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    Clinical Trial Results:
    A Phase 3 Randomized, Placebo-controlled Study to Evaluate the Safety and Efficacy of Pemetrexed + Platinum Chemotherapy + Pembrolizumab (MK-3475) with or without Lenvatinib (E7080/MK-7902) as First-line Intervention in Participants with Metastatic Nonsquamous Non-small Cell Lung Cancer (LEAP-006)

    Summary
    EudraCT number
    		 2018-003824-35
    Trial protocol
    		 GB   DE   ES   PL   FR  
    Global end of trial date
    30 Aug 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 Sep 2025
    First version publication date
    05 Sep 2025
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    MK-7902-006
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03829319
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme LLC
    Sponsor organisation address
    126 East Lincoln Avenue, P.O. Box 2000, Rahway, NJ, United States, 07065
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme LLC, ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme LLC, ClinicalTrialsDisclosure@merck.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    30 Aug 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 Aug 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Aug 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is to assess the safety and efficacy of pemetrexed + platinum chemotherapy + pembrolizumab (MK-3475) with or without lenvatinib (MK-7902/E7080) as first-line intervention in adults with metastatic nonsquamous non-small cell lung cancer. The primary study hypotheses state that: 1) the combination of lenvatinib + platinum doublet chemotherapy + pembrolizumab prolongs Progression-free Survival (PFS) as assessed by blinded independent central review (BICR) per modified Response Evaluation Criteria in Solid Tumors version 1.1 (RESIST 1.1) compared to matching placebo + platinum doublet chemotherapy + pembrolizumab, and 2) the combination of lenvatinib + platinum doublet chemotherapy + pembrolizumab prolongs Overall Survival (OS) compared to matching placebo + platinum doublet chemotherapy + pembrolizumab.
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    25 Mar 2019
    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: 55
    Country: Number of subjects enrolled
    Australia: 16
    Country: Number of subjects enrolled
    Canada: 17
    Country: Number of subjects enrolled
    Chile: 74
    Country: Number of subjects enrolled
    China: 134
    Country: Number of subjects enrolled
    Germany: 19
    Country: Number of subjects enrolled
    Spain: 110
    Country: Number of subjects enrolled
    France: 26
    Country: Number of subjects enrolled
    United Kingdom: 21
    Country: Number of subjects enrolled
    Israel: 36
    Country: Number of subjects enrolled
    Japan: 50
    Country: Number of subjects enrolled
    Korea, Democratic People's Republic of: 42
    Country: Number of subjects enrolled
    New Zealand: 4
    Country: Number of subjects enrolled
    Poland: 33
    Country: Number of subjects enrolled
    Russian Federation: 47
    Country: Number of subjects enrolled
    Türkiye: 59
    Country: Number of subjects enrolled
    United States: 18
    Worldwide total number of subjects
    761
    EEA total number of subjects
    188
    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)
    415
    From 65 to 84 years
    343
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants with treatment-naïve, metastatic nonsquamous Non-small cell lung cancer (NSCLC) were recruited in this study.

    Pre-assignment
    Screening details
    		 Per protocol, Part 1 participants were excluded from all Part 2 efficacy and safety outcome measures.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Part 1 First Course: Pembrolizumab+Chemotherapy+Lenvatinib
    Arm description
    		 Participants received carboplatin AUC5 or cisplatin 75 mg/m^2 via IV infusion Q3W for 4 cycles PLUS pemetrexed 500 mg/m^2 via IV infusion Q3W for 4 cycles PLUS pembrolizumab 200 mg via IV infusion Q3W for up to 35 cycles (up to 2 years) PLUS lenvatinib 8 mg via oral capsule once daily.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    MK-3475 KEYTRUDA®
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    200 mg via intravenous (IV) infusion on Day 1 of each 3-week cycle (Q3W) for up to 35 administrations (up to approximately 2 years)

    Investigational medicinal product name
    Lenvatinib
    Investigational medicinal product code
    Other name
    MK-7902 E7080 LENVIMA®
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    8 mg via oral capsule once daily (QD) on Days 1-21 of each 3-week cycle until progressive disease or unacceptable toxicity or intercurrent illness that prevents further administration of treatment or investigator’s decision to withdraw treatment or participant withdrawal of consent or pregnancy or noncompliance with study intervention or procedure requirements, or administrative reasons requiring cessation of treatment

