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    Clinical Trial Results:
    A randomized, double-blind, placebo-controlled, phase III study comparing the combination of PDR001, dabrafenib and trametinib versus placebo, dabrafenib and trametinib in previously untreated patients with unresectable or metastatic BRAF V600 mutant melanoma

    Summary
    EudraCT number
    		 2016-002794-35
    Trial protocol
    		 DE   SE   GB   ES   AT   CZ   PL   BG   GR   BE   PT   NL   DK   HU   IT  
    Global end of trial date
    21 Aug 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Aug 2025
    First version publication date
    27 Aug 2025
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CPDR001F2301
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02967692
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    Lichtstrasse 35, Basel, Switzerland, 4056
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@Novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@Novartis.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    21 Aug 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Aug 2024
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The purpose of this study was to evaluate safety and efficacy of the combination of an anti-PD-1 antibody (PDR001), a BRAF inhibitor (dabrafenib) and a MEK inhibitor (trametinib) in patients with BRAF V600 mutant, unresectable and metastatic melanoma.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    17 Feb 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 11
    Country: Number of subjects enrolled
    Australia: 14
    Country: Number of subjects enrolled
    Austria: 11
    Country: Number of subjects enrolled
    Belgium: 4
    Country: Number of subjects enrolled
    Brazil: 9
    Country: Number of subjects enrolled
    Bulgaria: 9
    Country: Number of subjects enrolled
    Canada: 7
    Country: Number of subjects enrolled
    Chile: 18
    Country: Number of subjects enrolled
    Czechia: 19
    Country: Number of subjects enrolled
    Denmark: 1
    Country: Number of subjects enrolled
    France: 92
    Country: Number of subjects enrolled
    Germany: 66
    Country: Number of subjects enrolled
    United Kingdom: 28
    Country: Number of subjects enrolled
    Greece: 10
    Country: Number of subjects enrolled
    Hungary: 10
    Country: Number of subjects enrolled
    Israel: 10
    Country: Number of subjects enrolled
    Italy: 83
    Country: Number of subjects enrolled
    Japan: 10
    Country: Number of subjects enrolled
    Mexico: 3
    Country: Number of subjects enrolled
    Netherlands: 8
    Country: Number of subjects enrolled
    Norway: 6
    Country: Number of subjects enrolled
    Poland: 14
    Country: Number of subjects enrolled
    Portugal: 3
    Country: Number of subjects enrolled
    Russian Federation: 51
    Country: Number of subjects enrolled
    Spain: 34
    Country: Number of subjects enrolled
    Sweden: 6
    Country: Number of subjects enrolled
    Switzerland: 13
    Country: Number of subjects enrolled
    Thailand: 2
    Country: Number of subjects enrolled
    United States: 16
    Worldwide total number of subjects
    568
    EEA total number of subjects
    376
    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)
    409
    From 65 to 84 years
    157
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 Part 1 and 2 were conducted in 18 centers across 12 countries. Part 3 is conducted in 190 centers across 29 countries

    Pre-assignment
    Screening details
    		 The screening phase began once written informed consent was provided and ended after 28 days or when subject received the first dose (Part 1 and 2) or was randomized (Part 3), whichever came first.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 P1-Safety: PDR001 400mg Q4W + dab 150mg BID + tram 2mg QD
    Arm description
    		 In Part 1, participants are treated with Spartalizumab (PDR001) 400 mg Q4W in combination with the approved dose of dabrafenib (150 mg BID) and trametinib (2 mg QD).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Spartalizumab
    Investigational medicinal product code
    Other name
    PDR001
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Spartalizumab powder for solution is used in Part 1 and Part 2, and as concentrate for solution for infusion for Part 3. Spartalizumab is administered via intravenous infusion over 30 minutes once every 4 weeks

    Investigational medicinal product name
    Trametinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Trametinib 2 mg tablets QD is administered orally for Days 1-28 of a 28-day cycle, in fasting conditions

    Investigational medicinal product name
    Dabrafenib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Dabrafenib 150 mg capsules BID is administered orally for Days 1-28 of a 28-day cycle, in fasting conditions.

    Arm title
    		 P2-Biomarker: PDR001 400mg Q4W + dab 150mg BID + tram 2mg QD
    Arm description
    		 In Part 2, participants are treated with Spartalizumab (PDR001) 400 mg Q4W in combination with the approved dose of dabrafenib (150 mg BID) and trametinib (2 mg QD).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Spartalizumab
    Investigational medicinal product code
    Other name
    PDR001
    Pharmaceutical forms
    Powder for solution for infusion, Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Spartalizumab powder for solution is used in Part 1 and Part 2, and as concentrate for solution for infusion for Part 3. Spartalizumab is administered via intravenous infusion over 30 minutes once every 4 weeks

    Investigational medicinal product name
    Trametinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Trametinib 2 mg tablets QD is administered orally for Days 1-28 of a 28-day cycle, in fasting conditions

    Investigational medicinal product name
    Dabrafenib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Dabrafenib 150 mg capsules BID is administered orally for Days 1-28 of a 28-day cycle, in fasting conditions.

    Arm title
    		 P3-Arm1: PDR001 400mg Q4W + dab 150mg BID + tram 2mg QD
    Arm description
    		 In Part 3, participants are randomized to receive Spartalizumab (PDR001) at the RP3R identified in Part 1 (400 mg Q4W) in combination with approved dose of dabrafenib (150 mg BID) and trametinib (2 mg QD)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Spartalizumab
    Investigational medicinal product code
    Other name
    PDR001
    Pharmaceutical forms
    Powder for solution for infusion, Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Spartalizumab powder for solution is used in Part 1 and Part 2, and as concentrate for solution for infusion for Part 3. Spartalizumab is administered via intravenous infusion over 30 minutes once every 4 weeks

    Investigational medicinal product name
    Trametinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Trametinib 2 mg tablets QD is administered orally for Days 1-28 of a 28-day cycle, in fasting conditions

    Investigational medicinal product name
    Dabrafenib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Dabrafenib 150 mg capsules BID is administered orally for Days 1-28 of a 28-day cycle, in fasting conditions.

    Arm title
    		 P3-Arm2: Placebo + dab 150mg BID + tram 2mg QD
    Arm description
    		 In Part 3, participants are randomized to receive matching placebo in combination with the approved dose of dabrafenib (150 mg BID) and trametinib (2 mg QD)
    Arm type
    		 Placebo

    Investigational medicinal product name
    Dabrafenib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Dabrafenib 150 mg capsules BID is administered orally for Days 1-28 of a 28-day cycle, in fasting conditions.

    Investigational medicinal product name
    Spartalizumab matching placebo
    Investigational medicinal product code
    Other name
    Placebo
    Pharmaceutical forms
    Powder for solution for infusion, Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Spartalizumab matching placebo is used as concentrate for solution for infusion for Part 3. Spartalizumab matching placebo is administered via intravenous infusion over 30 minutes once every 4 weeks

    Investigational medicinal product name
    Trametinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Trametinib 2 mg tablets QD is administered orally for Days 1-28 of a 28-day cycle, in fasting conditions

    Number of subjects in period 1
    		P1-Safety: PDR001 400mg Q4W + dab 150mg BID + tram 2mg QD P2-Biomarker: PDR001 400mg Q4W + dab 150mg BID + tram 2mg QD P3-Arm1: PDR001 400mg Q4W + dab 150mg BID + tram 2mg QD P3-Arm2: Placebo + dab 150mg BID + tram 2mg QD
    Started
    9
    27
    267
    265
    Treated
    9
    27
    267
    264
    Completed
    0
    0
    0
    0
    Not completed
    9
    27
    267
    265
         Adverse event, serious fatal
    -
    1
    13
    13
         Physician decision
    -
    -
    22
    13
         Adverse event, non-fatal
    2
    9
    60
    28
         Protocol deviation
    1
    -
    1
    1
         Study terminated by sponsor
    2
    1
    42
    37
         Progressive disease
    3
    15
    114
    151
         Lost to follow-up
    -
    -
    1
    -
         Subject/guardian decision
    1
    1
    14
    22

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    P1-Safety: PDR001 400mg Q4W + dab 150mg BID + tram 2mg QD
    Reporting group description
    		 In Part 1, participants are treated with Spartalizumab (PDR001) 400 mg Q4W in combination with the approved dose of dabrafenib (150 mg BID) and trametinib (2 mg QD).

    Reporting group title
    P2-Biomarker: PDR001 400mg Q4W + dab 150mg BID + tram 2mg QD
    Reporting group description
    		 In Part 2, participants are treated with Spartalizumab (PDR001) 400 mg Q4W in combination with the approved dose of dabrafenib (150 mg BID) and trametinib (2 mg QD).

    Reporting group title
    P3-Arm1: PDR001 400mg Q4W + dab 150mg BID + tram 2mg QD
    Reporting group description
    		 In Part 3, participants are randomized to receive Spartalizumab (PDR001) at the RP3R identified in Part 1 (400 mg Q4W) in combination with approved dose of dabrafenib (150 mg BID) and trametinib (2 mg QD)

    Reporting group title
    P3-Arm2: Placebo + dab 150mg BID + tram 2mg QD
    Reporting group description
    		 In Part 3, participants are randomized to receive matching placebo in combination with the approved dose of dabrafenib (150 mg BID) and trametinib (2 mg QD)

    Reporting group values
    		 P1-Safety: PDR001 400mg Q4W + dab 150mg BID + tram 2mg QD P2-Biomarker: PDR001 400mg Q4W + dab 150mg BID + tram 2mg QD P3-Arm1: PDR001 400mg Q4W + dab 150mg BID + tram 2mg QD P3-Arm2: Placebo + dab 150mg BID + tram 2mg QD Total
    Number of subjects
    		 9 27 267 265 568
    Age Categorical
    Units: Participants
        <=18 years
    		 0 0 0 0 0
        Between 18 and 65 years
    		 7 18 189 195 409
        >=65 years
    		 2 9 78 70 159
    Sex: Female, Male
    Units: Participants
        Female
    		 2 12 119 106 239
        Male
    		 7 15 148 159 329
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 9 24 225 227 485
        Asian
    		 0 2 5 5 12
        Other
    		 0 1 15 14 30
        Unknown
    		 0 0 22 19 41

    End points

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    End points reporting groups
    Reporting group title
    P1-Safety: PDR001 400mg Q4W + dab 150mg BID + tram 2mg QD
    Reporting group description
    		 In Part 1, participants are treated with Spartalizumab (PDR001) 400 mg Q4W in combination with the approved dose of dabrafenib (150 mg BID) and trametinib (2 mg QD).

    Reporting group title
    P2-Biomarker: PDR001 400mg Q4W + dab 150mg BID + tram 2mg QD
    Reporting group description
    		 In Part 2, participants are treated with Spartalizumab (PDR001) 400 mg Q4W in combination with the approved dose of dabrafenib (150 mg BID) and trametinib (2 mg QD).

    Reporting group title
    P3-Arm1: PDR001 400mg Q4W + dab 150mg BID + tram 2mg QD
    Reporting group description
    		 In Part 3, participants are randomized to receive Spartalizumab (PDR001) at the RP3R identified in Part 1 (400 mg Q4W) in combination with approved dose of dabrafenib (150 mg BID) and trametinib (2 mg QD)

    Reporting group title
    P3-Arm2: Placebo + dab 150mg BID + tram 2mg QD
    Reporting group description
    		 In Part 3, participants are randomized to receive matching placebo in combination with the approved dose of dabrafenib (150 mg BID) and trametinib (2 mg QD)

    Primary: Safety Run-In (Part 1): Number of participants with dose limiting toxicities (DLTs)

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    End point title
    		 Safety Run-In (Part 1): Number of participants with dose limiting toxicities (DLTs) [1] [2]
    End point description
    DLT was defined as an adverse event or abnormal laboratory value that was unrelated to disease, disease progression, inter-current illness, or concomitant medications and occured within 8 weeks of treatment with spartalizumab in combination with dabrafenib and trametinib. The DLT criteria included Grade 4 hematological adverse events, Grade 4 bilirubin elevation, specific gastrointestinal adverse events, symptomatic serum amylase or lipase elevation, Grade 3 or higher hypertension, Grade 3 or higher cardiac events, Grade 2 or higher pneumonitis, Grade 3 or higher immune-related toxicities, infusion-related reactions, other clinically significant adverse events, and toxicities leading to a dosing delay of over 12 weeks. NCI CTCAE v4.03 was used for grading DLTs
    End point type
    Primary
    End point timeframe
    Up to 8 weeks (Part 1)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive statistics performed
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only applicable to Part 1 Arm
    End point values
    		 P1-Safety: PDR001 400mg Q4W + dab 150mg BID + tram 2mg QD
    Number of subjects analysed
    9
    Units: Participants
    1
    No statistical analyses for this end point

    Primary: Biomarker cohort (Part 2): Change from baseline in programmed cell death-ligand 1 (PD-L1) expression upon treatment with spartalizumab in combination with dabrafenib and trametinib

