of start of treatment until first documented response (CR/PR) or data censoring date, whichever occurred first. CR =complete disappearance of all target and non-T lesions sustained for at least 4 weeks apart before progression. Any pathological lymph nodes (Target/Non-Target) reduced in short axis to <10 mm. PR=at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. Subjects who did not achieve a confirmed PR/CR, were censored at last adequate tumor assessment date when they did not progress (including deaths not due to underlying disease) or at maximum follow-up (from study start to study end date) when subject had an event for progression-free survival. Full analysis set was used. Number of subjects analyzed = subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    From the date of start of treatment to the first documentation of objective response (CR or PR) or data censoring date, whichever occurred first (maximum duration of up to 33 months)
    End point values
    		 Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF
    Number of subjects analysed
    2
    17
    3
    Units: months
        median (confidence interval 95%)
    2.2 (1.8 to 2.5)
    1.9 (1.8 to 3.7)
    1.8 (1.8 to 1.8)
    No statistical analyses for this end point

    Secondary: Number of Subjects With Grade 3 or 4 Treatment-Emergent Adverse Reactions Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.0

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    End point title
    		 Number of Subjects With Grade 3 or 4 Treatment-Emergent Adverse Reactions Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.0
    End point description
    Adverse drug reaction (ADR) was any untoward medical occurrence attributed to study drug in subjects who received study drug. As per NCI-CTCAE v4.0, Grade (G) 1: asymptomatic or mild symptoms, clinical or diagnostic observations only, intervention not indicated; G2: moderate, minimal, local or non-invasive intervention indicated, limiting age-appropriate instrumental activities of daily life (ADL); G3: severe or medically significant but not immediately life-threatening, hospitalization or prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; G4:life-threatening consequence, urgent intervention indicated; G5:death related to study drug. Treatment-emergent ADRs are between first dose of study drug and up to 30 days after last dose of study drug, that were absent before treatment or that worsened relative to pretreatment state. Number of subjects with any G3/4 treatment-emergent ADR were reported in this endpoint. Safety analysis set was used.
    End point type
    Secondary
    End point timeframe
    Baseline up to 30 days after last dose of study drug (for a maximum duration of up to 11 years, approximately)
    End point values
    		 Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF
    Number of subjects analysed
    41
    117
    25
    Units: Subjects
    19
    52
    13
    No statistical analyses for this end point

    Secondary: Number of Subjects With Serious Adverse Reactions

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    End point title
    		 Number of Subjects With Serious Adverse Reactions
    End point description
    A serious ADR was an ADR resulting in any of the following outcomes or deemed significant for any other reason: death; life-threatening experience (immediate risk of dying); initial or prolonged inpatient hospitalization; persistent or significant disability/incapacity; congenital anomaly, important medical event. Safety analysis set included all subjects who had received at least one dose of study drug and had at least one valid post-baseline safety assessment.
    End point type
    Secondary
    End point timeframe
    Baseline up to 30 days after last dose of study drug (for a maximum duration of up to 11 years, approximately)
    End point values
    		 Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF
    Number of subjects analysed
    41
    117
    25
    Units: Subjects
    2
    12
    4
    No statistical analyses for this end point

    Secondary: Number of Subjects With Shift From Baseline in Laboratory Parameter Values Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE) Grade, Version 4.0 (Hematology)

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    End point title
    		 Number of Subjects With Shift From Baseline in Laboratory Parameter Values Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE) Grade, Version 4.0 (Hematology)
    End point description
    Hematology per NCI-CTCAE included, Lymphocyte count decreased(G1:<0.8, G2:<0.8-0.5, G3:<0.5-0.2, G4:<0.2[*10^9/L]); Lymphocyte count increased(G2:>4-20, G3:>20[*10^9/L]); Neutrophil count dec(G1:<1.5, G2:<1.5-1.0, G3:<1.0-0.5, G4:<0.5[*10^9/L]); Activated partial thromboplastin(APT) time prolonged (seconds)-(G1:>1.5*ULN, G2:>1.5-2.5*ULN, G3:>2.5*ULN); Platelet count dec(G1:<75.0, G2:<75.0-50.0, G3:<50.0-25.0, G4:<25.0[*10^9/L]); Fibrinogen dec(G1:<1.0-0.75*LLN, G2:<0.75-0.5*LLN, G3:<0.5-0.25*LLN G4:<0.25*LLN); Anemia(G1:<LLN-100, G2:<100-80, G3:<80 [g/L], G4:Life-threatening, G5:death); Hemoglobin inc(G1:>0-2 g/dL above ULN, G2:>2-4 g/dL above ULN, G3:>4 g/dL above ULN); Prothrombin time (INR) inc(G1:>1-1.5, G2:>1.5-2.5, G3:>2.5[*ULN]); WBC dec(G1:<3.0*10^9/L, G2:<3.0-2.0*10^9/L, G3:<2.0-1.0*10^9/L, G4:<1.0*10^9/L); WBC inc(G3:>100,000/mm3, G4:Clinical manifestations of inc in WBC, G5:death). Here:Baseline=B,Post-Baseline=PB;Segmented and Band(S&B). Safety analysis set was used.
    End point type
    Secondary
    End point timeframe
    Baseline up to 30 days after last dose of study drug (for a maximum duration of up to 11 years, approximately)
    End point values
    		 Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF
    Number of subjects analysed
    41
    117
    25
    Units: Subjects
        Absolute Lymphocytes decreased: G0 B-G0 PB
    28
    63
    10
        Absolute Lymphocytes decreased: G0 B-G1 PB
    1
    8
    1
        Absolute Lymphocytes decreased: G0 B-G2 PB
    1
    7
    0
        Absolute Lymphocytes decreased: G0 B-G3 PB
    0
    0
    1
        Absolute Lymphocytes decreased: G0 B-Missing PB
    1
    0
    1
        Absolute Lymphocytes decreased: G1 B-G0 PB
    2
    6
    3
        Absolute Lymphocytes decreased: G1 B-G1 PB
    3
    12
    3
        Absolute Lymphocytes decreased: G1 B-G2 PB
    1
    4
    1
        Absolute Lymphocytes decreased: G1 B-G3 PB
    1
    0
    0
        Absolute Lymphocytes decreased: G2 B-G0 PB
    1
    4
    0
        Absolute Lymphocytes decreased: G2 B-G1 PB
    2
    2
    0
        Absolute Lymphocytes decreased: G2 B-G2 PB
    0
    4
    4
        Absolute Lymphocytes decreased: G2 B-G3 PB
    0
    3
    1
        Absolute Lymphocytes decreased: G3 B-G2 PB
    0
    2
    0
        Absolute Lymphocytes decreased: G3 B-G3 PB
    0
    1
    0
        Absolute Lymphocytes decreased: Missing B-G0 PB
    0
    1
    0
        Absolute Lymphocytes increased: G0 B to G0 PB
    36
    110
    22
        Absolute Lymphocytes increased: G0 B to G2 PB
    4
    6
    2
        Absolute Lymphocytes increased: G0 B to Missing PB
    1
    0
    1
        Absolute Lymphocytes increased: Missing B to G0 PB
    0
    1
    0
        Absolute Neutrophils (S&B): G0 B to G0 PB
    38
    100
    21
        Absolute Neutrophils (S&B): G0 B to G1 PB
    0
    2
    0
        Absolute Neutrophils (S&B): G0 B to G3 PB
    0
    0
    2
        Absolute Neutrophils (S&B): G0 B to Missing PB
    1
    0
    1
        Absolute Neutrophils (S&B): G1 B to G0 PB
    0
    1
    0
        Absolute Neutrophils (S&B): G1 B to G1 PB
    0
    2
    0
        Absolute Neutrophils (S&B): G1 B to G2 PB
    0
    1
    0
        Absolute Neutrophils (S&B): G1 B to G3 PB
    1
    0
    0
        Absolute Neutrophils (S&B): G2 B to G1 PB
    0
    1
    0
        Absolute Neutrophils (S&B): G2 B to G3 PB
    0
    1
    0
        Absolute Neutrophils (S&B): G3 B to G1 PB
    1
    0
    0
        Absolute Neutrophils (S&B): G3 B to G3 PB
    0
    0
    1
        Absolute Neutrophils (S&B): G4 B to G0 PB
    0
    1
    0
        Absolute Neutrophils (S&B): G missing B to G0 PB
    0
    4
    0
        Absolute Neutrophils (S&B): MissingB to MissingPB
    0
    4
    0
        APT time: G0 B to G0 PB
    31
    96
    19
        APT time: G0 B to G1 PB
    3
    14
    2
        APT time: G0 B to G2 PB
    0
    1
    1
        APT time: G0 B to G3 PB
    1
    0
    0
        APT time: G0 B to Missing PB
    1
    0
    1
        APT time: G1 B to G0 PB
    0
    1
    0
        APT time: G1 B to G1 PB
    1
    3
    1
        APT time: G1 B to G2 PB
    1
    1
    0
        APT time: G2 B to G2 PB
    0
    1
    0
        APT time: Missing B to G0 PB
    2
    0
    1
        APT time: Missing B to Missing PB
    1
    0
    0
        Platelet count (Direct): G0 B to G0 PB
    36
    97
    21
        Platelet count (Direct): G0 B to G1 PB
    2
    14
    3
        Platelet count (Direct): G0 B to G2 PB
    0
    1
    0
        Platelet count (Direct): G0 B to Missing PB
    1
    0
    1
        Platelet count (Direct): G1 B to G0 PB
    1
    0
    0
        Platelet count (Direct): G1 B to G1 PB
    0
    4
    0
        Platelet count (Direct): G1 B to G3 PB
    0
    1
    0
        Platelet count (Direct): Missing B to G0 PB
    1
    0
    0
        Fibrinogen decreased: G0 B to G0 PB
    8
    19
    8
        Fibrinogen decreased: G0 B to G1 PB
    11
    52
    6
        Fibrinogen decreased: G0 B to G2 PB
    10
    32
    7
        Fibrinogen decreased: G0 B to G3 PB
    0
    8
    2
        Fibrinogen decreased: G0 B to G4 PB
    2
    1
    0
        Fibrinogen decreased: G0 B to Missing PB
    1
    0
    1
        Fibrinogen decreased: G2 B to G0 PB
    0
    1
    0
        Fibrinogen decreased: Missing B to G0 PB
    6
    4
    1
        Fibrinogen decreased: Miising B to Missing PB
    3
    0
    0
        Haemoglobin decreased: G0 B to G0 PB
    3
    22
    7
        Haemoglobin decreased: G0 B to G1 PB
    10
    35
    4
        Haemoglobin decreased: G0 B to G2 PB
    1
    4
    1
        Haemoglobin decreased: G0 B to G3 PB
    0
    1
    0
        Haemoglobin decreased: G0 B to Missing PB
    1
    0
    1
        Haemoglobin decreased: G1 B to G0 PB
    0
    4
    1
        Haemoglobin decreased: G1 B to G1 PB
    16
    27
    6
        Haemoglobin decreased: G1 B to G2 PB
    5
    16
    4
        Haemoglobin decreased: G1 B to G3 PB
    0
    3
    1
        Haemoglobin decreased: G2 B to G1 PB
    2
    0
    0
        Haemoglobin decreased: G2 B to G2 PB
    3
    3
    0
        Haemoglobin decreased: G2 B to G3 PB
    0
    2
    0
        Haemoglobin increased: G0 B to G0 PB
    40
    115
    24
        Haemoglobin increased: G0 B to G1 PB
    0
    2
    0
        Haemoglobin increased: G0 B to Missing PB
    1
    0
    1
        Prothrombin time: G0 B to G0 PB
    15
    40
    11
        Prothrombin time: G0 B to G1 PB
    20
    56
    9
        Prothrombin time: G0 B to G2 PB
    0
    2
    1
        Prothrombin time: G0 B to G3 PB
    1
    2
    0
        Prothrombin time: G0 B to Missing PB
    0
    0
    1
        Prothrombin time: G1 B to G1 PB
    0
    5
    0
        Prothrombin time: G1 B to G3 PB
    0
    0
    1
        Prothrombin time: G2 B to G2 PB
    1
    0
    0
        Prothrombin time: G2 B to G3 PB
    0
    1
    0
        Prothrombin time: G3 B to G3 PB
    1
    0
    0
        Prothrombin time: Missing B to G0 PB
    2
    0
    1
        Prothrombin time: Missing B to MissingPB
    1
    11
    1
        WBC (Total) decreased: G0 B to G0 PB
    35
    93
    20
        WBC (Total) decreased: G0 B to G1 PB
    2
    10
    1
        WBC (Total) decreased: G0 B to G2 PB
    0
    1
    0
        WBC (Total) decreased: G0 B to G3 PB
    0
    0
    1
        WBC (Total) decreased: G0 B to Missing PB
    1
    0
    1
        WBC (Total) decreased: G1 B to G0 PB
    2
    4
    0
        WBC (Total) decreased: G1 B to G1 PB
    0
    5
    0
        WBC (Total) decreased: G1 B to G2 PB
    0
    1
    1
        WBC (Total) decreased: G2 B to G1 PB
    1
    2
    0
        WBC (Total) decreased: G2 B to G2 PB
    0
    1
    1
        WBC (Total) increased: G0 B to G0 PB
    40
    117
    24
        WBC (Total) increased: G0 B to Missing PB
    1
    0
    1
    No statistical analyses for this end point