    Investigational medicinal product name
    Pemetrexed
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    500 mg/m2 via IV infusion Q3W for 4 cycles until progressive disease or unacceptable toxicity or intercurrent illness that prevents further administration of treatment or investigator’s decision to withdraw treatment or participant withdrawal of consent or pregnancy or noncompliance with study intervention or procedure requirements, or administrative reasons requiring cessation of treatment

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5 mg/m^2 via IV infusion on Day 1 of each Q3W for 4 cycles (up to approximately 2 years)

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Area Under Curve 5 mg/mL/min (AUC5) IV infusion on Day 1 of each Q3W for 4 cycles (up to approximately 2 years)

    Arm title
    		 Part 2 First Course: Pembrolizumab+Chemotherapy+Lenvatinib
    Arm description
    		 Participants received carboplatin Area Under Curve 5 mg/mL/min (AUC5) or cisplatin 75 mg/m^2 via intravenous (IV) infusion on Day 1 of each 3-week cycle (Q3W) for 4 cycles PLUS pemetrexed 500 mg/m^2 via IV infusion Q3W for 4 cycles PLUS pembrolizumab 200 mg via IV infusion Q3W for up to 35 cycles (up to 2 years) PLUS lenvatinib 8 mg via oral capsule once daily.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    MK-3475 KEYTRUDA®
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    200 mg via intravenous (IV) infusion on Day 1 of each 3-week cycle (Q3W) for up to 35 administrations (up to approximately 2 years)

    Investigational medicinal product name
    Lenvatinib
    Investigational medicinal product code
    Other name
    MK-7902 E7080 LENVIMA®
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    8 mg via oral capsule once daily (QD) on Days 1-21 of each 3-week cycle until progressive disease or unacceptable toxicity or intercurrent illness that prevents further administration of treatment or investigator’s decision to withdraw treatment or participant withdrawal of consent or pregnancy or noncompliance with study intervention or procedure requirements, or administrative reasons requiring cessation of treatment

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Area Under Curve 5 mg/mL/min (AUC5) IV infusion on Day 1 of each Q3W for 4 cycles (up to approximately 2 years)

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5 mg/m^2 via IV infusion on Day 1 of each Q3W for 4 cycles (up to approximately 2 years)

    Investigational medicinal product name
    Pemetrexed
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    500 mg/m2 via IV infusion Q3W for 4 cycles until progressive disease or unacceptable toxicity or intercurrent illness that prevents further administration of treatment or investigator’s decision to withdraw treatment or participant withdrawal of consent or pregnancy or noncompliance with study intervention or procedure requirements, or administrative reasons requiring cessation of treatment

    Arm title
    		 Part 2 First Course: Pembrolizumab+Chemotherapy+Placebo
    Arm description
    		 Participants received carboplatin AUC5 or cisplatin 75 mg/m^2 via IV infusion Q3W for 4 cycles PLUS pemetrexed 500 mg/m^2 via IV infusion Q3W for 4 cycles PLUS pembrolizumab 200 mg via IV infusion Q3W for up to 35 cycles (up to 2 years) PLUS placebo matching lenvatinib via oral capsule once daily.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Lenvatinib
    Investigational medicinal product code
    Other name
    MK-7902 E7080 LENVIMA®
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    8 mg via oral capsule once daily (QD) on Days 1-21 of each 3-week cycle until progressive disease or unacceptable toxicity or intercurrent illness that prevents further administration of treatment or investigator’s decision to withdraw treatment or participant withdrawal of consent or pregnancy or noncompliance with study intervention or procedure requirements, or administrative reasons requiring cessation of treatment

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Area Under Curve 5 mg/mL/min (AUC5) IV infusion on Day 1 of each Q3W for 4 cycles (up to approximately 2 years)

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    MK-3475 KEYTRUDA®
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    200 mg via intravenous (IV) infusion on Day 1 of each 3-week cycle (Q3W) for up to 35 administrations (up to approximately 2 years)