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    End point title
    		 Biomarker cohort (Part 2): Change from baseline in programmed cell death-ligand 1 (PD-L1) expression upon treatment with spartalizumab in combination with dabrafenib and trametinib [3] [4]
    End point description
    Change from baseline in PD-L1 expression (as determined by immunohistochemistry in tissue samples) upon treatment with spartalizumab in combination with dabrafenib and trametinib in participants from Part 2
    End point type
    Primary
    End point timeframe
    Baseline, Cycle 1 Day 15 and Cycle 3 Day 1 (Part 2). Each cycle is 28 days
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive statistics performed
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only applicable to Part 2 Arm
    End point values
    		 P2-Biomarker: PDR001 400mg Q4W + dab 150mg BID + tram 2mg QD
    Number of subjects analysed
    9
    Units: Percentage of positive tumor cells
    arithmetic mean (standard deviation)
        Cycle 1 Day 15
    1.7 ( 13.05 )
        Cycle 3 Day 1
    2.7 ( 7.63 )
    No statistical analyses for this end point

    Primary: Biomarker cohort (Part 2): Change from baseline in CD8+ cells upon treatment with spartalizumab in combination with dabrafenib and trametinib

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    End point title
    		 Biomarker cohort (Part 2): Change from baseline in CD8+ cells upon treatment with spartalizumab in combination with dabrafenib and trametinib [5] [6]
    End point description
    Change from baseline in CD8+ cells (as determined by flow cytometry in blood samples) upon treatment with spartalizumab in combination with dabrafenib and trametinib in participants from Part 2
    End point type
    Primary
    End point timeframe
    Baseline, Cycle 1 Day 15 and Cycle 3 Day 1 (Part 2). Each cycle is 28 days
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive statistics performed
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only applicable to Part 2 Arm
    End point values
    		 P2-Biomarker: PDR001 400mg Q4W + dab 150mg BID + tram 2mg QD
    Number of subjects analysed
    6
    Units: Percentage Marker Area
    arithmetic mean (standard deviation)
        Cycle 1 Day 15
    0.4 ( 3.22 )
        Cycle 3 Day 1
    1.2 ( 2.43 )
    No statistical analyses for this end point

    Primary: Randomized (Part 3): Progression-Free Survival (PFS) as per investigator's assessment by RECIST 1.1

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    End point title
    		 Randomized (Part 3): Progression-Free Survival (PFS) as per investigator's assessment by RECIST 1.1 [7]
    End point description
    Progression-free survival was defined as the time from the date of first dose to the date of the first documented radiological progression per investigator's assessment according to RECIST 1.1 or death due to any cause. The distribution of PFS was estimated using the Kaplan-Meier (KM) method. If a patient had not had an event at the time of data cut-off, progression-free survival was censored at the date of last adequate tumor assessment.
    End point type
    Primary
    End point timeframe
    Up to disease progression or death due to any cause, whichever occurs first, assessed up to 2.8 years (Part 3)
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only applicable to Part 3-Arm 1 and Part 3-Arm 2
    End point values
    		 P3-Arm1: PDR001 400mg Q4W + dab 150mg BID + tram 2mg QD P3-Arm2: Placebo + dab 150mg BID + tram 2mg QD
    Number of subjects analysed
    267
    265
    Units: Months
        median (confidence interval 95%)
    16.2 (12.7 to 23.9)
    12.0 (10.2 to 15.4)
    Statistical analysis title
    		 P3: PFS per inv. assessment (RECIST 1.1)
    Comparison groups
    P3-Arm1: PDR001 400mg Q4W + dab 150mg BID + tram 2mg QD v P3-Arm2: Placebo + dab 150mg BID + tram 2mg QD
    Number of subjects included in analysis
    532
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.042
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.82
    Confidence interval
         level
    		 2%
         sides
    2-sided
         lower limit
    		 0.655
         upper limit
    		 1.027

    Secondary: Overall survival (OS)

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    End point title
    		 Overall survival (OS)
    End point description
    Overall survival was defined as the time from date of randomization to date of death due to any cause
    End point type
    Secondary
    End point timeframe
    Up to death due to any cause, assessed up to approximately 7 years
    End point values
    		 P1-Safety: PDR001 400mg Q4W + dab 150mg BID + tram 2mg QD P2-Biomarker: PDR001 400mg Q4W + dab 150mg BID + tram 2mg QD P3-Arm1: PDR001 400mg Q4W + dab 150mg BID + tram 2mg QD P3-Arm2: Placebo + dab 150mg BID + tram 2mg QD
    Number of subjects analysed
    9
    27
    267
    265
    Units: Months
        median (confidence interval 95%)
    999 (12.2 to 999)
    30.7 (21.3 to 67.4)
    61.5 (41.6 to 999)
    41.6 (30.6 to 56.9)
    No statistical analyses for this end point

    Secondary: Overall response rate (ORR) as per investigator's assessment by RECIST 1.1

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    End point title
    		 Overall response rate (ORR) as per investigator's assessment by RECIST 1.1
    End point description
    ORR was defined as the percentage of subjects with confirmed best overall response of complete response (CR) or partial response (PR), as per investigator's assessment by RECIST 1.1. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to <10 mm PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters
    End point type
    Secondary
    End point timeframe
    Part 1: Up to 3.3 years. Part 2: Up to 3 years. Part 3: Up to 2.8 years
    End point values
    		 P1-Safety: PDR001 400mg Q4W + dab 150mg BID + tram 2mg QD P2-Biomarker: PDR001 400mg Q4W + dab 150mg BID + tram 2mg QD P3-Arm1: PDR001 400mg Q4W + dab 150mg BID + tram 2mg QD P3-Arm2: Placebo + dab 150mg BID + tram 2mg QD
    Number of subjects analysed
    9
    27
    267
    265
    Units: Percentage of participants
        number (confidence interval 95%)
    100.0 (66.4 to 100.0)
    70.4 (49.8 to 86.2)
    68.5 (62.6 to 74.1)
    64.2 (58.1 to 69.9)
    No statistical analyses for this end point

    Secondary: Duration of response (DOR) as per investigator’s assessment by RECIST 1.1

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    End point title
    		 Duration of response (DOR) as per investigator’s assessment by RECIST 1.1
    End point description
    DOR was defined as the time from first documented response of CR or PR to date of first documented progression or death, according to RECIST 1.1 criteria. The distribution of DOR was estimated using the KM method. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to <10 mm PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters
    End point type
    Secondary
    End point timeframe
    From first documented response to date of first documented progression or death, up to 3.3 years (Part 1), 3 years (Part 2) and 2.8 years (Part 3)
    End point values
    		 P1-Safety: PDR001 400mg Q4W + dab 150mg BID + tram 2mg QD P2-Biomarker: PDR001 400mg Q4W + dab 150mg BID + tram 2mg QD P3-Arm1: PDR001 400mg Q4W + dab 150mg BID + tram 2mg QD P3-Arm2: Placebo + dab 150mg BID + tram 2mg QD
    Number of subjects analysed
    9
    19
    183
    170
    Units: Months
        median (confidence interval 95%)
    999 (8.3 to 999)
    20.0 (9.4 to 999)
    999 (18.6 to 999)
    20.7 (13.0 to 999)
    No statistical analyses for this end point

    Secondary: Disease control rate (DCR) as per investigator’s assessment by RECIST 1.1

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    End point title
    		 Disease control rate (DCR) as per investigator’s assessment by RECIST 1.1
    End point description
    DCR was defined as the percentage of participants with CR or PR or subjects with stable disease (SD) lasting for a duration of at least 24 weeks as per local review according to RECIST 1.1 criteria. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to <10 mm PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters SD: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease.
    End point type
    Secondary
    End point timeframe
    Part 1: Up to 3.3 years. Part 2: Up to 3 years. Part 3: Up to 2.8 year
    End point values
    		 P1-Safety: PDR001 400mg Q4W + dab 150mg BID + tram 2mg QD P2-Biomarker: PDR001 400mg Q4W + dab 150mg BID + tram 2mg QD P3-Arm1: PDR001 400mg Q4W + dab 150mg BID + tram 2mg QD P3-Arm2: Placebo + dab 150mg BID + tram 2mg QD
    Number of subjects analysed
    9
    27
    267
    265
    Units: Percentage of participants
        number (confidence interval 95%)
    100.0 (66.4 to 100.0)
    92.6 (75.7 to 99.1)
    84.3 (79.3 to 88.4)
    86.4 (81.7 to 90.3)
    No statistical analyses for this end point

    Secondary: Randomized (Part 3): Change from baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) C30- Global health status scores

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    End point title
    		 Randomized (Part 3): Change from baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) C30- Global health status scores [8]
    End point description
    The EORTC QLQ-C30 was a 30-item questionnaire that patients complete, consisting of both multi-item scales and single-item measures. It included five functional scales, three symptom scales, six single items, and a Global Health Status/Quality of Life (GHS/QoL) scale. The GHS/QoL scale had seven possible response scores ranging from 1 (very poor) to 7 (excellent), which were averaged and transformed to a 0-100 scale. A higher score on this scale indicated a better quality of life. The change from baseline in GHS/QoL scores was calculated. A positive change from baseline indicated improvement in the patient's quality of life.
    End point type
    Secondary
    End point timeframe
    From baseline to 60 days post progression, assessed up to 2.8 years (Part 3)
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only applicable to Part 3-Arm 1 and Part 3-Arm 2
    End point values
    		 P3-Arm1: PDR001 400mg Q4W + dab 150mg BID + tram 2mg QD P3-Arm2: Placebo + dab 150mg BID + tram 2mg QD
    Number of subjects analysed
    175
    186
    Units: Score on a Scale
    arithmetic mean (standard deviation)
        Cycle 4 Day 1
    0.81 ( 19.300 )
    2.20 ( 24.918 )
        Cycle 6 Day 1
    1.22 ( 25.050 )
    1.90 ( 21.197 )
        Cycle 8 Day 1
    0.00 ( 24.526 )
    0.50 ( 19.608 )
        Cycle 10 Day 1
    1.88 ( 23.088 )
    0.27 ( 18.752 )
        Cycle 12 Day 1
    0.61 ( 25.906 )
    0.00 ( 24.541 )
        Cycle 14 Day 1
    0.65 ( 23.561 )
    -0.89 ( 23.306 )
        Cycle 16 Day 1
    0.82 ( 25.186 )
    1.76 ( 24.142 )
        Cycle 18 Day 1
    -0.46 ( 24.106 )
    -0.10 ( 19.193 )
        Cycle 20 Day 1
    1.93 ( 21.766 )
    -1.02 ( 23.144 )
        Cycle 22 Day 1
    0.95 ( 22.047 )
    2.29 ( 21.947 )
        Cycle 25 Day 1
    3.57 ( 23.981 )
    -0.24 ( 25.497 )
        Cycle 28 Day 1
    4.50 ( 19.793 )
    1.06 ( 22.513 )
        Cycle 31 Day 1
    11.59 ( 24.967 )
    6.73 ( 21.084 )
        Cycle 34 Day 1
    16.67 ( 47.140 )
    13.89 ( 20.184 )
        30 days post-progression
    -11.59 ( 24.967 )
    -7.78 ( 29.274 )
        60 days post-progression
    -11.54 ( 16.506 )
    -17.19 ( 24.050 )
    No statistical analyses for this end point

    Secondary: Randomized (Part 3): Change from baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) C30- Physical functioning scale scores

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    End point title
    		 Randomized (Part 3): Change from baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) C30- Physical functioning scale scores [9]
    End point description
    The EORTC QLQ-C30 was a patient completed 30 item questionnaire that was composed of both multi-item scales and single-item measures. These included five functional scales, three symptom scales, six single items and a global health status/QoL scale. The EORTC QLQ-C30 physical functioning scale measured a patient's ability to carry out daily activities and tasks requiring physical exertion. It consisted of five questions asking patients to rate their level of physical functioning, with response options ranging from 1="not at all" to 4="very much". The scores for each item were summed and transformed to a 0 to 100 scale, with higher scores indicating better physical functioning. The change from baseline in physical functioning scale scores was calculated. A positive change from baseline indicated improvement in physical functioning.
    End point type
    Secondary
    End point timeframe
    From baseline to 60 days post progression, assessed up to 2.8 years (Part 3)
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only applicable to Part 3-Arm 1 and Part 3-Arm 2
    End point values
    		 P3-Arm1: PDR001 400mg Q4W + dab 150mg BID + tram 2mg QD P3-Arm2: Placebo + dab 150mg BID + tram 2mg QD
    Number of subjects analysed
    175
    186
    Units: Score on a Scale
    arithmetic mean (standard deviation)
        Cycle 4 Day 1
    -1.52 ( 16.243 )
    -0.70 ( 17.618 )
        Cycle 6 Day 1
    -2.38 ( 16.121 )
    -0.60 ( 14.824 )
        Cycle 8 Day 1
    -1.29 ( 18.350 )
    -0.59 ( 15.687 )
        Cycle 10 Day 1
    -0.18 ( 17.985 )
    -1.11 ( 13.736 )
        Cycle 12 Day 1
    -1.39 ( 18.108 )
    -0.85 ( 10.652 )
        Cycle 14 Day 1
    -2.42 ( 16.720 )
    -2.61 ( 12.320 )
        Cycle 16 Day 1
    -4.19 ( 20.301 )
    -2.24 ( 13.331 )
        Cycle 18 Day 1
    -3.48 ( 18.862 )
    -3.55 ( 13.474 )
        Cycle 20 Day 1
    -4.07 ( 15.316 )
    -1.73 ( 11.536 )
        Cycle 22 Day 1
    -3.21 ( 15.538 )
    -0.85 ( 11.157 )
        Cycle 25 Day 1
    -1.35 ( 16.510 )
    -2.67 ( 13.158 )
        Cycle 28 Day 1
    -0.80 ( 13.843 )
    -2.67 ( 15.953 )
        Cycle 31 Day 1
    -2.03 ( 10.719 )
    -1.79 ( 9.533 )
        Cycle 34 Day 1
    0.00 ( 0.000 )
    -3.33 ( 5.578 )
        30 days post-progression
    -6.67 ( 18.641 )
    -8.67 ( 19.973 )
        60 days post-progression
    -13.85 ( 15.977 )
    -21.25 ( 27.991 )
    No statistical analyses for this end point