    Secondary: Number of Subjects With Shift From Baseline in Laboratory Parameter Values Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE) Grade, Version 4.0 (Clinical Chemistry)

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    End point title
    		 Number of Subjects With Shift From Baseline in Laboratory Parameter Values Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE) Grade, Version 4.0 (Clinical Chemistry)
    End point description
    Albumin(G1:<30,G2:<30-20,G3:<20[g/L],G4:life-threatening, G5:death[D]);ALP(G1:>2.5,G2:>2.5-5.0,G3:>5.0-20.0,G4:>20.0[*ULN]);Creatine(CT) kinase(G1:>2.5,G2:>2.5-5,G3:>5-10,G4:>10[*ULN]);CT clearance (G1:<LLN-60,G2:59-30,G3:29-15,G3:<15[ml/min/1.73m^2],G5:D);CT(G1:>1.5,G2:>1.5-3.0,G3:>3.0-6.0,G4:>6.0[*ULN]);Hypomagnesemia(G1:<0.5,G2:<0.5-0.4,G3:<0.4-0.3,G4 <0.3[mmol/L],G5:D); Hypermagnesemia(G1:>1.23,G3:>1.23-3.30, G4:>3.30[mmol/L],G5:D);Hypophosphatemia Inorganic Phosphorus;IP(G1:<0.8,G2:<0.8-0.6,G3:<0.6-0.3,G4:<0.3[mmol/L], G5:D);Hypokalemia (G1:<3.0,G2:<3.0, G3:<3.0-2.5,G4:<2.5[mmol/L],G5:D);Hyperkalemia(G1:>5.5,G2:>5.5-6.0,G3:>6.0-7.0, G4:>7.0[mmol/L], G5:D);AST(G1:>3.0,G2:>3.0-5.0,G3:>5.0-20.0,G4:>20.0[*ULN]);ALT(G1:>3.0,G2:>3.0-5.0,G3:>5.0-20.0,G4:>20.0[*ULN]);Hyponatremia(G1:<130,G3:<130-120,G4 <120[mmol/L],G5:D);Hypernatremia (G1:150,G2:>150-155,G3:>155-160,G4:>160[mmol/L],G5:D);High blood bilirubin (G1:>1.5,G2:>1.5-3.0,G3:>3.0-10.0,G4:>10.0[*ULN]).Safety analysis set was used.
    End point type
    Secondary
    End point timeframe
    Baseline up to 30 days after last dose of study drug (for a maximum duration of up to 11 years, approximately)
    End point values
    		 Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF
    Number of subjects analysed
    41
    117
    25
    Units: Subjects
        Albumin: G0 B to G0 PB
    14
    43
    11
        Albumin: G0 B to G1 PB
    13
    41
    4
        Albumin: G0 B to G2 PB
    4
    19
    2
        Albumin: G0 B to G3 PB
    0
    0
    1
        Albumin: G0 B to Missing PB
    1
    0
    1
        Albumin: G1 B to G1 PB
    0
    2
    1
        Albumin: G1 B to G2 PB
    4
    3
    5
        Albumin: G2 B to G0 PB
    1
    0
    0
        Albumin: G2 B to G2 PB
    1
    3
    0
        Albumin: G2 B to G3 PB
    2
    1
    0
        Albumin: Missing B to G0 PB
    0
    3
    0
        Albumin: Missing B to G1 PB
    1
    1
    0
        Albumin: Missing B to G2 PB
    0
    1
    0
        Alkaline phosphatase, serum: G0 B to G0 PB
    0
    44
    0
        Alkaline phosphatase, serum: G0 B to G1 PB
    0
    21
    0
        Alkaline phosphatase, serum: G0 B to G2 PB
    0
    2
    0
        Alkaline phosphatase, serum: G0 B to G3 PB
    0
    1
    0
        Alkaline phosphatase, serum: G1 B to G0 PB
    0
    1
    0
        Alkaline phosphatase, serum: G1 B to G1 PB
    0
    7
    0
        Alkaline phosphatase, serum: G1 B to G2 PB
    0
    3
    0
        Alkaline phosphatase, serum: G1 B to G3 PB
    0
    1
    0
        Alkaline phosphatase, serum: G2 B to G1 PB
    0
    1
    0
        Alkaline phosphatase, serum: G2 B to G2 PB
    0
    1
    0
        Alkaline phosphatase, serum: G3 B to G3 PB
    0
    1
    0
        Alkaline phosphatase, serum: Missing B to G0 PB
    0
    2
    3
        Alkaline phosphatase, serum: Missing B to G1 PB
    0
    1
    1
        Alkaline phosphatase, serum: MissingB to MissingPB
    41
    31
    21
        Creatine Kinase: G0 B to G0 PB
    10
    20
    3
        Creatine Kinase: G0 B to G1 PB
    11
    34
    6
        Creatine Kinase: G0 B to G2 PB
    6
    27
    4
        Creatine Kinase: G0 B to G3 PB
    4
    13
    6
        Creatine Kinase: G0 B to G4 PB
    1
    9
    1
        Creatine Kinase: G0 B to Missing PB
    2
    0
    1
        Creatine Kinase: G1 B to G3 PB
    2
    2
    0
        Creatine Kinase: G1 B to G4 PB
    1
    2
    0
        Creatine Kinase: G2 B to G1 PB
    0
    1
    0
        Creatine Kinase: G2 B to G4 PB
    0
    1
    0
        Creatine Kinase: G3 B to G4 PB
    0
    0
    1
        Creatine Kinase: Missing B to G1 PB
    2
    4
    0
        Creatine Kinase: Missing B to G2 PB
    1
    0
    2
        Creatine Kinase: Missing B to G3 PB
    1
    3
    0
        Creatine Kinase: Missing B to PB Missing
    0
    1
    1
        Creatinine Clearance: G0 B to G0 PB
    22
    57
    16
        Creatinine Clearance: G0 B to G1 PB
    5
    17
    4
        Creatinine Clearance: G0 B to G2 PB
    2
    7
    0
        Creatinine Clearance G0 B to G3 PB
    0
    1
    1
        Creatinine Clearance: G0 B to G4 PB
    0
    1
    0
        Creatinine Clearance G0 B to Missing PB
    1
    0
    1
        Creatinine Clearance: G1 B to G0 PB
    0
    1
    0
        Creatinine Clearance: G1 B to G1 PB
    6
    12
    0
        Creatinine Clearance: G1 B to G2 PB
    1
    7
    2
        Creatinine Clearance: G2 B to G1 PB
    2
    0
    0
        Creatinine Clearance: G2 B to G2 PB
    1
    6
    0
        Creatinine Clearance: G2 B to Missing PB
    1
    0
    0
        Creatinine Clearance: Missing B to Missing PB
    0
    8
    1
        Creatinine: G0 B to G0 PB
    9
    12
    4
        Creatinine: G0 B to G1 PB
    27
    91
    16
        Creatinine: G0 B to G2 PB
    1
    9
    0
        Creatinine: G0 B to G3 PB
    0
    0
    1
        Creatinine: G0 B to Missing PB
    1
    0
    1
        Creatinine: G1 B to G0 PB
    1
    0
    0
        Creatinine: G1 B to G1 PB
    1
    4
    2
        Creatinine: G1 B to G2 PB
    1
    1
    1
        Hypomagnesemia: G0 B to G0 PB
    30
    78
    22
        Hypomagnesemia: G0 B to G1 PB
    4
    21
    2
        Hypomagnesemia: G0 B to G2 PB
    0
    1
    0
        Hypomagnesemia: G0 B to Missing PB
    2
    0
    1
        Hypomagnesemia: G1 B to G0 PB
    0
    1
    0
        Hypomagnesemia: G1 B to G1 PB
    1
    8
    0
        Hypomagnesemia: G1 B to G2 PB
    0
    1
    0
        Hypomagnesemia: Missing B to G0 PB
    3
    5
    0
        Hypomagnesemia: Missing B to G1 PB
    1
    1
    0
        Hypomagnesemia: Missing B to Missing PB
    0
    1
    0
        Hypermagnesemia: G0 B to G0 PB
    35
    108
    22
        Hypermagnesemia: G0 B to G1 PB
    0
    1
    2
        Hypermagnesemia: G0 B to Missing PB
    2
    0
    1
        Hypermagnesemia: G3 B to G0 PB
    0
    1
    0
        Hypermagnesemia: Missing B to G0 PB
    4
    6
    0
        Hypermagnesemia: Missing B to Missing PB
    0
    1
    0
        Hypophosphatemia (IP): G0 B to G0 PB
    36
    79
    20
        Hypophosphatemia (IP): G0 B to G1 PB
    1
    6
    0
        Hypophosphatemia (IP): G0 B to G2 PB
    0
    7
    0
        Hypophosphatemia (IP): G0 B to G3 PB
    0
    4
    1
        Hypophosphatemia (IP): G0 B to Missing PB
    2
    0
    1
        Hypophosphatemia (IP): G1 B to G0 PB
    1
    3
    1
        Hypophosphatemia (IP): G1 B to G2 PB
    0
    1
    0
        Hypophosphatemia (IP): G2 B to G0 PB
    0
    8
    1
        Hypophosphatemia (IP): G2 B to G2 PB
    0
    7
    1
        Hypophosphatemia (IP): G2 B to G3 PB
    0
    1
    0
        Hypophosphatemia (IP): Missing B to G0 PB
    1
    1
    0
        Hypokalemia: G0 B to G0 PB
    33
    93
    18
        Hypokalemia: G0 B to G2 PB
    3
    19
    6
        Hypokalemia: G0 B to G3 PB
    1
    0
    0
        Hypokalemia: G0 B to G4 PB
    1
    0
    0
        Hypokalemia: G0 B to Missing PB
    1
    0
    1
        Hypokalemia: G2 B to G0 PB
    1
    1
    0
        Hypokalemia: G2 B to G2 PB
    0
    3
    0
        Hypokalemia: G2 B to G4 PB
    1
    1
    0
        Hyperkalemia: G0 B to G0 PB
    35
    104
    21
        Hyperkalemia: G0 B to G1 PB
    3
    6
    1
        Hyperkalemia: G0 B to G2 PB
    0
    2
    1
        Hyperkalemia: G0 B to G3 PB
    0
    0
    1
        Hyperkalemia: G0 B to G4 PB
    0
    1
    0
        Hyperkalemia: G0 B to Missing PB
    1
    0
    1
        Hyperkalemia: G1 B to G0 PB
    0
    4
    0
        Hyperkalemia: G1 B to G1 PB
    1
    0
    0
        Hyperkalemia: G2 B to G0 PB
    1
    0
    0
        AST: G0 B to G0 PB
    11
    33
    5
        AST: G0 B to G1 PB
    24
    67
    13
        AST: G0 B to G2 PB
    0
    5
    1
        AST: G0 B to G3 PB
    0
    1
    0
        AST: G0 B to G4 PB
    0
    0
    1
        AST: G0 B to Missing PB
    1
    0
    1
        AST: G1 B to G0 PB
    1
    0
    0
        AST: G1 B to G1 PB
    1
    6
    3
        AST: G1 B to G2 PB
    2
    2
    0
        AST: G1 B to G3 PB
    0
    1
    1
        AST: G2 B to G3 PB
    0
    1
    0
        AST: G3 B to G3 PB
    1
    0
    0
        AST: Missing B to G1 PB
    0
    1
    0
        ALT: G0 B to G0 PB
    20
    58
    15
        ALT: G0 B to G1 PB
    17
    39
    5
        ALT: G0 B to G2 PB
    0
    5
    0
        ALT: G0 B to G3 PB
    0
    1
    0
        ALT: G0 B to G4 PB
    0
    0
    1
        ALT: G0 B to Missing PB
    1
    0
    1
        ALT: G1 B to G0 PB
    0
    1
    0
        ALT: G1 B to G1 PB
    3
    7
    2
        ALT: G1 B to G2 PB
    0
    4
    1
        ALT: G1 B to G3 PB
    0
    1
    0
        ALT: G2 B to G3 PB
    0
    1
    0
        Hyponatremia: G0 B to G0 PB
    25
    92
    17
        Hyponatremia: G0 B to G1 PB
    7
    11
    3
        Hyponatremia: G0 B to G3 PB
    1
    5
    0
        Hyponatremia: G0 B to Missing PB
    1
    0
    1
        Hyponatremia: G1 B to G0 PB
    3
    5
    2
        Hyponatremia: G1 B to G1 PB
    4
    2
    2
        Hyponatremia: G1 B to G3 PB
    0
    1
    0
        Hyponatremia: G3 B to G3 PB
    0
    1
    0
        Hypernatremia: G0 B to G0 PB
    37
    101
    24
        Hypernatremia: G0 B to G1 PB
    2
    14
    0
        Hypernatremia: G0 B to Missing PB
    1
    0
    1
        Hypernatremia: G1 B to G0 PB
    1
    2
    0
        Bilirubin (total) increased: G0 B to G0 PB
    36
    105
    22
        Bilirubin (total) increased: G0 B to G1 PB
    1
    7
    0
        Bilirubin (total) increased: G0 B to G2 PB
    0
    0
    1
        Bilirubin (total) increased: G0 B to G3 PB
    0
    2
    0
        Bilirubin (total) increased: G0 B to G4 PB
    0
    1
    0
        Bilirubin (total) increased: G0 B to Missing PB
    2
    0
    1
        Bilirubin (total) increased: G1 B to G0 PB
    1
    1
    1
        Bilirubin (total) increased: G1 B to G1 PB
    1
    1
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Shift From Baseline in Vital Signs Values Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE) Grade, Version 4.0 (Blood Pressure)