    Investigational medicinal product name
    Pemetrexed
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    500 mg/m2 via IV infusion Q3W for 4 cycles until progressive disease or unacceptable toxicity or intercurrent illness that prevents further administration of treatment or investigator’s decision to withdraw treatment or participant withdrawal of consent or pregnancy or noncompliance with study intervention or procedure requirements, or administrative reasons requiring cessation of treatment

    Investigational medicinal product name
    Placebo for lenvatinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    oral capsule QD on Days 1-21 of each Q3W until progressive disease or unacceptable toxicity or intercurrent illness that prevents further administration of treatment or investigator’s decision to withdraw treatment or participant withdrawal of consent or pregnancy or noncompliance with study intervention or procedure requirements, or administrative reasons requiring cessation of treatment

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5 mg/m^2 via IV infusion on Day 1 of each Q3W for 4 cycles (up to approximately 2 years)

    Number of subjects in period 1
    		Part 1 First Course: Pembrolizumab+Chemotherapy+Lenvatinib Part 2 First Course: Pembrolizumab+Chemotherapy+Lenvatinib Part 2 First Course: Pembrolizumab+Chemotherapy+Placebo
    Started
    13
    375
    373
    Treated during first course
    13
    373
    372
    Treated during second Course
    1
    3
    5
    Completed
    0
    0
    0
    Not completed
    13
    375
    373
         Adverse event, serious fatal
    8
    277
    266
         Consent withdrawn by subject
    1
    5
    4
         Physician decision
    -
    3
    -
         Sponsor's Decision
    4
    90
    102
         Lost to follow-up
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part 1 First Course: Pembrolizumab+Chemotherapy+Lenvatinib
    Reporting group description
    		 Participants received carboplatin AUC5 or cisplatin 75 mg/m^2 via IV infusion Q3W for 4 cycles PLUS pemetrexed 500 mg/m^2 via IV infusion Q3W for 4 cycles PLUS pembrolizumab 200 mg via IV infusion Q3W for up to 35 cycles (up to 2 years) PLUS lenvatinib 8 mg via oral capsule once daily.

    Reporting group title
    Part 2 First Course: Pembrolizumab+Chemotherapy+Lenvatinib
    Reporting group description
    		 Participants received carboplatin Area Under Curve 5 mg/mL/min (AUC5) or cisplatin 75 mg/m^2 via intravenous (IV) infusion on Day 1 of each 3-week cycle (Q3W) for 4 cycles PLUS pemetrexed 500 mg/m^2 via IV infusion Q3W for 4 cycles PLUS pembrolizumab 200 mg via IV infusion Q3W for up to 35 cycles (up to 2 years) PLUS lenvatinib 8 mg via oral capsule once daily.

    Reporting group title
    Part 2 First Course: Pembrolizumab+Chemotherapy+Placebo
    Reporting group description
    		 Participants received carboplatin AUC5 or cisplatin 75 mg/m^2 via IV infusion Q3W for 4 cycles PLUS pemetrexed 500 mg/m^2 via IV infusion Q3W for 4 cycles PLUS pembrolizumab 200 mg via IV infusion Q3W for up to 35 cycles (up to 2 years) PLUS placebo matching lenvatinib via oral capsule once daily.