    Secondary: Randomized (Part 3): Change from baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) C30- Pain symptom scale scores

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    End point title
    		 Randomized (Part 3): Change from baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) C30- Pain symptom scale scores [10]
    End point description
    The EORTC QLQ-C30 was a patient completed 30 item questionnaire that was composed of both multi-item scales and single-item measures. These included five functional scales, three symptom scales, six single items and a global health status/QoL scale. The EORTC QLQ-C30 pain symptom scale was one of the symptom scales in the questionnaire, which measured the severity of pain experienced by the patient. The pain symptom scale consisted of two items, one measuring the severity of pain and the other measuring the use of painkillers. The items were rated on a 4-point scale ranging from 1="not at all" to 4="very much". The scores for each item were summed and transformed to a 0 to 100 scale, with higher scores indicating more severe pain. The change from baseline in pain symptom scale scores was calculated. A negative change from baseline indicated improvement.
    End point type
    Secondary
    End point timeframe
    From baseline to 60 days post progression, assessed up to 2.8 years (Part 3)
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only applicable to Part 3-Arm 1 and Part 3-Arm 2
    End point values
    		 P3-Arm1: PDR001 400mg Q4W + dab 150mg BID + tram 2mg QD P3-Arm2: Placebo + dab 150mg BID + tram 2mg QD
    Number of subjects analysed
    175
    186
    Units: Score on a Scale
    arithmetic mean (standard deviation)
        Cycle 4 Day 1
    -5.24 ( 26.434 )
    -5.29 ( 24.881 )
        Cycle 6 Day 1
    -6.43 ( 28.820 )
    -7.49 ( 23.611 )
        Cycle 8 Day 1
    -4.91 ( 29.176 )
    -4.11 ( 24.420 )
        Cycle 10 Day 1
    -7.95 ( 28.346 )
    -4.76 ( 23.557 )
        Cycle 12 Day 1
    -8.33 ( 28.890 )
    -5.26 ( 22.646 )
        Cycle 14 Day 1
    -5.50 ( 28.140 )
    -3.56 ( 23.062 )
        Cycle 16 Day 1
    -5.86 ( 26.220 )
    -4.44 ( 25.820 )
        Cycle 18 Day 1
    -3.15 ( 30.178 )
    -3.21 ( 20.898 )
        Cycle 20 Day 1
    -4.47 ( 30.659 )
    -2.85 ( 23.249 )
        Cycle 22 Day 1
    -5.49 ( 27.049 )
    -3.54 ( 23.969 )
        Cycle 25 Day 1
    -6.25 ( 28.868 )
    -4.76 ( 20.685 )
        Cycle 28 Day 1
    -3.00 ( 26.872 )
    -3.03 ( 22.701 )
        Cycle 31 Day 1
    -10.14 ( 24.995 )
    -7.05 ( 34.696 )
        Cycle 34 Day 1
    -8.33 ( 11.785 )
    -5.56 ( 8.607 )
        30 days post-progression
    9.42 ( 28.791 )
    0.56 ( 28.190 )
        60 days post-progression
    15.38 ( 19.792 )
    11.46 ( 24.884 )
    No statistical analyses for this end point

    Secondary: Randomized (Part 3): Time to 10 point definitive deterioration in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) C30- Global Health Status

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    End point title
    		 Randomized (Part 3): Time to 10 point definitive deterioration in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) C30- Global Health Status [11]
    End point description
    The EORTC QLQ-C30 was a patient completed 30 item questionnaire that was composed of both multi-item scales and single-item measures. These included five functional scales, three symptom scales, six single items and a global health status/QoL scale. The GHS/QoL scale had seven possible response scores ranging from 1 (very poor) to 7 (excellent), which were averaged and transformed to a 0-100 scale. A higher score on this scale indicated a better quality of life. The time to definitive 10 point deterioration is defined as the time from the date of randomization to the date of event, which is defined as at least 10 points relative to baseline worsening of the GHS/QoL score or death due to any cause. If a subject had not had an event, the time to deterioration was censored at the date of the last adequate assessment. The distribution was estimated using KM method.
    End point type
    Secondary
    End point timeframe
    From baseline to date of at least 10 points relative to baseline worsening of the global health status score or death due to any cause, up to 2.8 years (Part 3)
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only applicable to Part 3-Arm 1 and Part 3-Arm 2
    End point values
    		 P3-Arm1: PDR001 400mg Q4W + dab 150mg BID + tram 2mg QD P3-Arm2: Placebo + dab 150mg BID + tram 2mg QD
    Number of subjects analysed
    267
    265
    Units: Months
        median (confidence interval 95%)
    19.4 (15.7 to 24.9)
    22.1 (17.5 to 999)
    Statistical analysis title
    		 P3: Time to 10pt def. det. in EORTC QLQ-C30 GHS
    Comparison groups
    P3-Arm1: PDR001 400mg Q4W + dab 150mg BID + tram 2mg QD v P3-Arm2: Placebo + dab 150mg BID + tram 2mg QD
    Number of subjects included in analysis
    532
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.2975
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.183
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.865
         upper limit
    		 1.619

    Secondary: Randomized (Part 3): Change from baseline in Function Assessment Cancer Therapy-melanoma (FACT-M) melanoma subscale score

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    End point title
    		 Randomized (Part 3): Change from baseline in Function Assessment Cancer Therapy-melanoma (FACT-M) melanoma subscale score [12]
    End point description
    The Functional Assessment of Cancer Therapy–Melanoma (FACT-M) quality of life questionnaire was composed of the FACT-General (FACT-G) plus the Melanoma Subscale and the Melanoma Surgery Subscale, which complemented the general scale with items specific to quality of life (QoL) in melanoma. The Melanoma Subscale of FACT-M included 16 questions, with response options of 0= "Not at all", 1= "a little bit", 2= "somewhat", 3= "quite a bit" and 4= "very much". The FACT-M melanoma subscale score ranged from 0 to 64, with higher scores indicating a higher quality of life in relation to melanoma. The change from baseline in melanoma subscale scores was calculated. A positive change from baseline indicated improvement.
    End point type
    Secondary
    End point timeframe
    From baseline to 60 days post progression, assessed up to 2.8 years (Part 3)
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only applicable to Part 3-Arm 1 and Part 3-Arm 2
    End point values
    		 P3-Arm1: PDR001 400mg Q4W + dab 150mg BID + tram 2mg QD P3-Arm2: Placebo + dab 150mg BID + tram 2mg QD
    Number of subjects analysed
    177
    190
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Cycle 4 Day 1
    0.83 ( 6.600 )
    0.87 ( 6.185 )
        Cycle 6 Day 1
    1.01 ( 7.370 )
    1.18 ( 6.219 )
        Cycle 8 Day 1
    1.14 ( 7.284 )
    1.09 ( 5.742 )
        Cycle 10 Day 1
    1.52 ( 7.314 )
    0.54 ( 6.492 )
        Cycle 12 Day 1
    1.21 ( 7.515 )
    0.47 ( 5.974 )
        Cycle 14 Day 1
    0.77 ( 7.071 )
    0.65 ( 6.681 )
        Cycle 16 Day 1
    0.93 ( 6.451 )
    0.71 ( 6.374 )
        Cycle 18 Day 1
    1.23 ( 7.095 )
    0.47 ( 6.152 )
        Cycle 20 Day 1
    1.28 ( 6.634 )
    0.53 ( 5.875 )
        Cycle 22 Day 1
    1.87 ( 6.215 )
    0.79 ( 5.970 )
        Cycle 25 Day 1
    2.73 ( 5.950 )
    0.74 ( 6.792 )
        Cycle 28 Day 1
    2.46 ( 5.195 )
    0.61 ( 8.020 )
        Cycle 31 Day 1
    3.29 ( 5.702 )
    1.88 ( 6.154 )
        Cycle 34 Day 1
    -0.50 ( 2.121 )
    4.60 ( 3.578 )
        30 days post-progression
    0.33 ( 7.620 )
    -1.07 ( 8.590 )
        60 days post-progression
    -2.60 ( 5.734 )
    -3.06 ( 8.948 )
    No statistical analyses for this end point

    Secondary: Randomized (Part 3): Change from baseline in EuroQoL 5-level instrument (EQ-5D-5L)- Visual Analog Scale (VAS) score

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    End point title
    		 Randomized (Part 3): Change from baseline in EuroQoL 5-level instrument (EQ-5D-5L)- Visual Analog Scale (VAS) score [13]
    End point description
    The EQ-5D-5L is a standardized questionnaire used to assess health-related quality of life, and it includes a Visual Analog Scale (VAS). The VAS score is obtained by asking the individual to rate their current health status on a scale from 0 to 100, where 0 represents the worst possible health state and 100 represents the best possible health state. The change from baseline in EQ-5D-5L VAS score was calculated. A positive change from baseline indicates improvement in the health status.
    End point type
    Secondary
    End point timeframe
    From baseline to 60 days post progression, assessed up to 2.8 years (Part 3)
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only applicable to Part 3-Arm 1 and Part 3-Arm 2
    End point values
    		 P3-Arm1: PDR001 400mg Q4W + dab 150mg BID + tram 2mg QD P3-Arm2: Placebo + dab 150mg BID + tram 2mg QD
    Number of subjects analysed
    176
    190
    Units: Score on a Scale
    arithmetic mean (standard deviation)
        Cycle 4 Day 1
    1.85 ( 16.567 )
    2.16 ( 19.733 )
        Cycle 6 Day 1
    1.55 ( 20.751 )
    3.10 ( 16.095 )
        Cycle 8 Day 1
    0.39 ( 20.246 )
    2.60 ( 15.200 )
        Cycle 10 Day 1
    2.45 ( 19.050 )
    2.52 ( 16.144 )
        Cycle 12 Day 1
    1.88 ( 24.653 )
    1.42 ( 15.695 )
        Cycle 14 Day 1
    2.62 ( 19.455 )
    1.71 ( 14.337 )
        Cycle 16 Day 1
    1.30 ( 18.640 )
    2.79 ( 16.996 )
        Cycle 18 Day 1
    2.16 ( 20.762 )
    1.91 ( 16.743 )
        Cycle 20 Day 1
    1.34 ( 17.831 )
    1.28 ( 16.108 )
        Cycle 22 Day 1
    3.01 ( 19.102 )
    1.55 ( 14.973 )
        Cycle 25 Day 1
    4.47 ( 19.489 )
    0.26 ( 14.784 )
        Cycle 28 Day 1
    4.20 ( 17.545 )
    -0.39 ( 18.529 )
        Cycle 31 Day 1
    6.45 ( 19.561 )
    -0.08 ( 16.747 )
        Cycle 34 Day 1
    -9.50 ( 14.849 )
    5.60 ( 19.008 )
        30 days post-progression
    -4.04 ( 22.033 )
    -10.24 ( 23.532 )
        60 days post-progression
    -19.25 ( 19.923 )
    -8.19 ( 21.192 )
    No statistical analyses for this end point

    Secondary: Randomized (Part 3): PFS as per investigator's assessment by RECIST 1.1 by PD-L1 expression

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    End point title
    		 Randomized (Part 3): PFS as per investigator's assessment by RECIST 1.1 by PD-L1 expression [14]
    End point description
    PFS was defined as the time from the date of first dose to the date of the first documented radiological progression as per investigator's assessment using RECIST 1.1 response criteria or death due to any cause. The distribution of PFS was estimated using the KM method. If a patient had not had an event at the time of data cut-off, progression-free survival was censored at the date of last adequate tumor assessment. PFS analysis was performed by PD-L1 status (positive, negative) where a positive status was defined as having ≥ 1% expression and a negative status was defined as having < 1% expression.
    End point type
    Secondary
    End point timeframe
    Up to disease progression or death due to any cause, up to 2.8 years (Part 3)
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only applicable to Part 3-Arm 1 and Part 3-Arm 2
    End point values
    		 P3-Arm1: PDR001 400mg Q4W + dab 150mg BID + tram 2mg QD P3-Arm2: Placebo + dab 150mg BID + tram 2mg QD
    Number of subjects analysed
    236
    241
    Units: Months
    median (confidence interval 95%)
        PD-L1 negative (<1%)
    12.0 (10.1 to 15.7)
    10.3 (7.5 to 13.0)
        PD-L1 positive (>=1%)
    26.6 (17.4 to 999)
    15.4 (10.2 to 25.3)
    No statistical analyses for this end point