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    End point title
    		 Number of Subjects With Shift From Baseline in Vital Signs Values Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE) Grade, Version 4.0 (Blood Pressure)
    End point description
    Blood pressure included sitting diastolic blood pressure (DBP) and sitting systolic blood pressure (SBP). Safety analysis set included all subjects who had received at least one dose of study drug and had at least one valid post-baseline safety assessment.
    End point type
    Secondary
    End point timeframe
    Baseline up to 30 days after last dose of study drug (up to maximum of 33 months)
    End point values
    		 Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF
    Number of subjects analysed
    41
    117
    25
    Units: Subjects
        Sitting SBP (mm Hg): G0 B to G0 PB
    4
    6
    0
        Sitting SBP (mm Hg): G0 B to G1 PB
    7
    14
    6
        Sitting SBP (mm Hg): G0 B to G2 PB
    1
    8
    0
        Sitting SBP (mm Hg): G0 B to G3 PB
    0
    2
    0
        Sitting SBP (mm Hg): G1 B to G0 PB
    2
    1
    1
        Sitting SBP (mm Hg): G1 B to G1 PB
    10
    29
    6
        Sitting SBP (mm Hg): G1 B to G2 PB
    7
    23
    6
        Sitting SBP (mm Hg): G1 B to G3 PB
    2
    10
    2
        Sitting SBP (mm Hg): G0 B to Missing PB
    1
    0
    1
        Sitting SBP (mm Hg): G2 B to G1 PB
    0
    4
    1
        Sitting SBP (mm Hg): G2 B to G2 PB
    3
    8
    1
        Sitting SBP (mm Hg): G2 B to G3 PB
    2
    5
    0
        Sitting SBP (mm Hg): G2 B to Missing PB
    1
    0
    0
        Sitting SBP (mm Hg): G3 B to G2 PB
    0
    3
    0
        Sitting SBP (mm Hg): G3 B to G3 PB
    1
    4
    1
        Sitting DBP (mm Hg): G0 B to G0 PB
    9
    14
    2
        Sitting DBP (mm Hg): G0 B to G1 PB
    7
    23
    6
        Sitting DBP (mm Hg): G0 B to G2 PB
    5
    8
    4
        Sitting DBP (mm Hg): G0 B to G3 PB
    3
    6
    2
        Sitting DBP (mm Hg): G0 B to Missing PB
    1
    0
    0
        Sitting DBP (mm Hg): G1 B to G0 PB
    1
    1
    0
        Sitting DBP (mm Hg): G1 B to G1 PB
    5
    19
    1
        Sitting DBP (mm Hg): G1 B to G2 PB
    5
    17
    5
        Sitting DBP (mm Hg): G1 B to G3 PB
    1
    10
    2
        Sitting DBP (mm Hg): G1 B to Missing PB
    1
    0
    1
        Sitting DBP (mm Hg): G2 B to G0 PB
    0
    1
    0
        Sitting DBP (mm Hg): G2 B to G1 PB
    0
    3
    0
        Sitting DBP (mm Hg): G2 B to G2 PB
    1
    9
    1
        Sitting DBP (mm Hg): G2 B to G3 PB
    1
    4
    1
        Sitting DBP (mm Hg): G3 B to G2 PB
    0
    1
    0
        Sitting DBP (mm Hg): G3 B to G3 PB
    1
    1
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Markedly Abnormal Vital Sign Values: Sitting Pulse Rate

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    End point title
    		 Number of Subjects With Markedly Abnormal Vital Sign Values: Sitting Pulse Rate
    End point description
    Pre-defined criteria of markedly abnormal vital signs abnormalities was defined as increase or decrease from baseline (>=15 beats per minute) in pulse rate of >=120 beats per minute or less than or equal to (<=) 50 beats per minute. Safety analysis set included all subjects who had received at least one dose of study drug and had at least one valid post-baseline safety assessment. Here “Overall number of subjects analyzed” signifies subjects evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline up to 30 days after last dose of study drug (up to maximum of 33 months)
    End point values
    		 Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF
    Number of subjects analysed
    39
    116
    24
    Units: Subjects
        Sitting pulse (High only) (beats per minute)
    1
    2
    1
        Sitting pulse (Low only) (beats per minute)
    1
    6
    1
        Sitting pulse (High and Low) (beats per minute)
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Markedly Abnormal Vital Sign Values: Weight

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    End point title
    		 Number of Subjects With Markedly Abnormal Vital Sign Values: Weight
    End point description
    Vital signs included assessment of body weight. Body weight (in kilograms) measurements included high and low. Pre-defined criteria of markedly abnormal vital signs abnormalities was defined as increase or decrease from baseline in weight of >=10%. Safety analysis set included all subjects who had received at least one dose of study drug and had at least one valid post-baseline safety assessment. Here “number of subjects analyzed” signifies subjects evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline up to 30 days after last dose of study drug (up to maximum of 33 months)
    End point values
    		 Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF
    Number of subjects analysed
    39
    117
    24
    Units: Subjects
        Weight (High)
    6
    11
    8
        Weight (Low)
    2
    8
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Notable Electrocardiogram (ECG) Values

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    End point title
    		 Number of Subjects With Notable Electrocardiogram (ECG) Values
    End point description
    ECG findings included maximum value of >450 millisecond (msec), >480 msec and >500 msec, increase from baseline >30 msec and >60 msec for QT interval corrected using Fridericia's formula (QTcF); maximum value of >450 msec, >480 msec and >500 msec, increase from baseline >30 msec and >60 msec for QT interval corrected using Bazett's formula (QTcB); maximum value of >450 msec, >480 msec and >500 msec, increase from baseline >30 msec and >60 msec for QT interval; RR decrease >25% and to a VR >100, RR increase >25% and to a VR <50 beats per minute (bpm) for VR interval; an increase >25% and to a value >200 msec for PR interval; an increase >25% and to a value >110 msec for QRS interval. Safety analysis set included all subjects who had received at least one dose of study drug and had at least one valid post-baseline safety assessment. Here n= subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    Baseline up to 30 days after last dose of study drug (up to maximum of 33 months)
    End point values
    		 Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF
    Number of subjects analysed
    41
    117
    25
    Units: Subjects
        QTcF (msec): New >450 (n=34,104,23)
    5
    15
    3
        QTcF (msec): New >480 (n=37,109,23)
    1
    4
    0
        QTcF(msec): New >500 (n=37,109,23)
    0
    0
    0
        QTcF(msec):Increase from baseline>30(n=37,109,23)
    4
    24
    5
        QTcF(msec):Increase from baseline>60(n=37,109,23)
    1
    1
    0
        QTcB(msec): New >450 (n=30,94,21)
    4
    26
    6
        QTcB (milsec): New >480 (n=35,108,22)
    3
    7
    2
        QTcB (msec): New >500 (n=37,109,23)
    0
    3
    1
        QTcB(msec):Increase from baseline>30(n=37,109,23)
    6
    29
    6
        QTcB(msec):Increasefrom baseline >60(n=37,109,23)
    0
    2
    3
        QT(msec): New >450 (n=37,105,23)
    6
    13
    1
        QT(msec): New >480 (n=37,107,23)
    2
    4
    0
        QT (msec): New >500 (n=37,109,23)
    1
    1
    0
        QT(msec):Increase from baseline>30(n=37,109,23)
    14
    54
    9
        QT(msec):Increase from baseline>60(n=37,109,23)
    3
    13
    3
        VR (bpm):RR decrease>25% & to VR>100(n=37,109,23)
    2
    6
    2
        VR (bpm):RR increase >25% & to VR<50(n=37,109,23)
    3
    8
    2
        PR(msec):Increase>25%& to value>200(n=36,106,23)
    1
    6
    0
        QRS(msec):Increase>25%&to value>110(n=37,109,23)
    1
    5
    1
    No statistical analyses for this end point

    Secondary: Number of Subjects With Change from Baseline in Abnormal Ophthalmoscopy Values- by Fundoscopy