    Reporting group values
    		 Part 1 First Course: Pembrolizumab+Chemotherapy+Lenvatinib Part 2 First Course: Pembrolizumab+Chemotherapy+Lenvatinib Part 2 First Course: Pembrolizumab+Chemotherapy+Placebo Total
    Number of subjects
    		 13 375 373 761
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 64.2 ( 7.6 ) 62.0 ( 9.9 ) 63.0 ( 9.7 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 6 121 126 253
        Male
    		 7 254 247 508
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 1 1
        Asian
    		 5 116 114 235
        Native Hawaiian or Other Pacific Islander
    		 0 2 1 3
        Black or African American
    		 0 0 3 3
        White
    		 8 248 237 493
        More than one race
    		 0 0 0 0
        Unknown or Not Reported
    		 0 9 17 26
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 0 75 77 152
        Not Hispanic or Latino
    		 13 291 279 583
        Unknown or Not Reported
    		 0 9 17 26
    Eastern Cooperative Oncology Group (ECOG) Performance Status
    Randomization of participants in the study was stratified by an ECOG Performance Status of 0 (Fully active, able to carry on all pre-disease performance without restriction) or 1 (Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature)
    Units: Subjects
        ECOG = 0
    		 8 135 133 276
        ECOG = 1
    		 5 240 240 485
    Programmed Cell Death Ligand 1 (PD-L1) Status at Baseline
    Participants were assessed for their PD-L1 tumor expression level by immunohistochemistry assay using tumor tissue from a newly obtained biopsy. Randomization of participants in the study was stratified by PD-L1 tumor proportion score (TPS) at baseline (< 50% or ≥ 50%). Higher percentages of PD-L1 TPS staining correspond to higher positivity of PD-L1 on a tumor.
    Units: Subjects
        TPS = < 50%
    		 10 272 269 551
        TPS = ≥ 50%
    		 3 90 91 184
        Not Evaluable
    		 0 13 13 26
    Geographic Region
    Randomization of participants in this study was stratified by geographic region of the enrolling site (East Asia or non-East Asia).
    Units: Subjects
        East Asia
    		 3 111 112 226
        Non-East Asia
    		 10 264 261 535

    End points

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    End points reporting groups
    Reporting group title
    Part 1 First Course: Pembrolizumab+Chemotherapy+Lenvatinib
    Reporting group description
    		 Participants received carboplatin AUC5 or cisplatin 75 mg/m^2 via IV infusion Q3W for 4 cycles PLUS pemetrexed 500 mg/m^2 via IV infusion Q3W for 4 cycles PLUS pembrolizumab 200 mg via IV infusion Q3W for up to 35 cycles (up to 2 years) PLUS lenvatinib 8 mg via oral capsule once daily.

    Reporting group title
    Part 2 First Course: Pembrolizumab+Chemotherapy+Lenvatinib
    Reporting group description
    		 Participants received carboplatin Area Under Curve 5 mg/mL/min (AUC5) or cisplatin 75 mg/m^2 via intravenous (IV) infusion on Day 1 of each 3-week cycle (Q3W) for 4 cycles PLUS pemetrexed 500 mg/m^2 via IV infusion Q3W for 4 cycles PLUS pembrolizumab 200 mg via IV infusion Q3W for up to 35 cycles (up to 2 years) PLUS lenvatinib 8 mg via oral capsule once daily.

    Reporting group title
    Part 2 First Course: Pembrolizumab+Chemotherapy+Placebo
    Reporting group description
    		 Participants received carboplatin AUC5 or cisplatin 75 mg/m^2 via IV infusion Q3W for 4 cycles PLUS pemetrexed 500 mg/m^2 via IV infusion Q3W for 4 cycles PLUS pembrolizumab 200 mg via IV infusion Q3W for up to 35 cycles (up to 2 years) PLUS placebo matching lenvatinib via oral capsule once daily.

    Primary: Part 1: Number of Participants with a Dose-limiting Toxicity (DLT)

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    End point title
    		 Part 1: Number of Participants with a Dose-limiting Toxicity (DLT) [1] [2]
    End point description
    Dose-limiting toxicity using Common Terminology Criteria for Adverse Events v4.0 for grading, is defined as any of the following hematologic toxicities: 1) Grade 4 neutropenia, 2) Grade 3 or 4 febrile neutropenia, 3) thrombocytopenia <25,000 cells/mm^3 associated with bleeding and/or which requires platelet transfusion, or any of the following non-hematologic toxicities: 4) any other Grade 4 or 5 toxicity, 5) Grade 3 toxicities lasting >3 days (exclusions apply), 6) Grade 3 hypertension not controlled by medication, 7) Grade 3 or above gastrointestinal perforation, 8) Grade 3 or above wound dehiscence requiring medical or surgical intervention, 9) any grade thromboembolic event, or 10) any Grade 3 nonhematologic laboratory value if medical intervention is required or the abnormality leads to hospitalization. The analysis population consisted of all participants enrolled in Part 1 who received at least 1 dose of study intervention.
    End point type
    Primary
    End point timeframe
    Cycle 1; each cycle is 21 days (up to 21 days)
    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: There are no statistical analyses planned for this endpoint.
    [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: There are no statistical analyses planned for this endpoint.
    End point values
    		 Part 1 First Course: Pembrolizumab+Chemotherapy+Lenvatinib
    Number of subjects analysed
    13
    Units: Participants
    2
    No statistical analyses for this end point