    Secondary: Randomized (Part 3): OS by PD-L1 expression

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    End point title
    		 Randomized (Part 3): OS by PD-L1 expression [15]
    End point description
    Overall survival was defined as the time from date of randomization to date of death due to any cause. OS analysis was performed by PD-L1 subgroup (positive, negative) where a positive status was defined as having ≥ 1% expression and a negative status was defined as having < 1% expression.
    End point type
    Secondary
    End point timeframe
    Up to death due to any cause, assessed up to approximately 7 years
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only applicable to Part 3-Arm 1 and Part 3-Arm 2
    End point values
    		 P3-Arm1: PDR001 400mg Q4W + dab 150mg BID + tram 2mg QD P3-Arm2: Placebo + dab 150mg BID + tram 2mg QD
    Number of subjects analysed
    112
    138
    Units: Months
    median (confidence interval 95%)
        PD-L1 negative (<1%)
    41.6 (27.6 to 999)
    21.0 (16.9 to 33.4)
        PD-L1 positive (>=1%)
    999 (45.4 to 999)
    61.3 (41.2 to 999)
    No statistical analyses for this end point

    Secondary: Spartalizumab ADA incidence

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    End point title
    		 Spartalizumab ADA incidence [16]
    End point description
    Spartalizumab ADA incidence was calculated as the percentage of participants who were treatment-induced spartalizumab ADA positive (post-baseline ADA positive with ADA-negative sample at baseline) and treatment-boosted spartalizumab ADA positive (post-baseline ADA positive with titer that is at least the fold titer change greater than the ADA-positive baseline titer)
    End point type
    Secondary
    End point timeframe
    Throughout study until 150 days after the last dose of spartalizumab, up to 3.3 years (Part 1), 3 years (Part 2) and 2.8 years (Part 3).
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only applicable to Part 1, Part 2 and Part 3-Arm 1
    End point values
    		 P1-Safety: PDR001 400mg Q4W + dab 150mg BID + tram 2mg QD P2-Biomarker: PDR001 400mg Q4W + dab 150mg BID + tram 2mg QD P3-Arm1: PDR001 400mg Q4W + dab 150mg BID + tram 2mg QD
    Number of subjects analysed
    9
    26
    244
    Units: Participants
    0
    5
    55
    No statistical analyses for this end point

    Secondary: Spartalizumab Anti-drug Antibody (ADA) prevalence at baseline

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    End point title
    		 Spartalizumab Anti-drug Antibody (ADA) prevalence at baseline [17]
    End point description
    Spartalizumab ADA prevalence at baseline was calculated as the percentage of participants who had an spartalizumab ADA positive result at baseline.
    End point type
    Secondary
    End point timeframe
    Baseline
    Notes
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only applicable to Part 1, Part 2 and Part 3-Arm 1
    End point values
    		 P1-Safety: PDR001 400mg Q4W + dab 150mg BID + tram 2mg QD P2-Biomarker: PDR001 400mg Q4W + dab 150mg BID + tram 2mg QD P3-Arm1: PDR001 400mg Q4W + dab 150mg BID + tram 2mg QD
    Number of subjects analysed
    9
    26
    244
    Units: Participants
    0
    0
    4
    No statistical analyses for this end point

    Secondary: Trough concentration (Ctrough) for spartalizumab

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    End point title
    		 Trough concentration (Ctrough) for spartalizumab [18]
    End point description
    Ctrough for spartalizumab refers to the serum concentration of spartalizumab immediately prior to the administration of a dose of spartalizumab on Day 1 of Cycle 2 and later cycles.
    End point type
    Secondary
    End point timeframe
    Pre-infusion on Day 1 of each Cycle starting from Cycle 2, up to 3.3 years (Part 1), 3 years (Part 2) and 2.8 years (Part 3). Cycle=28 days
    Notes
    [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only applicable to Part 1, Part 2 and Part 3-Arm 1
    End point values
    		 P1-Safety: PDR001 400mg Q4W + dab 150mg BID + tram 2mg QD P2-Biomarker: PDR001 400mg Q4W + dab 150mg BID + tram 2mg QD P3-Arm1: PDR001 400mg Q4W + dab 150mg BID + tram 2mg QD
    Number of subjects analysed
    5
    17
    138
    Units: microgram (μg)/miliLiter (mL)
    arithmetic mean (standard deviation)
        Cycle 2
    31.9 ( 4.59 )
    31.5 ( 20.3 )
    28.4 ( 13.4 )
        Cycle 3
    41.1 ( 7.07 )
    56.1 ( 34.2 )
    43.5 ( 19.1 )
        Cycle 4
    47.8 ( 999 )
    46.9 ( 18.8 )
    50.5 ( 24.2 )
        Cycle 5
    46.3 ( 999 )
    56.7 ( 19.5 )
    56.4 ( 24.5 )
        Cycle 6
    53.8 ( 16.9 )
    60.9 ( 23.6 )
    58.8 ( 26.5 )
        Cycle 7
    56.1 ( 12.1 )
    62.2 ( 33.3 )
    63.7 ( 29.6 )
        Cycle 8
    57.9 ( 12.7 )
    65.8 ( 32.8 )
    64.1 ( 29.9 )
        Cycle 9
    60.2 ( 30.9 )
    69.5 ( 25.2 )
    67.8 ( 33.5 )
        Cycle 10
    62.1 ( 22.5 )
    68.4 ( 33.2 )
    63.8 ( 28.4 )
        Cycle 11
    66.9 ( 15.8 )
    63.2 ( 35.8 )
    62.1 ( 27.9 )
        Cycle 12
    67.0 ( 16.5 )
    61.6 ( 29.3 )
    60.7 ( 27.2 )
    No statistical analyses for this end point

    Secondary: Pre-dose plasma concentration for dabrafenib

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    End point title
    		 Pre-dose plasma concentration for dabrafenib
    End point description
    Plasma concentration of dabrafenib immediately prior to the administration of a dose of dabrafenib.
    End point type
    Secondary
    End point timeframe
    Pre-infusion on Day 1 of every cycle from Cycle 2 to 12, and then every 6 cycles from Cycle 18 to 36, up to 3.3 years (Part 1), 3 years (Part 2) and 2.8 years (Part 3). Cycle=28 days
    End point values
    		 P1-Safety: PDR001 400mg Q4W + dab 150mg BID + tram 2mg QD P2-Biomarker: PDR001 400mg Q4W + dab 150mg BID + tram 2mg QD P3-Arm1: PDR001 400mg Q4W + dab 150mg BID + tram 2mg QD P3-Arm2: Placebo + dab 150mg BID + tram 2mg QD
    Number of subjects analysed
    4
    18
    127
    162
    Units: nanogram (ng)/ miliLiter (mL)
    arithmetic mean (standard deviation)
        Cycle 2
    33.7 ( 27.4 )
    149 ( 391 )
    208 ( 473 )
    234 ( 475 )
        Cycle 3
    25.5 ( 10.4 )
    183 ( 469 )
    192 ( 607 )
    135 ( 266 )
        Cycle 4
    23.0 ( 15.8 )
    372 ( 811 )
    169 ( 404 )
    167 ( 328 )
        Cycle 5
    28.8 ( 30.6 )
    152 ( 293 )
    130 ( 317 )
    152 ( 363 )
        Cycle 6
    15.1 ( 16.3 )
    73.7 ( 131 )
    198 ( 521 )
    94.6 ( 186 )
        Cycle 7
    20.9 ( 13.9 )
    40.0 ( 20.0 )
    180 ( 510 )
    121 ( 279 )
        Cycle 8
    22.9 ( 16.8 )
    28.0 ( 10.4 )
    173 ( 532 )
    97.2 ( 177 )
        Cycle 9
    22.3 ( 7.59 )
    43.3 ( 40.6 )
    143 ( 394 )
    133 ( 259 )
        Cycle 10
    24.5 ( 9.19 )
    60.0 ( 28.3 )
    167 ( 472 )
    122 ( 266 )
        Cycle 11
    154 ( 250 )
    33.8 ( 22.6 )
    174 ( 667 )
    119 ( 238 )
        Cycle 12
    10.9 ( 10.3 )
    41.3 ( 37.2 )
    148 ( 396 )
    146 ( 295 )
        Cycle 18
    19.0 ( 999 )
    50.6 ( 49.7 )
    180 ( 618 )
    167 ( 385 )
        Cycle 24
    999 ( 999 )
    91.5 ( 98.3 )
    147 ( 344 )
    60.2 ( 67.9 )
        Cycle 30
    40.2 ( 999 )
    999 ( 999 )
    226 ( 488 )
    47.6 ( 23.2 )
        Cycle 36
    47.6 ( 999 )
    999 ( 999 )
    999 ( 999 )
    999 ( 999 )
    No statistical analyses for this end point

    Secondary: Pre-dose plasma concentration for trametinib

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    End point title
    		 Pre-dose plasma concentration for trametinib
    End point description
    Plasma concentration of trametinib immediately prior to the administration of a dose of trametinib.
    End point type
    Secondary
    End point timeframe
    Pre-infusion on Day 1 of every cycle from Cycle 2 to 12, and then every 6 cycles from Cycle 18 to 36, up to 3.3 years (Part 1), 3 years (Part 2) and 2.8 years (Part 3). Cycle=28 days
    End point values
    		 P1-Safety: PDR001 400mg Q4W + dab 150mg BID + tram 2mg QD P2-Biomarker: PDR001 400mg Q4W + dab 150mg BID + tram 2mg QD P3-Arm1: PDR001 400mg Q4W + dab 150mg BID + tram 2mg QD P3-Arm2: Placebo + dab 150mg BID + tram 2mg QD
    Number of subjects analysed
    3
    14
    103
    143
    Units: ng/mL
    arithmetic mean (standard deviation)
        Cycle 2
    11.7 ( 4.09 )
    11.2 ( 3.4 )
    11.5 ( 4.73 )
    13.9 ( 9.36 )
        Cycle 3
    8.34 ( 0.354 )
    12.2 ( 2.55 )
    11.4 ( 5.98 )
    12.3 ( 5.59 )
        Cycle 4
    10.7 ( 1.64 )
    12.5 ( 4.84 )
    11.7 ( 4.62 )
    11.9 ( 5.04 )
        Cycle 5
    10.1 ( 999 )
    12.6 ( 5.03 )
    11.3 ( 4.91 )
    11.6 ( 4.49 )
        Cycle 6
    10.0 ( 1.38 )
    11.8 ( 3.73 )
    11.6 ( 5.12 )
    10.9 ( 3.52 )
        Cycle 7
    11.6 ( 3.8 )
    11.8 ( 5.24 )
    12.0 ( 4.86 )
    11.0 ( 4.26 )
        Cycle 8
    9.24 ( 3.06 )
    10.2 ( 4.13 )
    10.3 ( 3.92 )
    11.3 ( 4.08 )
        Cycle 9
    8.73 ( 3.35 )
    10.5 ( 4.43 )
    10.9 ( 4.57 )
    11.6 ( 4.22 )
        Cycle 10
    8.24 ( 999 )
    10.5 ( 4.02 )
    10.9 ( 4.47 )
    11.8 ( 4.26 )
        Cycle 11
    10.7 ( 999 )
    11.6 ( 4.69 )
    10.3 ( 3.67 )
    11.4 ( 3.57 )
        Cycle 12
    10.6 ( 3.92 )
    11.0 ( 4.53 )
    10.6 ( 4.31 )
    11.2 ( 3.82 )
        Cycle 18
    10.1 ( 999 )
    13.0 ( 4.6 )
    9.66 ( 3.49 )
    12.1 ( 5.13 )
        Cycle 24
    999 ( 999 )
    13.4 ( 8.03 )
    10.7 ( 4.89 )
    10.7 ( 2.21 )
        Cycle 30
    10.8 ( 999 )
    999 ( 999 )
    9.34 ( 7.56 )
    10.1 ( 2.76 )
        Cycle 36
    8.97 ( 999 )
    999 ( 999 )
    999 ( 999 )
    999 ( 999 )
    No statistical analyses for this end point

    Secondary: Number of participants with dose interruptions

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    End point title
    		 Number of participants with dose interruptions
    End point description
    Number of participants with dose interruptions for spartalizumab, dabrafenib and trametinib
    End point type
    Secondary
    End point timeframe
    From baseline to end of treatment, assessed up to approximately 7 years
    End point values
    		 P1-Safety: PDR001 400mg Q4W + dab 150mg BID + tram 2mg QD P2-Biomarker: PDR001 400mg Q4W + dab 150mg BID + tram 2mg QD P3-Arm1: PDR001 400mg Q4W + dab 150mg BID + tram 2mg QD P3-Arm2: Placebo + dab 150mg BID + tram 2mg QD
    Number of subjects analysed
    9
    27
    267
    264
    Units: Participants
        Spartalizumab|With no dose interruption
    4
    11
    120
    170
        Dabrafenib|With no dose interruption
    0
    2
    29
    74
        Trametinib|With no dose interruption
    0
    1
    29
    64
        Spartalizumab|With at least one dose interruption
    5
    16
    147
    94
        Dabrafenib|With at least one dose interruption
    9
    25
    238
    190
        Trametinib|With at least one dose interruption
    9
    26
    238
    200
    No statistical analyses for this end point