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    End point title
    		 Number of Subjects With Change from Baseline in Abnormal Ophthalmoscopy Values- by Fundoscopy
    End point description
    Fundoscopy examination included an examination of the retina, vitreous, macula, optic nerve, optic nerve pallor, choroid and other new abnormalities in either or both eyes. New abnormalities (New Ab) were identified where the baseline assessment showed no abnormalities in a particular eye, but at the post-dose time point an abnormality was observed. New abnormalities at any time point were reported and included unscheduled assessments. Safety analysis set included all subjects who had received at least one dose of study drug and had at least one valid post-baseline safety assessment. Here n= subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    Baseline up to 30 days after last dose of study drug (for a maximum duration of up to 33 months)
    End point values
    		 Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF
    Number of subjects analysed
    41
    117
    25
    Units: Subjects
        Retina: New Ab (At any time) (38,112,24)
    10
    43
    13
        Vitreous: New Ab (At any time) (38,112,24)
    2
    4
    1
        Macula: New Ab (At any time) (38,113,24)
    7
    39
    9
        Optic Nerve: New Ab (At any time) (38,113,24)
    1
    5
    1
        Optic Nerve Pallor: New Ab(At any time)(38,112,24)
    0
    2
    0
        Choroid: New Ab(At any time) (38,112,24)
    1
    5
    2
        Other: New Ab (At any time) (n=5,14,2)
    0
    6
    1
    No statistical analyses for this end point

    Secondary: Number of Subjects With Change from Baseline in Abnormal Ophthalmoscopy Values- by Slit Lamp Examination

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    End point title
    		 Number of Subjects With Change from Baseline in Abnormal Ophthalmoscopy Values- by Slit Lamp Examination
    End point description
    Slit lamp examination included an examination of the conjunctiva, cornea, iris, lens, anterior chamber, lids and other new abnormalities (New Ab) in either or both eyes. New abnormalities were identified where the baseline assessment showed no abnormalities in a particular eye, but at the post-dose time point an abnormality was observed. New abnormalities at any time point were reported and included unscheduled assessments. Safety analysis set included all subjects who had received at least one dose of study drug and had at least one valid post-baseline safety assessment. Here 99999 indicates data could not be estimated due to no subject analyzed. n=subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    Baseline up to 30 days after last dose of study drug (for a maximum duration of up to 33 months)
    End point values
    		 Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF
    Number of subjects analysed
    41
    117
    25
    Units: Subjects
        Conjunctiva: New Ab(At any time) (n=37,112,14)
    4
    25
    7
        Cornea: New Ab (At any time) (n=37,112,24)
    3
    8
    5
        Iris: New Ab (At any time) (n=37,112,24)
    0
    1
    0
        Lens: New Ab (At any time) (n=37,112,24)
    5
    17
    3
        Anterior chamber: New Ab(At any time)(n=36,112,24)
    0
    1
    0
        Lids: New Ab (At any time) (n=37,112,24)
    6
    25
    5
        Other: New abnormalities (At any time) (n=2,9,0)
    1
    8
    99999
    No statistical analyses for this end point

    Secondary: Area Under the Curve From Time Zero to end of Dosing Interval at Steady-State (AUCtau) of Binimetinib

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    End point title
    		 Area Under the Curve From Time Zero to end of Dosing Interval at Steady-State (AUCtau) of Binimetinib
    End point description
    Pharmacokinetic (PK) analysis set included all subjects who had at least one blood sample providing evaluable PK data. Here 99999 indicates data could not be estimated due to one subject analyzed. ‘Number analyzed’ signifies subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hour), 0.5, 1.5, 3, 8 hours on Day 1 and Day 15 of Cycle 1
    End point values
    		 Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF
    Number of subjects analysed
    37
    105
    23
    Units: hours*nanogram per milliliter
    geometric mean (geometric coefficient of variation)
        Cycle 1, Day 1 (n=4,3,8)
    1606.73 ( 42.55 )
    1704.80 ( 20.37 )
    1587.47 ( 42.49 )
        Cycle 1, Day 15 (n=1,6,4)
    2438.22 ( 99999 )
    2051.70 ( 32.63 )
    2637.48 ( 22.04 )
    No statistical analyses for this end point

    Secondary: Maximum Plasma Concentration (Cmax) of Binimetinib

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    End point title
    		 Maximum Plasma Concentration (Cmax) of Binimetinib
    End point description
    PK analysis set included all subjects who had at least one blood sample providing evaluable PK data. Here ‘number analyzed’ signifies subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hour), 0.5, 1.5, 3, 8 hours on Day 1 and Day 15 of Cycle 1
    End point values
    		 Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF
    Number of subjects analysed
    37
    105
    23
    Units: nanogram per milliliter
    geometric mean (geometric coefficient of variation)
        Cycle 1, Day 1 (n=12,11,19)
    445.8 ( 45.8 )
    471.6 ( 34.4 )
    542.5 ( 29.6 )
        Cycle 1, Day 15 (n=9,13,20)
    385.2 ( 50.1 )
    479.7 ( 41.1 )
    531.3 ( 44.0 )
    No statistical analyses for this end point

    Secondary: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Binimetinib

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    End point title
    		 Time to Reach Maximum Observed Plasma Concentration (Tmax) of Binimetinib
    End point description
    PK analysis set included all subjects who had at least one blood sample providing evaluable PK data. Here ‘number analyzed’ signifies subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hour), 0.5, 1.5, 3, 8 hours on Day 1 and Day 15 of Cycle 1
    End point values
    		 Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF
    Number of subjects analysed
    37
    105
    23
    Units: hours
    median (full range (min-max))
        Cycle 1, Day 1 (n=12,11,19)
    0.68 (0.50 to 3.25)
    1.50 (0.50 to 3.00)
    0.75 (0.50 to 7.98)
        Cycle 1, Day 15 (n=9,13,20)
    1.50 (0.75 to 3.17)
    1.48 (0.42 to 8.00)
    1.42 (0.00 to 5.17)
    No statistical analyses for this end point

    Secondary: Area Under the Curve From Time Zero to Time of Last Quantifiable Concentration (AUC0-last) of Binimetinib

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    End point title
    		 Area Under the Curve From Time Zero to Time of Last Quantifiable Concentration (AUC0-last) of Binimetinib
    End point description
    PK analysis set included all subjects who had at least one blood sample providing evaluable PK data. Here ‘number analyzed’ signifies subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hour), 0.5, 1.5, 3, 8 hours on Day 1 and Day 15 of Cycle 1
    End point values
    		 Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF
    Number of subjects analysed
    37
    105
    23
    Units: hours*nanogram per milliliter
    geometric mean (geometric coefficient of variation)
        Cycle 1, Day 1 (n=12,11,19)
    1318.38 ( 47.38 )
    1447.07 ( 21.34 )
    1622.66 ( 37.46 )
        Cycle 1, Day 15 (n=9,13,20)
    1806.28 ( 40.86 )
    1832.06 ( 30.71 )
    2263.46 ( 39.84 )
    No statistical analyses for this end point

    Secondary: The Last Time Point of the Last Quantifiable Concentration (Tlast) of Binimetinib

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    End point title
    		 The Last Time Point of the Last Quantifiable Concentration (Tlast) of Binimetinib
    End point description
    PK analysis set included all subjects who had at least one blood sample providing evaluable PK data. Here ‘number analyzed’ signifies subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hour), 0.5, 1.5, 3, 8 hours on Day 1 and Day 15 of Cycle 1
    End point values
    		 Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF
    Number of subjects analysed
    37
    105
    23
    Units: hours
    median (full range (min-max))
        Cycle 1, Day 1 (n=12,11,19
    7.23 (3.23 to 8.00)
    7.98 (7.03 to 8.05)
    7.00 (3.00 to 8.28)
        Cycle 1, Day 15 (n=9,13,20)
    7.50 (7.00 to 8.17)
    8.00 (7.02 to 8.43)
    7.50 (3.58 to 8.25)
    No statistical analyses for this end point

    Secondary: Trough Plasma Concentration (Ctrough) of Binimetinib

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    End point title
    		 Trough Plasma Concentration (Ctrough) of Binimetinib
    End point description
    Ctrough refers to plasma concentration of Binimetinib observed just before treatment administration. PK analysis set included all subjects who had at least one blood sample providing evaluable PK data. Here “Overall number of subjects analyzed” signifies participants evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hour) on Day 15 of Cycle 1
    End point values
    		 Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF
    Number of subjects analysed
    25
    65
    20
    Units: nanogram per milliliter
        geometric mean (geometric coefficient of variation)
    127.0 ( 69.6 )
    102.3 ( 79.1 )
    136.1 ( 67.2 )
    No statistical analyses for this end point

    Secondary: Apparent Total Body Clearance (CL/F) of Binimetinib

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    End point title
    		 Apparent Total Body Clearance (CL/F) of Binimetinib
    End point description
    Drug clearance was defined as a quantitative measure of the rate at which a drug substance was removed from the plasma. Clearance obtained after oral dose was influenced by the fraction of the dose absorbed. PK analysis set included all subjects who had at least one blood sample providing evaluable PK data. Here 99999 indicates data could not be estimated due to one subject analyzed. 'Number analyzed’ signifies subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hour), 0.5, 1.5, 3, 8 hours on Day 1 and Day 15 of Cycle 1
    End point values
    		 Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF
    Number of subjects analysed
    37
    105
    23
    Units: liter/hour
    geometric mean (geometric coefficient of variation)
        Cycle 1, Day 1 (n=4,3,8)
    28.01 ( 46.90 )
    26.40 ( 20.98 )
    37.80 ( 30.48 )
        Cycle 1, Day 15 (n=1,6,4)
    18.46 ( 99999 )
    20.50 ( 26.73 )
    21.17 ( 24.18 )
    No statistical analyses for this end point

    Secondary: Area Under the Curve From Time Zero to end of Dosing Interval at Steady-State (AUCtau) of Binimetinib's Metabolite

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    End point title
    		 Area Under the Curve From Time Zero to end of Dosing Interval at Steady-State (AUCtau) of Binimetinib's Metabolite
    End point description
    PK analysis set included all subjects who had at least one blood sample providing evaluable PK data. Here, 99999 indicates data could not be estimated due to insufficient subject analyzed. ‘Number analyzed’ signifies subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hour), 0.5, 1.5, 3, 8 hours on Day 1 and Day 15 of Cycle 1
    End point values
    		 Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF
    Number of subjects analysed
    37
    105
    23
    Units: hours*nanogram per milliliter
    geometric mean (geometric coefficient of variation)
        Cycle 1, Day 1 (n-2,2,3)
    257.73 ( 7.43 )
    170.11 ( 12.96 )
    248.82 ( 18.33 )
        Cycle 1, Day 15 (n=0,1,1)
    99999 ( 99999 )
    253.93 ( 99999 )
    322.21 ( 99999 )
    No statistical analyses for this end point

    Secondary: Maximum Plasma Concentration (Cmax) of Binimetinib's Metabolite

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    End point title
    		 Maximum Plasma Concentration (Cmax) of Binimetinib's Metabolite
    End point description
    PK analysis set included all subjects who had at least one blood sample providing evaluable PK data. Here ‘number analyzed’ signifies subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hour), 0.5, 1.5, 3, 8 hours on Day 1 and Day 15 of Cycle 1
    End point values
    		 Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF
    Number of subjects analysed
    37
    105
    23
    Units: nanogram per milliliter
    geometric mean (geometric coefficient of variation)
        Cycle 1, Day 1 (n=12,11,19)
    56.37 ( 39.22 )
    49.42 ( 26.49 )
    56.71 ( 47.62 )
        Cycle 1, Day 15 (n=9,13,20)
    32.31 ( 78.98 )
    33.55 ( 58.34 )
    25.47 ( 76.76 )
    No statistical analyses for this end point

    Secondary: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Binimetinib's Metabolite