    Primary: Part 1: Number of Participants Who Experienced an Adverse Event (AE)

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    End point title
    		 Part 1: Number of Participants Who Experienced an Adverse Event (AE) [3] [4]
    End point description
    An adverse event is defined as any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The number of participants who experience one of more adverse events during Part 1 of this study will be presented. The analysis population consisted of all participants enrolled in Part 1 who received at least 1 dose of study intervention.
    End point type
    Primary
    End point timeframe
    Up to approximately 48 months
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There are no statistical analyses planned for this endpoint.
    [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: There are no statistical analyses planned for this endpoint.
    End point values
    		 Part 1 First Course: Pembrolizumab+Chemotherapy+Lenvatinib
    Number of subjects analysed
    13
    Units: Participants
    13
    No statistical analyses for this end point

    Primary: Part 2: Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)

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    End point title
    		 Part 2: Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) [5]
    End point description
    PFS was defined as the time from date of randomization to the date of the first documentation of progressive disease (PD) or death from any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. Note: The appearance of one or more new lesions was also considered PD. Data are from the product-limit (Kaplan-Meier) method for censored data. PFS as assessed by blinded independent central review (BICR) per RECIST 1.1 is presented. The analysis population consisted of all randomized participants in Part 2 who received at least 1 dose of study intervention and were evaluable for response.
    End point type
    Primary
    End point timeframe
    Up to approximately 36 months
    Notes
    [5] - 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: The statistical analysis planned for part 2 first course for this endpoint.
    End point values
    		 Part 2 First Course: Pembrolizumab+Chemotherapy+Lenvatinib Part 2 First Course: Pembrolizumab+Chemotherapy+Placebo
    Number of subjects analysed
    375
    373
    Units: Months
        median (confidence interval 95%)
    12.1 (10.4 to 14.1)
    9.5 (8.3 to 10.7)
    Statistical analysis title
    		 Hazard Ratio (HR)
    Statistical analysis description
    Comparison based on Cox regression model with Efron’s method of tie handling with treatment as a covariate stratified by ECOG performance status (0 versus 1), geographic region of the enrolling site (East Asia versus non-East Asia), and Baseline PD-L1 Status (<50% versus >=50%).
    Comparison groups
    Part 2 First Course: Pembrolizumab+Chemotherapy+Lenvatinib v Part 2 First Course: Pembrolizumab+Chemotherapy+Placebo
    Number of subjects included in analysis
    748
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.07976
    Method
    		 Stratified Log Rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.74
         upper limit
    		 1.05

    Primary: Part 2: Overall Survival (OS)

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    End point title
    		 Part 2: Overall Survival (OS) [6]
    End point description
    OS is defined as the time from randomization to the time of death from any cause. OS is presented. The analysis population consisted of all randomized participants in Part 2 who received at least 1 dose of study intervention and were evaluable for response.
    End point type
    Primary
    End point timeframe
    Up to approximately 47 months
    Notes
    [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: The statistical analysis planned for part 2 first course for this endpoint.
    End point values
    		 Part 2 First Course: Pembrolizumab+Chemotherapy+Lenvatinib Part 2 First Course: Pembrolizumab+Chemotherapy+Placebo
    Number of subjects analysed
    375
    373
    Units: Months
        median (confidence interval 95%)
    21.8 (18.6 to 24.0)
    22.1 (19.7 to 24.2)
    Statistical analysis title
    		 Hazard Ratio (HR)
    Statistical analysis description
    Comparison based on Cox regression model with Efron’s method of tie handling with treatment as a covariate stratified by ECOG performance status (0 versus 1), geographic region of the enrolling site (East Asia versus non-East Asia), and Baseline PD-L1 Status (<50% versus >=50%).
    Comparison groups
    Part 2 First Course: Pembrolizumab+Chemotherapy+Lenvatinib v Part 2 First Course: Pembrolizumab+Chemotherapy+Placebo
    Number of subjects included in analysis
    748
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.70818
    Method
    		 Stratified Log Rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.88
         upper limit
    		 1.26