    Secondary: Number of participants with dose reductions

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    End point title
    		 Number of participants with dose reductions
    End point description
    Number of patients with dose reductions for spartalizumab, dabrafenib and trametinib
    End point type
    Secondary
    End point timeframe
    From baseline to end of treatment, assessed up to approximately 7 years
    End point values
    		 P1-Safety: PDR001 400mg Q4W + dab 150mg BID + tram 2mg QD P2-Biomarker: PDR001 400mg Q4W + dab 150mg BID + tram 2mg QD P3-Arm1: PDR001 400mg Q4W + dab 150mg BID + tram 2mg QD P3-Arm2: Placebo + dab 150mg BID + tram 2mg QD
    Number of subjects analysed
    9
    27
    267
    264
    Units: Participants
        Dabrafenib|No dose reduction or interruption
    0
    2
    25
    68
        Trametinib|No dose reduction or interruption
    0
    1
    28
    63
        Dabrafenib|≥1 dose red./interruption
    9
    25
    242
    196
        Trametinib|≥1 dose red./interruption
    9
    26
    239
    201
    No statistical analyses for this end point

    Secondary: Relative dose intensity

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    End point title
    		 Relative dose intensity
    End point description
    Relative dose intensity for spartalizumab, dabrafenib and trametinib computed as the ratio (expressed as percentage) of dose intensity and planned dose intensity: * Spartalizumab (PDR001) = [Dose intensity (mg/4W) / planned dose intensity (mg/4W)]*100. * Trametinib and Dabrafenib = [Dose intensity (mg/day) / planned dose intensity (mg/day)]*100.
    End point type
    Secondary
    End point timeframe
    From baseline to end of treatment, assessed up to approximately 7 years
    End point values
    		 P1-Safety: PDR001 400mg Q4W + dab 150mg BID + tram 2mg QD P2-Biomarker: PDR001 400mg Q4W + dab 150mg BID + tram 2mg QD P3-Arm1: PDR001 400mg Q4W + dab 150mg BID + tram 2mg QD P3-Arm2: Placebo + dab 150mg BID + tram 2mg QD
    Number of subjects analysed
    9
    27
    267
    264
    Units: Percentage of planned dose intensity
    arithmetic mean (standard deviation)
        Spartalizumab (PDR001)
    90.7 ( 16.83 )
    91.7 ( 10.41 )
    94.4 ( 9.21 )
    97.5 ( 5.33 )
        Dabrafenib
    62.2 ( 26.36 )
    71.3 ( 21.13 )
    78.1 ( 21.21 )
    89.6 ( 15.10 )
        Trametinib
    65.9 ( 16.90 )
    76.2 ( 17.19 )
    79.8 ( 19.58 )
    89.5 ( 14.86 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events (AEs) were collected from first dose of study medication until the last dose plus 30 days safety follow-up, assessed up to approximately 86 months.
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    27.0
    Reporting groups
    Reporting group title
    Part I PDR001 + D + T
    Reporting group description
    		 Part I PDR001 + D + T

    Reporting group title
    Part III Placebo + D + T
    Reporting group description
    		 Part III Placebo + D + T

    Reporting group title
    Part III PDR001 + D + T
    Reporting group description
    		 Part III PDR001 + D + T

    Reporting group title
    Part II PDR001 + D + T
    Reporting group description
    		 Part II PDR001 + D + T