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    End point title
    		 Time to Reach Maximum Observed Plasma Concentration (Tmax) of Binimetinib's Metabolite
    End point description
    PK analysis set included all subjects who had at least one blood sample providing evaluable PK data. Here ‘number analyzed’ signifies subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hour), 0.5, 1.5, 3, 8 hours on Day 1 and Day 15 of Cycle 1
    End point values
    		 Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF
    Number of subjects analysed
    37
    105
    23
    Units: hours
    median (full range (min-max))
        Cycle 1, Day 1 (n=12,11,19)
    1.50 (0.50 to 3.25)
    1.50 (0.50 to 3.00)
    1.50 (0.50 to 7.98)
        Cycle 1, Day 15 (n=9,13,20)
    2.50 (0.75 to 3.17)
    1.50 (0.50 to 8.00)
    1.50 (0.00 to 8.00)
    No statistical analyses for this end point

    Secondary: Area Under the Curve From Time Zero to Time of Last Quantifiable Concentration (AUC0-last) of Binimetinib's Metabolite

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    End point title
    		 Area Under the Curve From Time Zero to Time of Last Quantifiable Concentration (AUC0-last) of Binimetinib's Metabolite
    End point description
    PK analysis set included all subjects who had at least one blood sample providing evaluable PK data. Here ‘number analyzed’ signifies subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hour), 0.5, 1.5, 3, 8 hours on Day 1 and Day 15 of Cycle 1
    End point values
    		 Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF
    Number of subjects analysed
    37
    105
    23
    Units: hours*nanogram per milliliter
    geometric mean (geometric coefficient of variation)
        Cycle 1, Day 1 (n=12,11,19)
    197.29 ( 46.15 )
    181.60 ( 29.22 )
    189.37 ( 50.78 )
        Cycle 1, Day 15 (n=9,13,20)
    157.35 ( 63.36 )
    129.13 ( 62.80 )
    87.11 ( 79.73 )
    No statistical analyses for this end point

    Secondary: The Last Time Point of the Last Quantifiable Concentration (Tlast) of Binimetinib's Metabolite

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    End point title
    		 The Last Time Point of the Last Quantifiable Concentration (Tlast) of Binimetinib's Metabolite
    End point description
    PK analysis set included all subjects who had at least one blood sample providing evaluable PK data. Here ‘number analyzed’ signifies subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hour), 0.5, 1.5, 3, 8 hours on Day 1 and Day 15 of Cycle 1
    End point values
    		 Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF
    Number of subjects analysed
    37
    105
    23
    Units: hours
    median (full range (min-max))
        Cycle 1, Day 1 (n=12,11,19)
    7.23 (3.23 to 8.00)
    7.98 (7.03 to 8.05)
    7.00 (3.00 to 8.28)
        Cycle 1, Day 15 (n=9,13,20)
    7.50 (7.00 to 8.17)
    8.00 (2.97 to 8.43)
    7.25 (1.42 to 8.25)
    No statistical analyses for this end point

    Secondary: Trough Plasma Concentration (Ctrough) of Binimetinib's Metabolite

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    End point title
    		 Trough Plasma Concentration (Ctrough) of Binimetinib's Metabolite
    End point description
    Ctrough refers to plasma concentration of Binimetinib's metabolite observed just before treatment administration. PK analysis set included all subjects who had at least one blood sample providing evaluable PK data. Here “Overall number of subjects analyzed” signifies subjects evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hour) on Day 15 of Cycle 1
    End point values
    		 Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF
    Number of subjects analysed
    25
    65
    20
    Units: nanogram per milliliter
        geometric mean (geometric coefficient of variation)
    12.85 ( 80.44 )
    11.63 ( 123.41 )
    16.10 ( 104.21 )
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Histological Score (H-score) for Phosphorylated Extracellular Signal-Regulated Kinase (pERK) From Tumor Samples of Cytoplasmic and Nuclear Cellular Compartment

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    End point title
    		 Percent Change From Baseline in Histological Score (H-score) for Phosphorylated Extracellular Signal-Regulated Kinase (pERK) From Tumor Samples of Cytoplasmic and Nuclear Cellular Compartment
    End point description
    Percent change from baseline in H-score for pERK from tumor samples was assessed and summarized. The H-score is a method of assessing the extent of nuclear immunoreactivity, applicable to steroid receptors. The full analysis set included all randomized subjects who received at least one dose of study drug. Here “Overall number of subjects analyzed” signifies subjects evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline up to maximum duration of up to 33 months
    End point values
    		 Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF
    Number of subjects analysed
    3
    8
    4
    Units: Percent change
    arithmetic mean (standard deviation)
        Cytoplasmic: Percent change from baseline
    -10.90 ( 26.460 )
    -50.11 ( 22.576 )
    -9.85 ( 59.566 )
        Nuclear: Percent change from baseline
    195.19 ( 219.585 )
    -66.83 ( 47.524 )
    -32.35 ( 83.258 )
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Delta CT Values for Dual Specificity Phosphatase 6 (DUSP6) Expression From Tumor Samples

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    End point title
    		 Percent Change From Baseline in Delta CT Values for Dual Specificity Phosphatase 6 (DUSP6) Expression From Tumor Samples
    End point description
    The percentage change in DUSP6 gene expression was derived from the Relative Expression Ratio (RER) computed via the Delta Ct method. DUSP6, a protein coding gene was used as a biomarker of inhibition of the mitogen-activated protein kinase (MEK) pathway. The full analysis set included all randomized subjects who received at least one dose of study drug. Here “Overall number of subjects analyzed” signifies subjects evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline up to maximum duration of up to 33 months
    End point values
    		 Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF
    Number of subjects analysed
    3
    8
    3
    Units: Percent change
        arithmetic mean (standard deviation)
    -50.25 ( 12.069 )
    -30.82 ( 42.836 )
    29.48 ( 73.145 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Baseline up to 30 days after last dose (for a maximum duration of up to 11 years, approximately)
    Adverse event reporting additional description
    Same event may appear as both an AE and Serious Adverse Events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Analysis performed on safety set.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Binimetinib 45 mg BRAF
    Reporting group description
    		 Subjects with BRAF mutations received an oral dose of 45 milligrams (mg) of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by subjects refusal or investigator's decision whichever occurred first. Subjects were followed up to 30 days after last dose of study drug.

    Reporting group title
    Binimetinib 45 mg NRAS
    Reporting group description
    		 Subjects with NRAS mutations received an oral dose of 45 mg of binimetinib (3 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by subjects refusal or investigator's decision whichever occurred first. Subjects were followed up to 30 days after last dose of study drug.

    Reporting group title
    Binimetinib 60 mg BRAF
    Reporting group description
    		 Subjects with BRAF mutations received an oral dose of 60 mg of binimetinib (4 tablets each of 15 mg) twice daily, for each 28 days treatment cycle until development of unacceptable toxicity, disease progression, treatment discontinuation by subjects refusal or investigator's decision whichever occurred first. Subjects were followed up to 30 days after last dose of study drug.