    Primary: Part 1: Number of Participants Who Discontinued Study Drug Due to an Adverse Event

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    End point title
    		 Part 1: Number of Participants Who Discontinued Study Drug Due to an Adverse Event [7] [8]
    End point description
    An adverse event is defined as any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The number of participants who discontinue study medication due to and adverse event during Part 1 of this study will be presented. The analysis population consisted of all participants enrolled in Part 1 who received at least 1 dose of study intervention.
    End point type
    Primary
    End point timeframe
    Up to approximately 48 months
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There are no statistical analyses planned for this endpoint.
    [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: There are no statistical analyses planned for this endpoint.
    End point values
    		 Part 1 First Course: Pembrolizumab+Chemotherapy+Lenvatinib
    Number of subjects analysed
    13
    Units: Participants
    9
    No statistical analyses for this end point

    Secondary: Part 2: Duration of Response (DOR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)

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    End point title
    		 Part 2: Duration of Response (DOR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) [9]
    End point description
    For participants who demonstrated CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of diameters of target lesions), DOR is defined as the time from the first documented evidence of CR or PR until PD or death from any cause, whichever occurs first. Per RECIST 1.1 modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, or death from any cause, PD is defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. Note: The appearance of one or more new lesions is also considered PD. DOR as assessed per modified RECIST 1.1 will be presented. The analysis population consisted of all randomized participants in Part 2 who received at least 1 dose of study intervention and were evaluable for response.
    End point type
    Secondary
    End point timeframe
    Up to approximately 48 months
    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: There are no statistical analyses planned for this endpoint.
    End point values
    		 Part 2 First Course: Pembrolizumab+Chemotherapy+Lenvatinib Part 2 First Course: Pembrolizumab+Chemotherapy+Placebo
    Number of subjects analysed
    375
    373
    Units: Months
        median (full range (min-max))
    1.6 (1.1 to 15.4)
    1.6 (1.2 to 20.7)
    No statistical analyses for this end point

    Secondary: Part 2: Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)

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    End point title
    		 Part 2: Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) [10]
    End point description
    ORR is defined as the percentage of participants in the analysis population who have a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. ORR as assessed per modified RECIST 1.1 will be presented. The analysis population consisted of all randomized participants in Part 2 who received at least 1 dose of study intervention and were evaluable for response.
    End point type
    Secondary
    End point timeframe
    Up to approximately 19 months
    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: The statistical analysis planned for part 2 first course for this endpoint.
    End point values
    		 Part 2 First Course: Pembrolizumab+Chemotherapy+Lenvatinib Part 2 First Course: Pembrolizumab+Chemotherapy+Placebo
    Number of subjects analysed
    212
    211
    Units: Percentage of Participants
        number (confidence interval 95%)
    57.1 (50.1 to 63.8)
    50.7 (43.8 to 57.6)
    Statistical analysis title
    		 Percent Difference
    Statistical analysis description
    Comparison based on Miettinen & Nurminen method stratified by ECOG performance status (0 versus 1), geographic region of the enrolling site (East Asia versus non-East Asia), and Baseline PD-L1 Status (<50% versus >=50% ).
    Comparison groups
    Part 2 First Course: Pembrolizumab+Chemotherapy+Lenvatinib v Part 2 First Course: Pembrolizumab+Chemotherapy+Placebo
    Number of subjects included in analysis
    423
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.08643
    Method
    		 Stratified Miettinen & Nurminen
    Parameter type
    		 Percent Difference
    Point estimate
    6.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.8
         upper limit
    		 15.4

    Secondary: Part 2: Number of Participants Who Experienced an Adverse Event (AE)

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    End point title
    		 Part 2: Number of Participants Who Experienced an Adverse Event (AE) [11]
    End point description
    An adverse event is defined as any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The number of participants who experienced one of more adverse events during Part 2 of this study were presented. The analysis population consisted of all randomized participants in Part 2 who received at least 1 dose of study intervention.
    End point type
    Secondary
    End point timeframe
    Up to approximately 65 months
    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: There are no statistical analyses planned for this endpoint.
    End point values
    		 Part 2 First Course: Pembrolizumab+Chemotherapy+Lenvatinib Part 2 First Course: Pembrolizumab+Chemotherapy+Placebo
    Number of subjects analysed
    373
    372
    Units: Participants
    372
    370
    No statistical analyses for this end point