    Serious adverse events
    		 Part I PDR001 + D + T Part III Placebo + D + T Part III PDR001 + D + T Part II PDR001 + D + T
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 9 (77.78%)
    123 / 264 (46.59%)
    151 / 267 (56.55%)
    18 / 27 (66.67%)
         number of deaths (all causes)
    2
    33
    28
    3
         number of deaths resulting from adverse events
    0
    2
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of colon
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to meninges
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma in situ
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Benign breast neoplasm
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    0 / 9 (0.00%)
    3 / 264 (1.14%)
    2 / 267 (0.75%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
    8 / 8
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Adenocarcinoma pancreas
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasm malignant
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-Hodgkin's lymphoma
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oncologic complication
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 264 (0.76%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thyroid neoplasm
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract neoplasm
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine neoplasm
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Aneurysm ruptured
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    2 / 267 (0.75%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Vasculitis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymphoedema
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Shock haemorrhagic
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Administration site extravasation
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Generalised oedema
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza like illness
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    4 / 267 (1.50%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    3 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    3 / 267 (1.12%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Discomfort
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 264 (0.76%)
    3 / 267 (1.12%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    3 / 267 (1.12%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 264 (0.76%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    2 / 267 (0.75%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    4 / 9 (44.44%)
    16 / 264 (6.06%)
    46 / 267 (17.23%)
    4 / 27 (14.81%)
         occurrences causally related to treatment / all
    7 / 7
    22 / 25
    65 / 70
    8 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Contrast media allergy
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sarcoidosis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    2 / 267 (0.75%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemophagocytic lymphohistiocytosis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cytokine release syndrome
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostatic disorder
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Autoimmune lung disease
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 9 (0.00%)
    3 / 264 (1.14%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    2 / 267 (0.75%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    1 / 267 (0.37%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 9 (0.00%)
    6 / 264 (2.27%)
    7 / 267 (2.62%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 6
    2 / 8
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 264 (0.76%)
    9 / 267 (3.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    9 / 10
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    2 / 267 (0.75%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 264 (0.76%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    2 / 267 (0.75%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Alanine aminotransferase abnormal
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    2 / 267 (0.75%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 264 (0.00%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase abnormal
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Amylase increased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    4 / 267 (1.50%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Body temperature increased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General physical condition abnormal
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    2 / 267 (0.75%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ejection fraction decreased
         subjects affected / exposed
    1 / 9 (11.11%)
    15 / 264 (5.68%)
    17 / 267 (6.37%)
    3 / 27 (11.11%)
         occurrences causally related to treatment / all
    1 / 1
    16 / 18
    18 / 18
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lipase increased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Streptococcus test positive
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Craniocerebral injury
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    2 / 267 (0.75%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post embolisation syndrome
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Scapula fracture
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound haemorrhage
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 264 (0.76%)
    2 / 267 (0.75%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arteriosclerosis coronary artery
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    0 / 267 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Cardiac disorder
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    3 / 267 (1.12%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinus node dysfunction
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Altered state of consciousness
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Amnesia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aphasia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Brain oedema
         subjects affected / exposed
    0 / 9 (0.00%)
    3 / 264 (1.14%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    Cerebral haematoma
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    3 / 267 (1.12%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 264 (0.76%)
    2 / 267 (0.75%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysarthria
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 264 (0.76%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 264 (0.76%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cognitive disorder
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 9 (0.00%)
    3 / 264 (1.14%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 9 (0.00%)
    4 / 264 (1.52%)
    3 / 267 (1.12%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningism
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic cerebral infarction
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Intracranial tumour haemorrhage
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intracranial pressure increased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Immune-mediated encephalopathy
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolic encephalopathy
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Monoparesis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nerve compression
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorder
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neuritis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    0 / 267 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neurological decompensation
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    2 / 267 (0.75%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Partial seizures
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral motor neuropathy
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Polyneuropathy
         subjects affected / exposed
    0 / 9 (0.00%)
    3 / 264 (1.14%)
    2 / 267 (0.75%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 9 (0.00%)
    4 / 264 (1.52%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    2 / 267 (0.75%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    0 / 267 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tremor
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 264 (0.76%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymphadenopathy mediastinal
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Conjunctival haemorrhage
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cataract
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angle closure glaucoma
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Detachment of retinal pigment epithelium
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    2 / 267 (0.75%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diplopia
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 264 (0.76%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vision blurred
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uveitis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    3 / 267 (1.12%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retinal degeneration
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Macular detachment
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Iridocyclitis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    5 / 267 (1.87%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    5 / 267 (1.87%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    5 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Autoimmune colitis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    2 / 267 (0.75%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aphthous ulcer
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal wall haematoma
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    2 / 267 (0.75%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis ischaemic
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 9 (11.11%)
    2 / 264 (0.76%)
    3 / 267 (1.12%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 264 (0.76%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    1 / 267 (0.37%)
    2 / 27 (7.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 264 (0.00%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 9 (0.00%)
    5 / 264 (1.89%)
    3 / 267 (1.12%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 5
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal haemorrhage
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Autoimmune hepatitis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    4 / 267 (1.50%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 264 (0.00%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertransaminasaemia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Portal vein thrombosis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Liver disorder
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune-mediated hepatitis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    2 / 267 (0.75%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin ulcer
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dermatitis acneiform
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dermatitis exfoliative generalised
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    0 / 267 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 264 (0.00%)
    2 / 267 (0.75%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Toxic skin eruption
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    0 / 267 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Immune-mediated nephritis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    2 / 267 (0.75%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Calculus urinary
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    1 / 9 (11.11%)
    2 / 264 (0.76%)
    9 / 267 (3.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 3
    6 / 9
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephritis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    2 / 267 (0.75%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urethral stenosis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tubulointerstitial nephritis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    2 / 267 (0.75%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 264 (0.76%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    2 / 267 (0.75%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Hypophysitis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Adrenal insufficiency
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypothyroidism
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 264 (0.76%)
    3 / 267 (1.12%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 9 (0.00%)
    4 / 264 (1.52%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bursitis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc disorder
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    1 / 267 (0.37%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscle haemorrhage
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Soft tissue necrosis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sacral pain
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    2 / 267 (0.75%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis perforated
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacterial food poisoning
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Biliary tract infection
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 264 (0.38%)
    5 / 267 (1.87%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis infectious
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Empyema
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile infection
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    2 / 267 (0.75%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    2 / 267 (0.75%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    0 / 267 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash pustular
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 9 (11.11%)
    3 / 264 (1.14%)
    5 / 267 (1.87%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    1 / 5
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural infection
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural sepsis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    3 / 267 (1.12%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Systemic infection
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sweating fever
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    2 / 267 (0.75%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 9 (0.00%)
    3 / 264 (1.14%)
    5 / 267 (1.87%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    1 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Urinary tract infection fungal
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    3 / 267 (1.12%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    1 / 267 (0.37%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gout
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 264 (0.00%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Part I PDR001 + D + T Part III Placebo + D + T Part III PDR001 + D + T Part II PDR001 + D + T
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 9 (100.00%)
    250 / 264 (94.70%)
    262 / 267 (98.13%)
    27 / 27 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Fibrous histiocytoma
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Basal cell carcinoma
         subjects affected / exposed
    1 / 9 (11.11%)
    9 / 264 (3.41%)
    2 / 267 (0.75%)
    1 / 27 (3.70%)
         occurrences all number
    4
    12
    4
    1
    Vascular disorders
    Hot flush
         subjects affected / exposed
    0 / 9 (0.00%)
    4 / 264 (1.52%)
    5 / 267 (1.87%)
    3 / 27 (11.11%)
         occurrences all number
    0
    5
    5
    4
    Superficial vein thrombosis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 264 (0.00%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Hypotension
         subjects affected / exposed
    2 / 9 (22.22%)
    7 / 264 (2.65%)
    10 / 267 (3.75%)
    1 / 27 (3.70%)
         occurrences all number
    3
    8
    11
    1
    Lymphoedema
         subjects affected / exposed
    1 / 9 (11.11%)
    4 / 264 (1.52%)
    7 / 267 (2.62%)
    3 / 27 (11.11%)
         occurrences all number
    1
    4
    7
    3
    Orthostatic hypotension
         subjects affected / exposed
    0 / 9 (0.00%)
    3 / 264 (1.14%)
    0 / 267 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    4
    0
    2
    Hypertension
         subjects affected / exposed
    0 / 9 (0.00%)
    34 / 264 (12.88%)
    20 / 267 (7.49%)
    2 / 27 (7.41%)
         occurrences all number
    0
    43
    25
    2
    General disorders and administration site conditions
    Face oedema
         subjects affected / exposed
    1 / 9 (11.11%)
    2 / 264 (0.76%)
    8 / 267 (3.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    2
    9
    0
    Fatigue
         subjects affected / exposed
    7 / 9 (77.78%)
    69 / 264 (26.14%)
    71 / 267 (26.59%)
    11 / 27 (40.74%)
         occurrences all number
    9
    141
    115
    15
    Influenza like illness
         subjects affected / exposed
    4 / 9 (44.44%)
    15 / 264 (5.68%)
    28 / 267 (10.49%)
    4 / 27 (14.81%)
         occurrences all number
    6
    21
    208
    5
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 9 (22.22%)
    1 / 264 (0.38%)
    5 / 267 (1.87%)
    1 / 27 (3.70%)
         occurrences all number
    2
    1
    5
    1
    Oedema
         subjects affected / exposed
    0 / 9 (0.00%)
    7 / 264 (2.65%)
    3 / 267 (1.12%)
    2 / 27 (7.41%)
         occurrences all number
    0
    7
    3
    3
    Oedema due to cardiac disease
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 264 (0.00%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Chills
         subjects affected / exposed
    8 / 9 (88.89%)
    63 / 264 (23.86%)
    86 / 267 (32.21%)
    9 / 27 (33.33%)
         occurrences all number
    17
    148
    303
    44
    Axillary pain
         subjects affected / exposed
    0 / 9 (0.00%)
    3 / 264 (1.14%)
    4 / 267 (1.50%)
    2 / 27 (7.41%)
         occurrences all number
    0
    3
    4
    2
    Asthenia
         subjects affected / exposed
    1 / 9 (11.11%)
    55 / 264 (20.83%)
    73 / 267 (27.34%)
    11 / 27 (40.74%)
         occurrences all number
    2
    116
    107
    17
    Oedema peripheral
         subjects affected / exposed
    1 / 9 (11.11%)
    28 / 264 (10.61%)
    30 / 267 (11.24%)
    2 / 27 (7.41%)
         occurrences all number
    1
    29
    34
    3
    Pain
         subjects affected / exposed
    1 / 9 (11.11%)
    10 / 264 (3.79%)
    7 / 267 (2.62%)
    5 / 27 (18.52%)
         occurrences all number
    1
    14
    10
    6
    Pyrexia
         subjects affected / exposed
    9 / 9 (100.00%)
    145 / 264 (54.92%)
    189 / 267 (70.79%)
    23 / 27 (85.19%)
         occurrences all number
    59
    670
    1330