    Serious adverse events
    		 Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 41 (26.83%)
    39 / 117 (33.33%)
    9 / 25 (36.00%)
         number of deaths (all causes)
    5
    51
    10
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute lymphocytic leukaemia
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Haematoma
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Retained placenta or membranes
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 117 (0.00%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    General physical health deterioration
         subjects affected / exposed
    1 / 41 (2.44%)
    3 / 117 (2.56%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Face oedema
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 117 (0.00%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 117 (0.00%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Performance status decreased
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Haemoptysis
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 41 (2.44%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Laryngeal oedema
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 117 (0.00%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 117 (1.71%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Heart rate irregular
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    International normalised ratio increased
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Troponin T increased
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ejection fraction decreased
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 117 (0.00%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Seizure
         subjects affected / exposed
    1 / 41 (2.44%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Retinal vein occlusion
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retinopathy
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 41 (2.44%)
    2 / 117 (1.71%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea haemorrhagic
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileus paralytic
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 117 (0.00%)
    2 / 25 (8.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 41 (2.44%)
    1 / 117 (0.85%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal perforation
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Acute hepatic failure
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic pain
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 117 (0.00%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis acneiform
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 117 (0.00%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pruritus
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin lesion
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 41 (2.44%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Skin infection
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia pseudomonal
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal viral infection
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 41 (0.00%)
    5 / 117 (4.27%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 41 (2.44%)
    2 / 117 (1.71%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    2 / 41 (4.88%)
    0 / 117 (0.00%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 117 (0.00%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Binimetinib 45 mg BRAF Binimetinib 45 mg NRAS Binimetinib 60 mg BRAF
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    40 / 41 (97.56%)
    117 / 117 (100.00%)
    25 / 25 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adrenal adenoma
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Blepharal papilloma
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Eye naevus
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 117 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    0
    Fibroma
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Haemangioma
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Metastatic pain
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Pyogenic granuloma
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    4
    Tumour pain
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    1 / 25 (4.00%)
         occurrences all number
    0
    1
    4
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 41 (4.88%)
    25 / 117 (21.37%)
    6 / 25 (24.00%)
         occurrences all number
    4
    49
    7
    Raynaud's phenomenon
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    1
    Peripheral coldness
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    1 / 25 (4.00%)
         occurrences all number
    0
    1
    1
    Thrombophlebitis superficial
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Venous thrombosis
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    1
    Erythromelalgia
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Flushing
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    0
    3
    Haematoma
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 117 (1.71%)
    0 / 25 (0.00%)
         occurrences all number
    0
    2
    0
    Hyperanemia
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Hypotension
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    2 / 25 (8.00%)
         occurrences all number
    0
    1
    2
    Lymphoedema
         subjects affected / exposed
    3 / 41 (7.32%)
    3 / 117 (2.56%)
    2 / 25 (8.00%)
         occurrences all number
    3
    3
    5
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    1
    Thrombophlebitis
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    1
    0
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    12 / 41 (29.27%)
    40 / 117 (34.19%)
    12 / 25 (48.00%)
         occurrences all number
    15
    59
    19
    Oedema peripheral
         subjects affected / exposed
    17 / 41 (41.46%)
    60 / 117 (51.28%)
    14 / 25 (56.00%)
         occurrences all number
    28
    127
    25
    Pyrexia
         subjects affected / exposed
    5 / 41 (12.20%)
    18 / 117 (15.38%)
    2 / 25 (8.00%)
         occurrences all number
    5
    30
    2
    Face oedema
         subjects affected / exposed
    5 / 41 (12.20%)
    11 / 117 (9.40%)
    5 / 25 (20.00%)
         occurrences all number
    7
    18
    5
    Asthenia
         subjects affected / exposed
    2 / 41 (4.88%)
    10 / 117 (8.55%)
    0 / 25 (0.00%)
         occurrences all number
    2
    14
    0
    General physical health deterioration
         subjects affected / exposed
    0 / 41 (0.00%)
    3 / 117 (2.56%)
    1 / 25 (4.00%)
         occurrences all number
    0
    3
    1
    Axillary pain
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 117 (1.71%)
    0 / 25 (0.00%)
         occurrences all number
    0
    2
    0
    Chest pain
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 117 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    0
    Chills
         subjects affected / exposed
    1 / 41 (2.44%)
    5 / 117 (4.27%)
    2 / 25 (8.00%)
         occurrences all number
    1
    7
    3
    Facial pain
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 117 (1.71%)
    0 / 25 (0.00%)
         occurrences all number
    0
    2
    0
    Feeling cold
         subjects affected / exposed
    1 / 41 (2.44%)
    4 / 117 (3.42%)
    0 / 25 (0.00%)
         occurrences all number
    1
    4
    0
    Gait disturbance
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    1 / 25 (4.00%)
         occurrences all number
    0
    1
    1
    Granuloma
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Hypothermia
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Inflammation
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    1 / 25 (4.00%)
         occurrences all number
    0
    1
    2
    Influenza like illness
         subjects affected / exposed
    0 / 41 (0.00%)
    3 / 117 (2.56%)
    2 / 25 (8.00%)
         occurrences all number
    0
    3
    2
    Localised oedema
         subjects affected / exposed
    0 / 41 (0.00%)
    3 / 117 (2.56%)
    1 / 25 (4.00%)
         occurrences all number
    0
    3
    1
    Malaise
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 117 (1.71%)
    0 / 25 (0.00%)
         occurrences all number
    0
    2
    0
    Mucosal dryness
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Mucosal inflammation
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 117 (1.71%)
    1 / 25 (4.00%)
         occurrences all number
    0
    2
    1
    Mucous membrane disorder
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    2
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 41 (4.88%)
    2 / 117 (1.71%)
    1 / 25 (4.00%)
         occurrences all number
    3
    2
    1
    Oedema
         subjects affected / exposed
    0 / 41 (0.00%)
    4 / 117 (3.42%)
    2 / 25 (8.00%)
         occurrences all number
    0
    4
    4
    Pain
         subjects affected / exposed
    1 / 41 (2.44%)
    2 / 117 (1.71%)
    1 / 25 (4.00%)
         occurrences all number
    1
    2
    1
    Performance status decreased
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 117 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    0
    Peripheral swelling
         subjects affected / exposed
    2 / 41 (4.88%)
    3 / 117 (2.56%)
    2 / 25 (8.00%)
         occurrences all number
    2
    3
    2
    Swelling
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 117 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    0
    Xerosis
         subjects affected / exposed
    1 / 41 (2.44%)
    5 / 117 (4.27%)
    1 / 25 (4.00%)
         occurrences all number
    1
    5
    1
    Ulcer
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Immune system disorders
    Allergy to vaccine
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Penile oedema
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Scrotal oedema
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Vaginal haemorrhage
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Vaginal inflammation
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 117 (1.71%)
    0 / 25 (0.00%)
         occurrences all number
    0
    3
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    2 / 41 (4.88%)
    11 / 117 (9.40%)
    1 / 25 (4.00%)
         occurrences all number
    6
    13
    1
    Cough
         subjects affected / exposed
    5 / 41 (12.20%)
    5 / 117 (4.27%)
    1 / 25 (4.00%)
         occurrences all number
    5
    5
    1
    Epistaxis
         subjects affected / exposed
    0 / 41 (0.00%)
    4 / 117 (3.42%)
    2 / 25 (8.00%)
         occurrences all number
    0
    4
    2
    Apnoea
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    1
    Dysphonia
         subjects affected / exposed
    1 / 41 (2.44%)
    3 / 117 (2.56%)
    0 / 25 (0.00%)
         occurrences all number
    1
    3
    0
    Dyspnoea exertional
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 41 (2.44%)
    4 / 117 (3.42%)
    0 / 25 (0.00%)
         occurrences all number
    1
    4
    0
    Nasal odour
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Pharyngeal ulceration
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Pleural effusion
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Pneumonitis
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    1 / 25 (4.00%)
         occurrences all number
    0
    1
    1
    Pulmonary oedema
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Rhinalgia
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 117 (1.71%)
    0 / 25 (0.00%)
         occurrences all number
    0
    2
    0
    Rhinitis allergic
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    1
    Sinus disorder
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    1
    0
    1
    Haemoptysis
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Lung disorder
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Nasal crusting
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    3
    Nasal discomfort
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Painful respiration
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    2
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 117 (1.71%)
    2 / 25 (8.00%)
         occurrences all number
    0
    2
    3
    Depression
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    1 / 25 (4.00%)
         occurrences all number
    0
    1
    1
    Hallucination
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Insomnia
         subjects affected / exposed
    1 / 41 (2.44%)
    3 / 117 (2.56%)
    0 / 25 (0.00%)
         occurrences all number
    1
    3
    0
    Mood swings
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Panic attack
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Schizophrenia, paranoid type
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    1
    Sleep disorder
         subjects affected / exposed
    0 / 41 (0.00%)
    3 / 117 (2.56%)
    0 / 25 (0.00%)
         occurrences all number
    0
    3
    0
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 41 (4.88%)
    20 / 117 (17.09%)
    2 / 25 (8.00%)
         occurrences all number
    2
    38
    4
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 41 (2.44%)
    18 / 117 (15.38%)
    2 / 25 (8.00%)
         occurrences all number
    1
    35
    3
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 41 (0.00%)
    10 / 117 (8.55%)
    3 / 25 (12.00%)
         occurrences all number
    0
    17
    4
    Ejection fraction decreased
         subjects affected / exposed
    0 / 41 (0.00%)
    10 / 117 (8.55%)
    1 / 25 (4.00%)
         occurrences all number
    0
    16
    1
    Blood creatine phosphokinase increased
         subjects affected / exposed
    12 / 41 (29.27%)
    60 / 117 (51.28%)
    14 / 25 (56.00%)
         occurrences all number
    48
    297
    90
    Weight decreased
         subjects affected / exposed
    2 / 41 (4.88%)
    8 / 117 (6.84%)
    0 / 25 (0.00%)
         occurrences all number
    2
    11
    0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 117 (1.71%)
    1 / 25 (4.00%)
         occurrences all number
    0
    3
    1
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 117 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    0
    Amylase increased
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 117 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    0
    Blood albumin increased
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    1
    0
    1
    Blood creatine phosphokinase MB increased
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 117 (1.71%)
    0 / 25 (0.00%)
         occurrences all number
    0
    2
    0
    C-reactive protein increased
         subjects affected / exposed
    0 / 41 (0.00%)
    5 / 117 (4.27%)
    0 / 25 (0.00%)
         occurrences all number
    0
    7
    0
    Blood fibrinogen increased
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 117 (1.71%)
    2 / 25 (8.00%)
         occurrences all number
    0
    2
    2
    Blood magnesium decreased
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 117 (1.71%)
    0 / 25 (0.00%)
         occurrences all number
    0
    3
    0
    Blood phosphorus decreased
         subjects affected / exposed
    0 / 41 (0.00%)
    3 / 117 (2.56%)
    0 / 25 (0.00%)
         occurrences all number
    0
    6
    0
    Blood phosphorus increased
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 117 (1.71%)
    0 / 25 (0.00%)
         occurrences all number
    0
    2
    0
    Blood potassium decreased
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 117 (1.71%)
    0 / 25 (0.00%)
         occurrences all number
    0
    2
    0
    Blood potassium increased
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    1
    Blood pressure increased
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    1
    Blood sodium decreased
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    2
    0
    Blood thyroid stimulating hormone decreased
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Blood urea increased
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    1
    Blood urine present
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 117 (1.71%)
    0 / 25 (0.00%)
         occurrences all number
    0
    2
    0
    Blood creatinine increased
         subjects affected / exposed
    0 / 41 (0.00%)
    6 / 117 (5.13%)
    2 / 25 (8.00%)
         occurrences all number
    0
    7
    2
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 117 (1.71%)
    0 / 25 (0.00%)
         occurrences all number
    0
    3
    0
    Electrocardiogram T wave abnormal
         subjects affected / exposed
    0 / 41 (0.00%)
    4 / 117 (3.42%)
    0 / 25 (0.00%)
         occurrences all number
    0
    8
    0
    Fibrin D dimer increased
         subjects affected / exposed
    0 / 41 (0.00%)
    4 / 117 (3.42%)
    0 / 25 (0.00%)
         occurrences all number
    0
    5
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 41 (0.00%)
    6 / 117 (5.13%)
    0 / 25 (0.00%)
         occurrences all number
    0
    10
    0
    International normalised ratio increased
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    1 / 25 (4.00%)
         occurrences all number
    0
    1
    4
    Intraocular pressure increased
         subjects affected / exposed
    1 / 41 (2.44%)
    7 / 117 (5.98%)
    0 / 25 (0.00%)
         occurrences all number
    1
    9
    0
    Lipase increased
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    2
    0
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Platelet count decreased
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 117 (1.71%)
    0 / 25 (0.00%)
         occurrences all number
    0
    2
    0
    Prothrombin time shortened
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 117 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    0
    Sinus rhythm
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Troponin T increased
         subjects affected / exposed
    0 / 41 (0.00%)
    4 / 117 (3.42%)
    0 / 25 (0.00%)
         occurrences all number
    0
    4
    0
    Weight increased
         subjects affected / exposed
    3 / 41 (7.32%)
    3 / 117 (2.56%)