    99
    Xerosis
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 264 (0.76%)
    3 / 267 (1.12%)
    2 / 27 (7.41%)
         occurrences all number
    0
    2
    4
    2
    Immune system disorders
    Cytokine release syndrome
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 264 (0.00%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Sarcoidosis
         subjects affected / exposed
    1 / 9 (11.11%)
    2 / 264 (0.76%)
    5 / 267 (1.87%)
    1 / 27 (3.70%)
         occurrences all number
    1
    2
    5
    1
    Reproductive system and breast disorders
    Ovarian cyst
         subjects affected / exposed
    1 / 9 (11.11%)
    2 / 264 (0.76%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    2
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 9 (11.11%)
    30 / 264 (11.36%)
    37 / 267 (13.86%)
    3 / 27 (11.11%)
         occurrences all number
    1
    36
    40
    3
    Cough
         subjects affected / exposed
    6 / 9 (66.67%)
    49 / 264 (18.56%)
    63 / 267 (23.60%)
    12 / 27 (44.44%)
         occurrences all number
    10
    63
    102
    15
    Epistaxis
         subjects affected / exposed
    1 / 9 (11.11%)
    8 / 264 (3.03%)
    17 / 267 (6.37%)
    1 / 27 (3.70%)
         occurrences all number
    2
    9
    31
    1
    Oropharyngeal pain
         subjects affected / exposed
    2 / 9 (22.22%)
    11 / 264 (4.17%)
    10 / 267 (3.75%)
    2 / 27 (7.41%)
         occurrences all number
    4
    12
    11
    2
    Pleurisy
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 264 (0.00%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pneumonitis
         subjects affected / exposed
    3 / 9 (33.33%)
    4 / 264 (1.52%)
    28 / 267 (10.49%)
    4 / 27 (14.81%)
         occurrences all number
    3
    4
    38
    5
    Pulmonary embolism
         subjects affected / exposed
    1 / 9 (11.11%)
    6 / 264 (2.27%)
    12 / 267 (4.49%)
    0 / 27 (0.00%)
         occurrences all number
    1
    6
    12
    0
    Pulmonary haemorrhage
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 264 (0.00%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Rhinorrhoea
         subjects affected / exposed
    1 / 9 (11.11%)
    5 / 264 (1.89%)
    10 / 267 (3.75%)
    1 / 27 (3.70%)
         occurrences all number
    1
    5
    13
    1
    Sinus congestion
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 9 (0.00%)
    16 / 264 (6.06%)
    12 / 267 (4.49%)
    1 / 27 (3.70%)
         occurrences all number
    0
    18
    12
    1
    Insomnia
         subjects affected / exposed
    1 / 9 (11.11%)
    18 / 264 (6.82%)
    22 / 267 (8.24%)
    1 / 27 (3.70%)
         occurrences all number
    2
    22
    23
    1
    Disorientation
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Bradyphrenia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 264 (0.00%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 9 (33.33%)
    41 / 264 (15.53%)
    67 / 267 (25.09%)
    7 / 27 (25.93%)
         occurrences all number
    7
    69
    99
    12
    Blood testosterone decreased
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 264 (0.00%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Amylase increased
         subjects affected / exposed
    4 / 9 (44.44%)
    22 / 264 (8.33%)
    46 / 267 (17.23%)
    4 / 27 (14.81%)
         occurrences all number
    14
    30
    73
    6
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 9 (22.22%)
    53 / 264 (20.08%)
    76 / 267 (28.46%)
    5 / 27 (18.52%)
         occurrences all number
    7
    77
    114
    13
    Blood albumin decreased
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 264 (0.38%)
    4 / 267 (1.50%)
    0 / 27 (0.00%)
         occurrences all number
    1
    1
    4
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    2 / 9 (22.22%)
    28 / 264 (10.61%)
    33 / 267 (12.36%)
    4 / 27 (14.81%)
         occurrences all number
    6
    38
    63
    8
    Blood cholesterol increased
         subjects affected / exposed
    1 / 9 (11.11%)
    11 / 264 (4.17%)
    12 / 267 (4.49%)
    3 / 27 (11.11%)
         occurrences all number
    2
    23
    29
    5
    Blood creatine phosphokinase increased
         subjects affected / exposed
    3 / 9 (33.33%)
    72 / 264 (27.27%)
    75 / 267 (28.09%)
    9 / 27 (33.33%)
         occurrences all number
    3
    160
    172
    13
    Blood creatinine increased
         subjects affected / exposed
    2 / 9 (22.22%)
    9 / 264 (3.41%)
    24 / 267 (8.99%)
    2 / 27 (7.41%)
         occurrences all number
    3
    12
    45
    4
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    1 / 9 (11.11%)
    21 / 264 (7.95%)
    27 / 267 (10.11%)
    1 / 27 (3.70%)
         occurrences all number
    4
    41
    44
    1
    Blood sodium decreased
         subjects affected / exposed
    1 / 9 (11.11%)
    2 / 264 (0.76%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences all number
    1
    3
    1
    0
    Blood thyroid stimulating hormone decreased
         subjects affected / exposed
    1 / 9 (11.11%)
    2 / 264 (0.76%)
    5 / 267 (1.87%)
    0 / 27 (0.00%)
         occurrences all number
    1
    2
    5
    0
    Blood triglycerides increased
         subjects affected / exposed
    1 / 9 (11.11%)
    2 / 264 (0.76%)
    3 / 267 (1.12%)
    0 / 27 (0.00%)
         occurrences all number
    1
    4
    6
    0
    C-reactive protein increased
         subjects affected / exposed
    2 / 9 (22.22%)
    11 / 264 (4.17%)
    12 / 267 (4.49%)
    2 / 27 (7.41%)
         occurrences all number
    3
    13
    12
    2
    Ejection fraction decreased
         subjects affected / exposed
    1 / 9 (11.11%)
    21 / 264 (7.95%)
    18 / 267 (6.74%)
    2 / 27 (7.41%)
         occurrences all number
    1
    26
    22
    2
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    2 / 9 (22.22%)
    20 / 264 (7.58%)
    17 / 267 (6.37%)
    3 / 27 (11.11%)
         occurrences all number
    5
    25
    22
    3
    Globulins increased
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 264 (0.00%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 9 (0.00%)
    5 / 264 (1.89%)
    5 / 267 (1.87%)
    2 / 27 (7.41%)
         occurrences all number
    0
    5
    6
    2
    Lipase increased
         subjects affected / exposed
    5 / 9 (55.56%)
    38 / 264 (14.39%)
    66 / 267 (24.72%)
    5 / 27 (18.52%)
         occurrences all number
    11
    65
    131
    8
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 9 (0.00%)
    5 / 264 (1.89%)
    5 / 267 (1.87%)
    2 / 27 (7.41%)
         occurrences all number
    0
    6
    7
    2
    Myoglobin blood increased
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 264 (0.00%)
    2 / 267 (0.75%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    3
    0
    Neutrophil count decreased
         subjects affected / exposed
    2 / 9 (22.22%)
    11 / 264 (4.17%)
    8 / 267 (3.00%)
    3 / 27 (11.11%)
         occurrences all number
    3
    12
    16
    4
    Transaminases increased
         subjects affected / exposed
    0 / 9 (0.00%)
    6 / 264 (2.27%)
    9 / 267 (3.37%)
    2 / 27 (7.41%)
         occurrences all number
    0
    6
    13
    2
    Weight decreased
         subjects affected / exposed
    0 / 9 (0.00%)
    11 / 264 (4.17%)
    17 / 267 (6.37%)
    4 / 27 (14.81%)
         occurrences all number
    0
    12
    25
    4
    White blood cell count decreased
         subjects affected / exposed
    1 / 9 (11.11%)
    6 / 264 (2.27%)
    9 / 267 (3.37%)
    2 / 27 (7.41%)
         occurrences all number
    1
    6
    12
    3
    Injury, poisoning and procedural complications
    Compression fracture
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 264 (0.00%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Contusion
         subjects affected / exposed
    1 / 9 (11.11%)
    2 / 264 (0.76%)
    2 / 267 (0.75%)
    0 / 27 (0.00%)
         occurrences all number
    1
    2
    2
    0
    Procedural pain
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 264 (0.00%)
    2 / 267 (0.75%)
    1 / 27 (3.70%)
         occurrences all number
    1
    0
    3
    1
    Radiation skin injury
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 264 (0.00%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Nervous system disorders
    Anosmia
         subjects affected / exposed
    2 / 9 (22.22%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Aphasia
         subjects affected / exposed
    1 / 9 (11.11%)
    2 / 264 (0.76%)
    4 / 267 (1.50%)
    0 / 27 (0.00%)
         occurrences all number
    1
    2
    4
    0
    Dizziness
         subjects affected / exposed
    2 / 9 (22.22%)
    23 / 264 (8.71%)
    21 / 267 (7.87%)
    1 / 27 (3.70%)
         occurrences all number
    2
    30
    25
    2
    Syncope
         subjects affected / exposed
    0 / 9 (0.00%)
    3 / 264 (1.14%)
    2 / 267 (0.75%)
    4 / 27 (14.81%)
         occurrences all number
    0
    4
    2
    4
    Peroneal nerve palsy
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    2 / 27 (7.41%)
         occurrences all number
    0
    0
    1
    2
    Paraesthesia
         subjects affected / exposed
    0 / 9 (0.00%)
    14 / 264 (5.30%)
    14 / 267 (5.24%)
    5 / 27 (18.52%)
         occurrences all number
    0
    18
    17
    8
    Migraine
         subjects affected / exposed
    1 / 9 (11.11%)
    2 / 264 (0.76%)
    2 / 267 (0.75%)
    0 / 27 (0.00%)
         occurrences all number
    1
    2
    6
    0
    Memory impairment
         subjects affected / exposed
    1 / 9 (11.11%)
    2 / 264 (0.76%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences all number
    1
    2
    1
    0
    Headache
         subjects affected / exposed
    5 / 9 (55.56%)
    74 / 264 (28.03%)
    80 / 267 (29.96%)
    8 / 27 (29.63%)
         occurrences all number
    31
    188
    208
    18
    Dysgeusia
         subjects affected / exposed
    0 / 9 (0.00%)
    6 / 264 (2.27%)
    13 / 267 (4.87%)
    3 / 27 (11.11%)
         occurrences all number
    0
    6
    14
    3
    Dysaesthesia
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 264 (0.76%)
    2 / 267 (0.75%)
    3 / 27 (11.11%)
         occurrences all number
    0
    2
    2
    3
    Dizziness postural
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 264 (0.00%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    2 / 9 (22.22%)
    14 / 264 (5.30%)
    23 / 267 (8.61%)
    1 / 27 (3.70%)
         occurrences all number
    3
    21
    50
    3
    Anaemia
         subjects affected / exposed
    4 / 9 (44.44%)
    31 / 264 (11.74%)
    49 / 267 (18.35%)
    10 / 27 (37.04%)
         occurrences all number
    6
    70
    92
    13
    Lymphopenia
         subjects affected / exposed
    1 / 9 (11.11%)
    11 / 264 (4.17%)
    20 / 267 (7.49%)
    4 / 27 (14.81%)
         occurrences all number
    3
    12
    30
    11
    Thrombocytosis
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 264 (0.38%)
    3 / 267 (1.12%)
    0 / 27 (0.00%)
         occurrences all number
    1
    2
    3
    0
    Thrombocytopenia
         subjects affected / exposed
    2 / 9 (22.22%)
    10 / 264 (3.79%)
    24 / 267 (8.99%)
    3 / 27 (11.11%)
         occurrences all number
    2
    23
    43
    7
    Neutropenia
         subjects affected / exposed
    4 / 9 (44.44%)
    37 / 264 (14.02%)
    44 / 267 (16.48%)
    3 / 27 (11.11%)
         occurrences all number
    8
    75
    111
    11
    Ear and labyrinth disorders
    Ear congestion
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Ear pain
         subjects affected / exposed
    3 / 9 (33.33%)
    1 / 264 (0.38%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences all number
    5
    1
    1
    0
    Motion sickness
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 264 (0.00%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Eye disorders
    Dry eye
         subjects affected / exposed
    0 / 9 (0.00%)
    9 / 264 (3.41%)
    5 / 267 (1.87%)
    9 / 27 (33.33%)
         occurrences all number
    0
    13
    6
    9
    Myopia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 264 (0.00%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Iridocyclitis
         subjects affected / exposed
    1 / 9 (11.11%)
    3 / 264 (1.14%)
    3 / 267 (1.12%)
    0 / 27 (0.00%)
         occurrences all number
    1
    4
    3
    0
    Ocular discomfort
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    2 / 27 (7.41%)
         occurrences all number
    0
    0
    1
    2
    Papilloedema
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 264 (0.38%)
    2 / 267 (0.75%)
    1 / 27 (3.70%)
         occurrences all number
    1
    1
    2
    1
    Vitreal cells
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 264 (0.00%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Visual impairment
         subjects affected / exposed
    0 / 9 (0.00%)
    6 / 264 (2.27%)
    10 / 267 (3.75%)
    2 / 27 (7.41%)
         occurrences all number
    0
    7
    10
    2
    Vision blurred
         subjects affected / exposed
    0 / 9 (0.00%)
    13 / 264 (4.92%)
    9 / 267 (3.37%)
    2 / 27 (7.41%)
         occurrences all number
    0
    16
    10
    2
    Uveitis
         subjects affected / exposed
    1 / 9 (11.11%)
    4 / 264 (1.52%)
    7 / 267 (2.62%)
    3 / 27 (11.11%)
         occurrences all number
    3
    5
    8
    3
    Retinopathy
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 264 (0.00%)
    0 / 267 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    1
    0
    0
    1
    Retinal haemorrhage
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Photophobia
         subjects affected / exposed
    1 / 9 (11.11%)
    3 / 264 (1.14%)
    6 / 267 (2.25%)
    0 / 27 (0.00%)
         occurrences all number
    1
    3
    6
    0
    Periorbital oedema
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 264 (0.38%)
    4 / 267 (1.50%)
    0 / 27 (0.00%)
         occurrences all number
    1
    1
    4
    0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 9 (11.11%)
    5 / 264 (1.89%)
    2 / 267 (0.75%)
    0 / 27 (0.00%)
         occurrences all number
    1
    6
    2
    0
    Glossitis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    1
    0
    2
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 9 (11.11%)
    6 / 264 (2.27%)
    9 / 267 (3.37%)
    0 / 27 (0.00%)
         occurrences all number
    1
    25
    10
    0
    Dyspepsia
         subjects affected / exposed
    0 / 9 (0.00%)
    13 / 264 (4.92%)
    18 / 267 (6.74%)
    0 / 27 (0.00%)
         occurrences all number
    0
    17
    21
    0
    Dry mouth
         subjects affected / exposed
    1 / 9 (11.11%)
    13 / 264 (4.92%)
    22 / 267 (8.24%)
    6 / 27 (22.22%)
         occurrences all number
    1
    14
    26
    8
    Nausea
         subjects affected / exposed
    1 / 9 (11.11%)
    78 / 264 (29.55%)
    90 / 267 (33.71%)
    8 / 27 (29.63%)
         occurrences all number
    4
    136
    162
    19
    Constipation
         subjects affected / exposed
    1 / 9 (11.11%)
    40 / 264 (15.15%)
    40 / 267 (14.98%)
    7 / 27 (25.93%)
         occurrences all number
    2
    49
    55
    10
    Cheilitis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 264 (0.00%)
    0 / 267 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    1
    0
    0
    1
    Abdominal pain upper
         subjects affected / exposed
    1 / 9 (11.11%)
    17 / 264 (6.44%)
    26 / 267 (9.74%)
    1 / 27 (3.70%)
         occurrences all number
    2
    29
    39
    1
    Abdominal pain
         subjects affected / exposed
    1 / 9 (11.11%)
    26 / 264 (9.85%)
    29 / 267 (10.86%)
    5 / 27 (18.52%)
         occurrences all number
    1
    40
    42
    10
    Diarrhoea
         subjects affected / exposed
    4 / 9 (44.44%)
    70 / 264 (26.52%)
    98 / 267 (36.70%)
    9 / 27 (33.33%)
         occurrences all number
    7
    173
    182
    14
    Vomiting
         subjects affected / exposed
    4 / 9 (44.44%)
    50 / 264 (18.94%)
    69 / 267 (25.84%)
    10 / 27 (37.04%)
         occurrences all number
    11
    116
    128
    14
    Odynophagia
         subjects affected / exposed
    1 / 9 (11.11%)
    4 / 264 (1.52%)
    4 / 267 (1.50%)
    0 / 27 (0.00%)
         occurrences all number
    1
    10
    4
    0
    Trichoglossia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 264 (0.00%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Hepatobiliary disorders
    Hepatic cytolysis
         subjects affected / exposed
    0 / 9 (0.00%)
    7 / 264 (2.65%)
    5 / 267 (1.87%)
    2 / 27 (7.41%)
         occurrences all number
    0
    10
    5
    2
    Hepatic function abnormal
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 264 (0.00%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Hepatic steatosis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Hypertransaminasaemia
         subjects affected / exposed
    2 / 9 (22.22%)
    4 / 264 (1.52%)
    6 / 267 (2.25%)
    0 / 27 (0.00%)
         occurrences all number
    3
    6
    7
    0
    Immune-mediated hepatitis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    1 / 27 (3.70%)
         occurrences all number
    1
    0
    1
    1
    Hepatitis
         subjects affected / exposed
    2 / 9 (22.22%)
    3 / 264 (1.14%)
    5 / 267 (1.87%)
    1 / 27 (3.70%)
         occurrences all number
    2
    5
    6
    2
    Skin and subcutaneous tissue disorders
    Dermatitis acneiform
         subjects affected / exposed
    3 / 9 (33.33%)
    14 / 264 (5.30%)
    13 / 267 (4.87%)
    2 / 27 (7.41%)
         occurrences all number
    5
    16
    14
    2
    Dry skin
         subjects affected / exposed
    0 / 9 (0.00%)
    15 / 264 (5.68%)
    14 / 267 (5.24%)
    4 / 27 (14.81%)
         occurrences all number
    0
    15
    17
    7
    Alopecia
         subjects affected / exposed
    0 / 9 (0.00%)
    9 / 264 (3.41%)
    17 / 267 (6.37%)
    2 / 27 (7.41%)
         occurrences all number
    0
    9
    17
    2
    Eczema
         subjects affected / exposed
    1 / 9 (11.11%)
    16 / 264 (6.06%)
    9 / 267 (3.37%)
    2 / 27 (7.41%)
         occurrences all number
    1
    19
    10
    3
    Erythema
         subjects affected / exposed
    0 / 9 (0.00%)
    11 / 264 (4.17%)
    27 / 267 (10.11%)
    3 / 27 (11.11%)
         occurrences all number
    0
    12
    37
    3
    Photosensitivity reaction
         subjects affected / exposed
    1 / 9 (11.11%)
    3 / 264 (1.14%)
    9 / 267 (3.37%)
    1 / 27 (3.70%)
         occurrences all number
    1
    3
    12
    1
    Panniculitis
         subjects affected / exposed
    1 / 9 (11.11%)
    8 / 264 (3.03%)
    9 / 267 (3.37%)
    2 / 27 (7.41%)
         occurrences all number
    3
    12
    15
    2
    Palmoplantar keratoderma
         subjects affected / exposed
    1 / 9 (11.11%)
    2 / 264 (0.76%)
    0 / 267 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    1
    4
    0
    2
    Night sweats
         subjects affected / exposed
    3 / 9 (33.33%)
    11 / 264 (4.17%)
    10 / 267 (3.75%)
    4 / 27 (14.81%)
         occurrences all number
    4
    18
    26
    5
    Ingrowing nail
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 264 (0.38%)
    3 / 267 (1.12%)
    0 / 27 (0.00%)
         occurrences all number
    1
    1
    3
    0
    Hyperkeratosis
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 264 (0.38%)
    5 / 267 (1.87%)
    0 / 27 (0.00%)
         occurrences all number
    1
    1
    7
    0
    Hyperhidrosis
         subjects affected / exposed
    2 / 9 (22.22%)
    14 / 264 (5.30%)
    7 / 267 (2.62%)
    1 / 27 (3.70%)
         occurrences all number
    12
    15
    7
    1
    Granuloma annulare
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Erythema nodosum
         subjects affected / exposed
    1 / 9 (11.11%)
    9 / 264 (3.41%)
    14 / 267 (5.24%)
    1 / 27 (3.70%)
         occurrences all number
    6
    12
    14
    2
    Pruritus
         subjects affected / exposed
    1 / 9 (11.11%)
    22 / 264 (8.33%)
    51 / 267 (19.10%)
    8 / 27 (29.63%)
         occurrences all number
    3
    26
    89
    12
    Skin disorder
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Sensitive skin
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 264 (0.00%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Seborrhoeic dermatitis
         subjects affected / exposed
    1 / 9 (11.11%)
    4 / 264 (1.52%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences all number
    1
    4
    2
    0
    Rash pruritic
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    7 / 267 (2.62%)
    2 / 27 (7.41%)
         occurrences all number
    0
    1
    8
    2
    Stasis dermatitis
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 264 (0.38%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences all number
    1
    1
    3
    0
    Rash macular
         subjects affected / exposed
    2 / 9 (22.22%)
    3 / 264 (1.14%)
    2 / 267 (0.75%)
    2 / 27 (7.41%)
         occurrences all number
    2
    4
    2
    3
    Rash erythematous
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 264 (0.38%)
    5 / 267 (1.87%)
    1 / 27 (3.70%)
         occurrences all number
    1
    1
    5
    1
    Rash
         subjects affected / exposed
    4 / 9 (44.44%)
    68 / 264 (25.76%)
    76 / 267 (28.46%)
    13 / 27 (48.15%)
         occurrences all number
    11
    97
    115
    20
    Psoriasis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    1 / 267 (0.37%)
    2 / 27 (7.41%)
         occurrences all number
    0
    1
    1
    4
    Rash maculo-papular
         subjects affected / exposed
    2 / 9 (22.22%)
    6 / 264 (2.27%)
    16 / 267 (5.99%)
    3 / 27 (11.11%)
         occurrences all number
    2
    39
    21
    3
    Urticaria
         subjects affected / exposed
    1 / 9 (11.11%)
    7 / 264 (2.65%)
    6 / 267 (2.25%)
    1 / 27 (3.70%)
         occurrences all number
    3
    7
    6
    1
    Vitiligo
         subjects affected / exposed
    0 / 9 (0.00%)
    3 / 264 (1.14%)
    21 / 267 (7.87%)
    2 / 27 (7.41%)
         occurrences all number
    0
    3
    21
    2
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 9 (0.00%)
    8 / 264 (3.03%)
    14 / 267 (5.24%)
    1 / 27 (3.70%)
         occurrences all number
    0
    11
    19
    1
    Haematuria
         subjects affected / exposed
    1 / 9 (11.11%)
    9 / 264 (3.41%)
    8 / 267 (3.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    9
    8
    0
    Nocturia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    1
    0
    2
    Acute kidney injury
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 264 (0.38%)
    6 / 267 (2.25%)
    2 / 27 (7.41%)
         occurrences all number
    1
    1
    8
    2
    Endocrine disorders
    Hypophysitis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 264 (0.00%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Hyperthyroidism
         subjects affected / exposed
    2 / 9 (22.22%)
    5 / 264 (1.89%)
    18 / 267 (6.74%)
    0 / 27 (0.00%)
         occurrences all number
    2
    5
    22
    0
    Hypothyroidism
         subjects affected / exposed
    4 / 9 (44.44%)
    17 / 264 (6.44%)
    20 / 267 (7.49%)
    1 / 27 (3.70%)
         occurrences all number
    4
    19
    24
    2
    Inappropriate antidiuretic hormone secretion
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 264 (0.00%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Thyroiditis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 264 (0.00%)
    3 / 267 (1.12%)
    1 / 27 (3.70%)
         occurrences all number
    1
    0
    3
    1
    Musculoskeletal and connective tissue disorders
    Groin pain
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 264 (0.38%)
    7 / 267 (2.62%)
    1 / 27 (3.70%)
         occurrences all number
    1
    1
    7
    1
    Flank pain
         subjects affected / exposed
    1 / 9 (11.11%)
    2 / 264 (0.76%)
    1 / 267 (0.37%)
    2 / 27 (7.41%)
         occurrences all number
    1
    2
    1
    2
    Back pain
         subjects affected / exposed
    2 / 9 (22.22%)
    37 / 264 (14.02%)
    33 / 267 (12.36%)
    5 / 27 (18.52%)
         occurrences all number
    2
    49
    40
    8
    Arthritis
         subjects affected / exposed
    1 / 9 (11.11%)
    4 / 264 (1.52%)
    6 / 267 (2.25%)
    0 / 27 (0.00%)
         occurrences all number
    1
    4
    6
    0
    Arthralgia
         subjects affected / exposed
    6 / 9 (66.67%)
    80 / 264 (30.30%)
    87 / 267 (32.58%)
    15 / 27 (55.56%)
         occurrences all number
    35
    155
    165
    26
    Joint swelling
         subjects affected / exposed
    1 / 9 (11.11%)
    5 / 264 (1.89%)
    6 / 267 (2.25%)
    2 / 27 (7.41%)
         occurrences all number
    3
    5
    6
    4
    Limb discomfort
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 264 (0.00%)
    2 / 267 (0.75%)
    1 / 27 (3.70%)
         occurrences all number
    1
    0
    3
    1
    Musculoskeletal stiffness
         subjects affected / exposed
    1 / 9 (11.11%)
    5 / 264 (1.89%)
    1 / 267 (0.37%)
    1 / 27 (3.70%)
         occurrences all number
    2
    5
    1
    2
    Musculoskeletal pain
         subjects affected / exposed
    0 / 9 (0.00%)
    8 / 264 (3.03%)
    3 / 267 (1.12%)
    2 / 27 (7.41%)
         occurrences all number
    0
    11
    3
    3
    Musculoskeletal chest pain
         subjects affected / exposed
    2 / 9 (22.22%)
    3 / 264 (1.14%)
    5 / 267 (1.87%)
    0 / 27 (0.00%)
         occurrences all number
    2
    5
    6
    0
    Muscular weakness
         subjects affected / exposed
    0 / 9 (0.00%)
    4 / 264 (1.52%)
    8 / 267 (3.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    4
    9
    2
    Muscle spasms
         subjects affected / exposed
    0 / 9 (0.00%)
    28 / 264 (10.61%)
    32 / 267 (11.99%)
    2 / 27 (7.41%)
         occurrences all number
    0
    36
    68
    2
    Myalgia
         subjects affected / exposed
    4 / 9 (44.44%)
    37 / 264 (14.02%)
    43 / 267 (16.10%)
    8 / 27 (29.63%)
         occurrences all number
    6
    83
    71
    11
    Neck pain
         subjects affected / exposed
    0 / 9 (0.00%)
    9 / 264 (3.41%)
    7 / 267 (2.62%)
    3 / 27 (11.11%)
         occurrences all number
    0
    9
    7
    4
    Osteopenia
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    1
    1
    0
    2
    Rotator cuff syndrome
         subjects affected / exposed
    1 / 9 (11.11%)
    2 / 264 (0.76%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    2
    0
    0
    Pain in extremity
         subjects affected / exposed
    1 / 9 (11.11%)
    23 / 264 (8.71%)
    31 / 267 (11.61%)
    6 / 27 (22.22%)
         occurrences all number
    1
    30
    48
    11
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 9 (0.00%)
    5 / 264 (1.89%)
    20 / 267 (7.49%)
    1 / 27 (3.70%)
         occurrences all number
    0
    5
    22
    1
    Candida infection
         subjects affected / exposed
    1 / 9 (11.11%)
    2 / 264 (0.76%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    2
    2
    0
    0
    COVID-19
         subjects affected / exposed
    0 / 9 (0.00%)
    13 / 264 (4.92%)
    18 / 267 (6.74%)
    0 / 27 (0.00%)
         occurrences all number
    0
    13
    20
    0
    Cellulitis
         subjects affected / exposed
    1 / 9 (11.11%)
    2 / 264 (0.76%)
    6 / 267 (2.25%)
    2 / 27 (7.41%)
         occurrences all number
    1
    3
    8
    3
    Gastrointestinal viral infection
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Furuncle
         subjects affected / exposed
    1 / 9 (11.11%)
    3 / 264 (1.14%)
    0 / 267 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    1
    3
    0
    1
    Fungal skin infection
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 264 (0.38%)
    2 / 267 (0.75%)
    0 / 27 (0.00%)
         occurrences all number
    1
    1
    2
    0
    Folliculitis
         subjects affected / exposed
    3 / 9 (33.33%)
    8 / 264 (3.03%)
    14 / 267 (5.24%)
    1 / 27 (3.70%)
         occurrences all number
    5
    10
    19
    2
    Conjunctivitis
         subjects affected / exposed
    2 / 9 (22.22%)
    9 / 264 (3.41%)
    14 / 267 (5.24%)
    3 / 27 (11.11%)
         occurrences all number
    2
    9
    15
    4
    Nasopharyngitis
         subjects affected / exposed
    2 / 9 (22.22%)
    32 / 264 (12.12%)
    28 / 267 (10.49%)
    3 / 27 (11.11%)
         occurrences all number
    2
    39
    44
    3
    Oral candidiasis
         subjects affected / exposed
    1 / 9 (11.11%)
    2 / 264 (0.76%)
    2 / 267 (0.75%)
    2 / 27 (7.41%)
         occurrences all number
    1
    2
    3
    2
    Tonsillitis
         subjects affected / exposed
    1 / 9 (11.11%)
    2 / 264 (0.76%)
    3 / 267 (1.12%)
    0 / 27 (0.00%)
         occurrences all number
    1
    2
    3
    0
    Sinusitis
         subjects affected / exposed
    1 / 9 (11.11%)
    2 / 264 (0.76%)
    12 / 267 (4.49%)
    2 / 27 (7.41%)
         occurrences all number
    1
    3
    15
    2
    Rhinitis
         subjects affected / exposed
    1 / 9 (11.11%)
    10 / 264 (3.79%)
    18 / 267 (6.74%)
    1 / 27 (3.70%)
         occurrences all number
    1
    11
    20
    1
    Postoperative wound infection
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 264 (0.38%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Pneumonia
         subjects affected / exposed
    1 / 9 (11.11%)
    9 / 264 (3.41%)
    9 / 267 (3.37%)
    2 / 27 (7.41%)
         occurrences all number
    1
    10
    10
    4
    Paronychia
         subjects affected / exposed
    1 / 9 (11.11%)
    3 / 264 (1.14%)
    4 / 267 (1.50%)
    0 / 27 (0.00%)
         occurrences all number
    1
    4
    5
    0
    Otitis media chronic
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 264 (0.00%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Otitis media
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 264 (0.38%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Oral herpes
         subjects affected / exposed
    1 / 9 (11.11%)
    4 / 264 (1.52%)
    8 / 267 (3.00%)
    1 / 27 (3.70%)
         occurrences all number
    1
    4
    10
    1
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 9 (33.33%)
    9 / 264 (3.41%)
    17 / 267 (6.37%)
    1 / 27 (3.70%)
         occurrences all number
    4
    10
    30
    1
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 9 (11.11%)
    2 / 264 (0.76%)
    2 / 267 (0.75%)
    0 / 27 (0.00%)
         occurrences all number
    1
    3
    2
    0
    Viral rhinitis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 264 (0.00%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Viral pharyngitis
         subjects affected / exposed
    2 / 9 (22.22%)
    0 / 264 (0.00%)
    0 / 267 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Viral infection
         subjects affected / exposed
    1 / 9 (11.11%)
    5 / 264 (1.89%)
    4 / 267 (1.50%)
    1 / 27 (3.70%)
         occurrences all number
    1
    5
    5
    1
    Urinary tract infection
         subjects affected / exposed
    0 / 9 (0.00%)
    25 / 264 (9.47%)
    26 / 267 (9.74%)
    5 / 27 (18.52%)
         occurrences all number
    0
    39
    55
    5
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 9 (22.22%)
    27 / 264 (10.23%)
    33 / 267 (12.36%)
    7 / 27 (25.93%)
         occurrences all number
    2
    30
    38
    9
    Dehydration
         subjects affected / exposed
    1 / 9 (11.11%)
    3 / 264 (1.14%)
    3 / 267 (1.12%)
    0 / 27 (0.00%)
         occurrences all number
    1
    4
    3
    0
    Hypophosphataemia
         subjects affected / exposed
    0 / 9 (0.00%)
    16 / 264 (6.06%)
    14 / 267 (5.24%)
    4 / 27 (14.81%)
         occurrences all number
    0
    25
    21
    9
    Hyperglycaemia
         subjects affected / exposed
    1 / 9 (11.11%)
    24 / 264 (9.09%)
    37 / 267 (13.86%)
    2 / 27 (7.41%)
         occurrences all number
    1
    35
    92
    3
    Hypocalcaemia
         subjects affected / exposed
    0 / 9 (0.00%)
    4 / 264 (1.52%)
    3 / 267 (1.12%)
    2 / 27 (7.41%)
         occurrences all number
    0
    4
    3
    2
    Hypokalaemia
         subjects affected / exposed
    1 / 9 (11.11%)
    6 / 264 (2.27%)
    15 / 267 (5.62%)
    2 / 27 (7.41%)
         occurrences all number
    2
    7
    27
    3
    Hyponatraemia
         subjects affected / exposed
    2 / 9 (22.22%)
    4 / 264 (1.52%)
    17 / 267 (6.37%)
    2 / 27 (7.41%)
         occurrences all number
    3
    5
    30
    2
    Hypercholesterolaemia
         subjects affected / exposed
    1 / 9 (11.11%)
    4 / 264 (1.52%)
    8 / 267 (3.00%)
    1 / 27 (3.70%)
         occurrences all number
    1
    10
    14
    1
    Iron deficiency
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 264 (0.00%)
    2 / 267 (0.75%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Type 2 diabetes mellitus
         subjects affected / exposed
    1 / 9 (11.11%)
    5 / 264 (1.89%)
    1 / 267 (0.37%)
    0 / 27 (0.00%)
         occurrences all number
    1
    5
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Jan 2017
    • Removed double barrier contraception from the list of highly effective methods of contraception and clarified this removal from the exclusion criterion.
    07 Mar 2017
    • Updated criteria for DLT for Part 1. • Added ‘≥ grade 3 AEs that were known to occur with dabrafenib, trametinib and/or spartalizumab, but cannot be controlled using the recommended product-specific management guidelines or lead to ˂ 50% of planned exposure to study medications’. • Changed threshold for subjects with normal baseline AST and ALT values: ‘AST or ALT > 8.0 × ULN’ (grade 4 AST or ALT elevation’ was subsequently removed) • ‘Active infection requiring systemic antibiotic therapy within 2 weeks prior to start of study treatment’ • Added requirement for a local HIV testing at screening for subjects in Germany to exclusion criterion • Updated primary objective and endpoint for Part 2 to specifically mention the main two biomarkers of interest (PD-L1 levels and CD+8 cells).
    14 Jul 2017
    • Changes were made to pyrexia management guidelines based on the safety profile observed in the safety run-in (part 1) and feedback received from investigators upon review of safety data. • Changes to improve data collection for radiotherapy events, central review using tumor response criteria based on guidelines for immunotherapy, ophthalmologic examination assessment frequency, and patient reported outcomes were implemented • The BRAF V600 testing method was clarified and language was added to reflect the AJCC edition 8 melanoma staging system • The frequency of the data monitoring committee review of safety data was revised from 6 to 3-6 months to ensure appropriate safety monitoring
    14 Aug 2018
    • Aligned the contraception requirements during and after study treatment based on the dabrafenib Investigator’s Brochure (IB) Edition 10 and trametinib IB Edition 9. • The safety follow-up periods were aligned with the contraception requirements after study treatment had been discontinued. • Revised individual subject unblinding requirements to limit the impact of unblinding on the scientific validity of the study results • Added a new exploratory objective and a corresponding endpoint to characterize the potential for TMB alone and in combination with PD-L1, or additional markers to identify subjects with an enhanced response to spartalizumab in combination with dabrafenib and trametinib versus placebo plus dabrafenib and trametinib. • Updated withdrawal of consent to reflect European Economic Area General Data Protection Regulation requirements. Except for US and Japan, all biological samples not yet analyzed at the time of withdrawal were no longer to be used for analysis.
    08 Mar 2019
    • Adjusted the timing of the final PFS analysis and included an interim analysis for PFS based on revised assumptions on the delayed treatment effect. • In order to achieve a statistical power of 80% based on a conservative assumption of a 5 months delayed treatment effect and followed by an effect of the same magnitude as assumed in the original protocol (i.e. HR=0.60), the number of PFS events for the final PFS analysis was increased from 246 to approximately 352 PFS events. Furthermore, an interim PFS analysis was introduced at approximately 260 PFS events. • In addition, OS analysis was also revised based on the assumed 5 months delayed treatment effect.
    13 Oct 2020
    • The primary objective of this amendment was to enable continuation of the study following the final PFS analysis, in order to characterize the overall survival benefit observed at the final PFS analysis. • Removal of the crossover schedule as it was no longer applicable as protocol defined criteria for crossover was not met. • Inclusion of all general recommendations already provided to the investigators in a letter dated 7-Apr-2020 to provide guidance on coronavirus disease-19 (COVID-19) related challenges that may affected the study protocol execution. • The contraception information was updated.
    18 Jan 2023
    • Revised the definition of end of study in section 4.3 of the protocol to include Post-Trial Access (PTA) program i.e., rollover protocol or a post study drug supply (PSDS) option for subjects still on study treatment and in the opinion of the investigator still deriving clinical benefit at the time of end of the study. • Updated safety information on hemophagocytic lymphohistiocytosis (HLH) and updated “dose modification and recommended clinical management guidelines” in the safety section including treatment resumption for recurrent grade 4 asymptomatic amylase or lipase elevation per UK Health Authority (MHRA) request. • A sub-section 2.7 related to public health emergency mitigation procedures was added. • Section 8.3 related to “Emergency unblinding of treatment assignment” was updated for clarification per Swissmedic feedback. • Language was updated to align with the latest Novartis protocol template (OneCTP version 5.0).

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

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

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