    3 / 25 (12.00%)
         occurrences all number
    5
    7
    4
    Electrocardiogram ST segment elevation
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Troponin increased
         subjects affected / exposed
    2 / 41 (4.88%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    2
    1
    0
    Injury, poisoning and procedural complications
    Anal injury
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Fall
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    1 / 25 (4.00%)
         occurrences all number
    0
    2
    1
    Injury
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    1
    Ligament injury
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 117 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    0
    Limb injury
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    1
    Procedural pain
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    1 / 25 (4.00%)
         occurrences all number
    0
    1
    1
    Scratch
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Wound
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Congenital, familial and genetic disorders
    Colour blindness
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 117 (1.71%)
    0 / 25 (0.00%)
         occurrences all number
    0
    2
    0
    Congenital cleft hand
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 117 (1.71%)
    1 / 25 (4.00%)
         occurrences all number
    0
    2
    2
    Congenital optic nerve anomaly
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    2
    0
    Corneal dystrophy
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 117 (1.71%)
    1 / 25 (4.00%)
         occurrences all number
    0
    2
    2
    Corneal opacity congenital
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    1
    Dermoid cyst
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Macular dystrophy congenital
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Cleft lip
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    3
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 117 (1.71%)
    0 / 25 (0.00%)
         occurrences all number
    0
    2
    0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Atrial fibrillation
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 117 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    0
    Atrioventricular block first degree
         subjects affected / exposed
    0 / 41 (0.00%)
    5 / 117 (4.27%)
    0 / 25 (0.00%)
         occurrences all number
    0
    5
    0
    Bundle branch block right
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Defect conduction intraventricular
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 117 (1.71%)
    0 / 25 (0.00%)
         occurrences all number
    0
    4
    0
    Diastolic dysfunction
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    1
    Hypertensive cardiomyopathy
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Left ventricular dysfunction
         subjects affected / exposed
    1 / 41 (2.44%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    1
    1
    0
    Left ventricular hypertrophy
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Palpitations
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    2 / 25 (8.00%)
         occurrences all number
    0
    1
    2
    Sinus bradycardia
         subjects affected / exposed
    0 / 41 (0.00%)
    5 / 117 (4.27%)
    0 / 25 (0.00%)
         occurrences all number
    0
    9
    0
    Sinus tachycardia
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 117 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    0
    Supraventricular extrasystoles
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Arrhythmia
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Tachycardia
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    1
    Mitral valve incompetence
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 117 (1.71%)
    0 / 25 (0.00%)
         occurrences all number
    0
    2
    0
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    9 / 41 (21.95%)
    8 / 117 (6.84%)
    1 / 25 (4.00%)
         occurrences all number
    9
    8
    1
    Headache
         subjects affected / exposed
    3 / 41 (7.32%)
    7 / 117 (5.98%)
    4 / 25 (16.00%)
         occurrences all number
    3
    7
    5
    Dizziness
    alternative dictionary used: MedDRA 17.0
         subjects affected / exposed
    3 / 41 (7.32%)
    6 / 117 (5.13%)
    4 / 25 (16.00%)
         occurrences all number
    3
    6
    4
    Visual field defect
         subjects affected / exposed
    1 / 41 (2.44%)
    8 / 117 (6.84%)
    1 / 25 (4.00%)
         occurrences all number
    1
    8
    1
    Disturbance in attention
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Dysaesthesia
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    1
    Dysarthria
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    1
    Hemianopia homonymous
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Hypoaesthesia
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 117 (1.71%)
    0 / 25 (0.00%)
         occurrences all number
    0
    2
    0
    Hypotonia
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Loss of consciousness
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Migraine
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    1 / 25 (4.00%)
         occurrences all number
    0
    1
    1
    Neurological symptom
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    1
    Neuropathy peripheral
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 117 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    2
    0
    0
    Peripheral motor neuropathy
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 117 (1.71%)
    0 / 25 (0.00%)
         occurrences all number
    0
    3
    0
    Syncope
         subjects affected / exposed
    0 / 41 (0.00%)
    3 / 117 (2.56%)
    3 / 25 (12.00%)
         occurrences all number
    0
    3
    3
    Somnolence
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    2
    Memory impairment
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    1 / 25 (4.00%)
         occurrences all number
    0
    1
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 41 (9.76%)
    17 / 117 (14.53%)
    3 / 25 (12.00%)
         occurrences all number
    4
    27
    3
    Eosinophilia
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    1
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Leukocytosis
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    1
    Thrombocytopenia
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 117 (1.71%)
    0 / 25 (0.00%)
         occurrences all number
    0
    5
    0
    Lymph node pain
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 117 (1.71%)
    0 / 25 (0.00%)
         occurrences all number
    0
    2
    0
    Lymphopenia
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    2 / 25 (8.00%)
         occurrences all number
    0
    3
    6
    Microcytic anaemia
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    1
    Neutropenia
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    6
    0
    Normochromic normocytic anaemia
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    1
    Leukopenia
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 117 (1.71%)
    0 / 25 (0.00%)
         occurrences all number
    0
    2
    0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Ear swelling
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 117 (1.71%)
    0 / 25 (0.00%)
         occurrences all number
    0
    2
    0
    Vertigo
         subjects affected / exposed
    0 / 41 (0.00%)
    3 / 117 (2.56%)
    2 / 25 (8.00%)
         occurrences all number
    0
    3
    2
    Eye disorders
    Chorioretinopathy
         subjects affected / exposed
    0 / 41 (0.00%)
    16 / 117 (13.68%)
    1 / 25 (4.00%)
         occurrences all number
    0
    23
    1
    Blepharitis
         subjects affected / exposed
    0 / 41 (0.00%)
    4 / 117 (3.42%)
    1 / 25 (4.00%)
         occurrences all number
    0
    5
    1
    Amblyopia
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Blepharospasm
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Cataract
         subjects affected / exposed
    2 / 41 (4.88%)
    3 / 117 (2.56%)
    0 / 25 (0.00%)
         occurrences all number
    3
    3
    0
    Conjunctival hyperaemia
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Conjunctival irritation
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Conjunctival oedema
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 117 (1.71%)
    0 / 25 (0.00%)
         occurrences all number
    0
    2
    0
    Conjunctivitis allergic
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 117 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    0
    Conjunctivochalasis
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Corneal disorder
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Corneal scar
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    1
    Detachment of macular retinal pigment epithelium
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Detachment of retinal pigment epithelium
         subjects affected / exposed
    1 / 41 (2.44%)
    8 / 117 (6.84%)
    0 / 25 (0.00%)
         occurrences all number
    2
    9
    0
    Diplopia
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    1
    Dry eye
         subjects affected / exposed
    0 / 41 (0.00%)
    5 / 117 (4.27%)
    3 / 25 (12.00%)
         occurrences all number
    0
    5
    3
    Eczema eyelids
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Extraocular muscle paresis
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Eye allergy
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Macular degeneration
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Eye degenerative disorder
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Eye discharge
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Eye disorder
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Eye irritation
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Eye movement disorder
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Eye pain
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    1 / 25 (4.00%)
         occurrences all number
    0
    1
    1
    Eye swelling
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 117 (1.71%)
    1 / 25 (4.00%)
         occurrences all number
    0
    2
    1
    Eyelid disorder
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Eyelid oedema
         subjects affected / exposed
    1 / 41 (2.44%)
    6 / 117 (5.13%)
    1 / 25 (4.00%)
         occurrences all number
    1
    7
    1
    Glaucoma
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    0
    2
    Lacrimation increased
         subjects affected / exposed
    1 / 41 (2.44%)
    2 / 117 (1.71%)
    1 / 25 (4.00%)
         occurrences all number
    1
    2
    1
    Lenticular opacities
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    1
    Eye colour change
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Macular oedema
         subjects affected / exposed
    0 / 41 (0.00%)
    4 / 117 (3.42%)
    0 / 25 (0.00%)
         occurrences all number
    0
    6
    0
    Posterior capsule opacification
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Meibomianitis
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 117 (1.71%)
    0 / 25 (0.00%)
         occurrences all number
    0
    4
    0
    Ocular discomfort
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Ocular hypertension
         subjects affected / exposed
    1 / 41 (2.44%)
    2 / 117 (1.71%)
    0 / 25 (0.00%)
         occurrences all number
    1
    2
    0
    Ocular vascular disorder
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Optic disc haemorrhage
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 117 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    0
    Optic nerve disorder
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    1
    Orbital oedema
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    1 / 25 (4.00%)
         occurrences all number
    0
    1
    1
    Papilloedema
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Paraneoplastic retinopathy
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Periorbital oedema
         subjects affected / exposed
    3 / 41 (7.32%)
    10 / 117 (8.55%)
    4 / 25 (16.00%)
         occurrences all number
    3
    10
    7
    Photophobia
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Photopsia
         subjects affected / exposed
    1 / 41 (2.44%)
    1 / 117 (0.85%)
    1 / 25 (4.00%)
         occurrences all number
    1
    1
    1
    Maculopathy
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    2
    0
    Punctate keratitis
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Retinal cyst
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Retinal detachment
         subjects affected / exposed
    2 / 41 (4.88%)
    3 / 117 (2.56%)
    0 / 25 (0.00%)
         occurrences all number
    3
    3
    0
    Retinal disorder
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 117 (1.71%)
    3 / 25 (12.00%)
         occurrences all number
    0
    2
    5
    Retinal exudates
         subjects affected / exposed
    1 / 41 (2.44%)
    2 / 117 (1.71%)
    0 / 25 (0.00%)
         occurrences all number
    1
    2
    0
    Retinal haemorrhage
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Trichiasis
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Retinal pigment epitheliopathy
         subjects affected / exposed
    0 / 41 (0.00%)
    5 / 117 (4.27%)
    1 / 25 (4.00%)
         occurrences all number
    0
    5
    1
    Retinal vein occlusion
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    2
    0
    Retinopathy
         subjects affected / exposed
    1 / 41 (2.44%)
    12 / 117 (10.26%)
    9 / 25 (36.00%)
         occurrences all number
    1
    14
    11
    Retinoschisis
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Subretinal fluid
         subjects affected / exposed
    0 / 41 (0.00%)
    8 / 117 (6.84%)
    1 / 25 (4.00%)
         occurrences all number
    0
    13
    1
    Retinal oedema
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Ulcerative keratitis
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Visual acuity reduced
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    2 / 25 (8.00%)
         occurrences all number
    0
    2
    2
    Visual impairment
         subjects affected / exposed
    1 / 41 (2.44%)
    5 / 117 (4.27%)
    0 / 25 (0.00%)
         occurrences all number
    1
    5
    0
    Vitreous detachment
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 117 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    0
    Vitreous disorder
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Vitreous floaters
         subjects affected / exposed
    2 / 41 (4.88%)
    2 / 117 (1.71%)
    0 / 25 (0.00%)
         occurrences all number
    3
    2
    0
    Vision blurred
         subjects affected / exposed
    1 / 41 (2.44%)
    7 / 117 (5.98%)
    1 / 25 (4.00%)
         occurrences all number
    1
    8
    1
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    4 / 41 (9.76%)
    21 / 117 (17.95%)
    10 / 25 (40.00%)
         occurrences all number
    4
    26
    20
    Nausea
         subjects affected / exposed
    10 / 41 (24.39%)
    37 / 117 (31.62%)
    12 / 25 (48.00%)
         occurrences all number
    10
    39
    20
    Diarrhoea
         subjects affected / exposed
    18 / 41 (43.90%)
    57 / 117 (48.72%)
    13 / 25 (52.00%)
         occurrences all number
    22
    78
    15
    Constipation
         subjects affected / exposed
    3 / 41 (7.32%)
    23 / 117 (19.66%)
    4 / 25 (16.00%)
         occurrences all number
    3
    24
    4
    Abdominal pain
         subjects affected / exposed
    1 / 41 (2.44%)
    13 / 117 (11.11%)
    5 / 25 (20.00%)
         occurrences all number
    1
    14
    7
    Abdominal pain upper
         subjects affected / exposed
    1 / 41 (2.44%)
    9 / 117 (7.69%)
    1 / 25 (4.00%)
         occurrences all number
    1
    11
    1
    Stomatitis
         subjects affected / exposed
    1 / 41 (2.44%)
    9 / 117 (7.69%)
    1 / 25 (4.00%)
         occurrences all number
    3
    17
    1
    Dyspepsia
         subjects affected / exposed
    1 / 41 (2.44%)
    7 / 117 (5.98%)
    3 / 25 (12.00%)
         occurrences all number
    1
    7
    4
    Dry mouth
         subjects affected / exposed
    3 / 41 (7.32%)
    5 / 117 (4.27%)
    1 / 25 (4.00%)
         occurrences all number
    3
    5
    1
    Abdominal discomfort
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Abdominal distension
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    0
    2
    Anal haemorrhage
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Anal inflammation
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    3
    0
    Aphthous ulcer
         subjects affected / exposed
    1 / 41 (2.44%)
    2 / 117 (1.71%)
    2 / 25 (8.00%)
         occurrences all number
    1
    6
    3
    Ascites
         subjects affected / exposed
    1 / 41 (2.44%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    2
    3
    0
    Cheilitis
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    1
    Chronic gastritis
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    1
    Gastric haemorrhage
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 117 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    0
    Flatulence
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 117 (1.71%)
    4 / 25 (16.00%)
         occurrences all number
    0
    2
    4
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 41 (2.44%)
    2 / 117 (1.71%)
    0 / 25 (0.00%)
         occurrences all number
    1
    2
    0
    Gingival bleeding
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    1
    Glossodynia
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 117 (1.71%)
    0 / 25 (0.00%)
         occurrences all number
    0
    2
    0
    Haematemesis
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 117 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    0
    Haematochezia
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Haemorrhoids
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 117 (1.71%)
    0 / 25 (0.00%)
         occurrences all number
    0
    2
    0
    Intussusception
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 117 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    0
    Lip dry
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    1
    Dysphagia
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    1 / 25 (4.00%)
         occurrences all number
    0
    1
    1
    Eructation
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 117 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    0
    Faecal incontinence
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Faeces soft
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Gastritis
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Mouth ulceration
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 117 (1.71%)
    0 / 25 (0.00%)
         occurrences all number
    0
    2
    0
    Oral discomfort
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    1
    Oral mucosal erythema
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Rectal obstruction
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Regurgitation
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 117 (1.71%)
    0 / 25 (0.00%)
         occurrences all number
    0
    2
    0
    Swollen tongue
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Tongue discolouration
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Oesophagitis
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    1 / 25 (4.00%)
         occurrences all number
    0
    1
    1
    Hepatobiliary disorders
    Portal vein thrombosis
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Dermatitis acneiform
         subjects affected / exposed
    15 / 41 (36.59%)
    64 / 117 (54.70%)
    8 / 25 (32.00%)
         occurrences all number
    34
    128
    13
    Rash
         subjects affected / exposed
    16 / 41 (39.02%)
    25 / 117 (21.37%)
    5 / 25 (20.00%)
         occurrences all number
    41
    62
    13
    Pruritus
         subjects affected / exposed
    4 / 41 (9.76%)
    21 / 117 (17.95%)
    3 / 25 (12.00%)
         occurrences all number
    4
    27
    7
    Dry skin
         subjects affected / exposed
    1 / 41 (2.44%)
    18 / 117 (15.38%)
    5 / 25 (20.00%)
         occurrences all number
    1
    25
    11
    Alopecia
         subjects affected / exposed
    3 / 41 (7.32%)
    15 / 117 (12.82%)
    2 / 25 (8.00%)
         occurrences all number
    3
    16
    4
    Erythema
         subjects affected / exposed
    4 / 41 (9.76%)
    8 / 117 (6.84%)
    3 / 25 (12.00%)
         occurrences all number
    4
    8
    10
    Eczema
         subjects affected / exposed
    3 / 41 (7.32%)
    6 / 117 (5.13%)
    3 / 25 (12.00%)
         occurrences all number
    5
    7
    3
    Angioedema
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Asteatosis
         subjects affected / exposed
    2 / 41 (4.88%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    2
    1
    0
    Milia
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Cutis laxa
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Dermatitis
         subjects affected / exposed
    0 / 41 (0.00%)
    3 / 117 (2.56%)
    1 / 25 (4.00%)
         occurrences all number
    0
    4
    5
    Dermatitis atopic
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    2 / 25 (8.00%)
         occurrences all number
    0
    1
    3
    Dermatitis contact
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Eczema asteatotic
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    1
    Eczema weeping
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Generalised erythema
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    1
    Hair colour changes
         subjects affected / exposed
    1 / 41 (2.44%)
    4 / 117 (3.42%)
    0 / 25 (0.00%)
         occurrences all number
    1
    4
    0
    Hair growth abnormal
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 117 (1.71%)
    0 / 25 (0.00%)
         occurrences all number
    0
    2
    0
    Hair texture abnormal
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    1
    Hyperkeratosis
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    1 / 25 (4.00%)
         occurrences all number
    0
    1
    1
    Intertrigo
         subjects affected / exposed
    0 / 41 (0.00%)
    3 / 117 (2.56%)
    0 / 25 (0.00%)
         occurrences all number
    0
    3
    0
    Keloid scar
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Chronic pigmented purpura
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Nail discolouration
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Rash maculovesicular
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Nail ridging
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    1
    Night sweats
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Pain of skin
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    2 / 25 (8.00%)
         occurrences all number
    0
    1
    4
    Petechiae
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 117 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    0
    Pigmentation disorder
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    1 / 25 (4.00%)
         occurrences all number
    0
    1
    2
    Pruritus generalised
         subjects affected / exposed
    1 / 41 (2.44%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    1
    1
    0
    Rash erythematous
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 117 (1.71%)
    0 / 25 (0.00%)
         occurrences all number
    0
    2
    0
    Rash follicular
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Rash generalised
         subjects affected / exposed
    0 / 41 (0.00%)
    3 / 117 (2.56%)
    0 / 25 (0.00%)
         occurrences all number
    0
    6
    0
    Rash macular
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Rash maculo-papular
         subjects affected / exposed
    1 / 41 (2.44%)
    7 / 117 (5.98%)
    1 / 25 (4.00%)
         occurrences all number
    3
    13
    2
    Nail disorder
         subjects affected / exposed
    0 / 41 (0.00%)
    4 / 117 (3.42%)
    0 / 25 (0.00%)
         occurrences all number
    0
    4
    0
    Rash papular
         subjects affected / exposed
    0 / 41 (0.00%)
    3 / 117 (2.56%)
    0 / 25 (0.00%)
         occurrences all number
    0
    5
    0
    Toxic skin eruption
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Scab
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    1
    Seborrhoeic dermatitis
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    1 / 25 (4.00%)
         occurrences all number
    0
    1
    1
    Skin discolouration
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    0
    4
    Skin erosion
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Skin exfoliation
         subjects affected / exposed
    2 / 41 (4.88%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    2
    0
    1
    Skin fissures
         subjects affected / exposed
    0 / 41 (0.00%)
    7 / 117 (5.98%)
    2 / 25 (8.00%)
         occurrences all number
    0
    8
    13
    Skin hypopigmentation
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    1
    Skin maceration
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    0
    2
    Skin plaque
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Skin ulcer
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 117 (1.71%)
    1 / 25 (4.00%)
         occurrences all number
    0
    3
    1
    Solar dermatitis
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Stasis dermatitis
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    2
    Rosacea
         subjects affected / exposed
    1 / 41 (2.44%)
    2 / 117 (1.71%)
    0 / 25 (0.00%)
         occurrences all number
    1
    2
    0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Dysuria
         subjects affected / exposed
    0 / 41 (0.00%)
    3 / 117 (2.56%)
    0 / 25 (0.00%)
         occurrences all number
    0
    3
    0
    Haematuria
         subjects affected / exposed
    1 / 41 (2.44%)
    4 / 117 (3.42%)
    0 / 25 (0.00%)
         occurrences all number
    1
    14
    0
    Incontinence
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Nocturia
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 117 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    0
    Proteinuria
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    1
    1
    0
    Renal colic
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    2
    0
    Renal failure
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Renal pain
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Urinary retention
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    1
    Obstructive uropathy
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 41 (7.32%)
    9 / 117 (7.69%)
    7 / 25 (28.00%)
         occurrences all number
    3
    10
    8
    Pain in extremity
         subjects affected / exposed
    3 / 41 (7.32%)
    14 / 117 (11.97%)
    2 / 25 (8.00%)
         occurrences all number
    3
    14
    2
    Myalgia
         subjects affected / exposed
    2 / 41 (4.88%)
    13 / 117 (11.11%)
    4 / 25 (16.00%)
         occurrences all number
    2
    26
    7
    Joint range of motion decreased
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    1
    Back pain
         subjects affected / exposed
    1 / 41 (2.44%)
    5 / 117 (4.27%)
    2 / 25 (8.00%)
         occurrences all number
    1
    5
    5
    Bone swelling
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    2
    0
    Bursitis
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 117 (1.71%)
    0 / 25 (0.00%)
         occurrences all number
    0
    2
    0
    Flank pain
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    2 / 25 (8.00%)
         occurrences all number
    0
    1
    2
    Groin pain
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    1 / 25 (4.00%)
         occurrences all number
    0
    1
    1
    Muscle fatigue
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Lupus-like syndrome
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Muscular weakness
         subjects affected / exposed
    1 / 41 (2.44%)
    8 / 117 (6.84%)
    0 / 25 (0.00%)
         occurrences all number
    1
    9
    0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    1 / 25 (4.00%)
         occurrences all number
    0
    1
    1
    Musculoskeletal stiffness
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Neck pain
         subjects affected / exposed
    1 / 41 (2.44%)
    1 / 117 (0.85%)
    1 / 25 (4.00%)
         occurrences all number
    1
    1
    1
    Pain in jaw
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Sjogren's syndrome
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Trigger finger
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    1
    Joint stiffness
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Joint swelling
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 117 (1.71%)
    0 / 25 (0.00%)
         occurrences all number
    0
    2
    0
    Limb discomfort
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Muscle spasms
         subjects affected / exposed
    0 / 41 (0.00%)
    3 / 117 (2.56%)
    0 / 25 (0.00%)
         occurrences all number
    0
    5
    0
    Arthropathy
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    1
    Infections and infestations
    Rash pustular
         subjects affected / exposed
    0 / 41 (0.00%)
    11 / 117 (9.40%)
    2 / 25 (8.00%)
         occurrences all number
    0
    14
    6
    Body tinea
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 117 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    0
    Cystitis
         subjects affected / exposed
    0 / 41 (0.00%)
    4 / 117 (3.42%)
    1 / 25 (4.00%)
         occurrences all number
    0
    5
    1
    Angular cheilitis
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    2
    0
    Bronchitis
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 117 (1.71%)
    0 / 25 (0.00%)
         occurrences all number
    0
    2
    0
    Candida infection
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 117 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    0
    Cellulitis
         subjects affected / exposed
    1 / 41 (2.44%)
    2 / 117 (1.71%)
    2 / 25 (8.00%)
         occurrences all number
    1
    4
    3
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Conjunctivitis
         subjects affected / exposed
    0 / 41 (0.00%)
    4 / 117 (3.42%)
    0 / 25 (0.00%)
         occurrences all number
    0
    4
    0
    Conjunctivitis bacterial
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Corona virus infection
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    1
    Bacteraemia
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Hordeolum
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    1
    Gingivitis
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrointestinal infection
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Folliculitis
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    1
    Escherichia infection
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    1
    Erysipelas
         subjects affected / exposed
    1 / 41 (2.44%)
    4 / 117 (3.42%)
    2 / 25 (8.00%)
         occurrences all number
    1
    6
    2
    Infection
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    3 / 25 (12.00%)
         occurrences all number
    0
    1
    3
    Orchitis
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Oral herpes
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    1
    0
    1
    Oral candidiasis
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 117 (1.71%)
    1 / 25 (4.00%)
         occurrences all number
    0
    2
    1
    Nasopharyngitis
         subjects affected / exposed
    0 / 41 (0.00%)
    5 / 117 (4.27%)
    0 / 25 (0.00%)
         occurrences all number
    0
    16
    0
    Lymphangitis
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    1
    Lung infection
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    1
    Lip infection
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Influenza
         subjects affected / exposed
    1 / 41 (2.44%)
    5 / 117 (4.27%)
    0 / 25 (0.00%)
         occurrences all number
    1
    6
    0
    Paronychia
         subjects affected / exposed
    1 / 41 (2.44%)
    3 / 117 (2.56%)
    1 / 25 (4.00%)
         occurrences all number
    1
    5
    1
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Pneumonia
         subjects affected / exposed
    1 / 41 (2.44%)
    3 / 117 (2.56%)
    1 / 25 (4.00%)
         occurrences all number
    1
    3
    1
    Post procedural infection
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Pulpitis dental
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    0
    2
    Rhinitis
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    2
    Viral infection
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Urinary tract infection
         subjects affected / exposed
    2 / 41 (4.88%)
    3 / 117 (2.56%)
    2 / 25 (8.00%)
         occurrences all number
    2
    3
    2
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Tinea pedis
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 117 (1.71%)
    1 / 25 (4.00%)
         occurrences all number
    0
    2
    1
    Staphylococcal bacteraemia
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    1
    Soft tissue infection
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Skin infection
         subjects affected / exposed
    0 / 41 (0.00%)
    3 / 117 (2.56%)
    2 / 25 (8.00%)
         occurrences all number
    0
    4
    15
    Sinusitis
         subjects affected / exposed
    0 / 41 (0.00%)
    3 / 117 (2.56%)
    1 / 25 (4.00%)
         occurrences all number
    0
    3
    1
    Pharyngitis
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Vulvovaginal candidiasis
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 117 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    1
    0
    0
    Wound infection
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Vulvovaginal mycotic infection
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    1
    Staphylococcal skin infection
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    2
    Fungal skin infection
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 117 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    2
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    5 / 41 (12.20%)
    19 / 117 (16.24%)
    3 / 25 (12.00%)
         occurrences all number
    6
    23
    4
    Dehydration
         subjects affected / exposed
    1 / 41 (2.44%)
    1 / 117 (0.85%)
    2 / 25 (8.00%)
         occurrences all number
    1
    1
    4
    Hyperglycaemia
         subjects affected / exposed
    1 / 41 (2.44%)
    1 / 117 (0.85%)
    1 / 25 (4.00%)
         occurrences all number
    1
    1
    3
    Hyperphosphataemia
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    1
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 117 (1.71%)
    2 / 25 (8.00%)
         occurrences all number
    0
    2
    2
    Hypokalaemia
         subjects affected / exposed
    3 / 41 (7.32%)
    4 / 117 (3.42%)
    1 / 25 (4.00%)
         occurrences all number
    4
    9
    1
    Hypomagnesaemia
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Hypophosphataemia
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    0 / 25 (0.00%)
         occurrences all number
    0
    1
    0
    Increased appetite
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    1
    Vitamin D deficiency
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 117 (0.85%)
    1 / 25 (4.00%)
         occurrences all number
    0
    1
    1
    Hyperkalaemia
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 117 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    4

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    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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