    Secondary: Part 2: Number of Participants Who Discontinued Study Drug Due to an Adverse Event

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    End point title
    		 Part 2: Number of Participants Who Discontinued Study Drug Due to an Adverse Event [12]
    End point description
    An adverse event is defined as any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The number of participants who discontinued study treatment during Part 2 of this study were presented. The analysis population consisted of all randomized participants in Part 2 who received at least 1 dose of study intervention.
    End point type
    Secondary
    End point timeframe
    Up to approximately 65 months
    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: There are no statistical analyses planned for this endpoint.
    End point values
    		 Part 2 First Course: Pembrolizumab+Chemotherapy+Lenvatinib Part 2 First Course: Pembrolizumab+Chemotherapy+Placebo
    Number of subjects analysed
    373
    372
    Units: Participants
    127
    92
    No statistical analyses for this end point

    Secondary: Part 2: Change from Baseline in Cough (EORTC Quality of Life Questionnaire-Lung Cancer Module 13 [QLQ-LC13] Item 31) Score

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    End point title
    		 Part 2: Change from Baseline in Cough (EORTC Quality of Life Questionnaire-Lung Cancer Module 13 [QLQ-LC13] Item 31) Score [13]
    End point description
    The EORTC QLQ-LC13 is a lung cancer-specific supplemental questionnaire used in combination with the EORTC QLQ-C30. Participant responses to the question “How much did you cough?” are scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. The change from baseline in cough (EORTC QLQ-LC13 Item 31) score will be presented. A lower score indicates a better outcome. The analysis population consisted of all randomized participants in Part 2 who received at least one dose of study treatment and have at least one EORTC-QLQ-C30 Item 31 assessment data available.
    End point type
    Secondary
    End point timeframe
    Baseline and week 27
    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: The statistical analysis planned for part 2 first course for this endpoint.
    End point values
    		 Part 2 First Course: Pembrolizumab+Chemotherapy+Lenvatinib Part 2 First Course: Pembrolizumab+Chemotherapy+Placebo
    Number of subjects analysed
    368
    371
    Units: Score on a scale
        least squares mean (confidence interval 95%)
    -11.77 (-14.72 to -8.81)
    -11.47 (-14.42 to -8.53)
    Statistical analysis title
    		 Difference in LS Means
    Statistical analysis description
    Comparision based on a cLDA model with the PRO scores as the response variable with covariates for treatment by time interaction, stratification factors (baseline ECOG performance status (0 versus 1), geographic region of the enrolling site (East Asia versus non-East Asia), and baseline PD-L1 Status ( <50% versus ≥50%)) as covariates.
    Comparison groups
    Part 2 First Course: Pembrolizumab+Chemotherapy+Lenvatinib v Part 2 First Course: Pembrolizumab+Chemotherapy+Placebo
    Number of subjects included in analysis
    739
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.8747
    Method
    		 t-test, 2-sided
    Parameter type
    		 Difference in Least Square Means
    Point estimate
    -0.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.95
         upper limit
    		 3.36

    Secondary: Part 2: Change from Baseline in Global Health Status (GHS) (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 [EORTC QLQ-C30] Items 29 and 30) Score

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    End point title
    		 Part 2: Change from Baseline in Global Health Status (GHS) (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 [EORTC QLQ-C30] Items 29 and 30) Score [14]
    End point description
    The EORTC QLQ-C30 is a questionnaire to assess the overall quality of life of cancer patients. Participant responses to the questions regarding Global Health Status (GHS; "How would you rate your overall health during the past week?") and Quality of Life (QoL; "How would you rate your overall quality of life during the past week?") are each scored on a 7-point scale (1=Very poor to 7=Excellent). The two raw scores were averaged into a combined score, then normalized using linear transformation so each participant’s score ranged from 0 to 100 (0=Worst overall health/quality of life and 100=Best overall health/quality of life). The change from baseline in GHS (EORTC QLQ-C30 Item 29) and QoL (EORTC QLQ-C30 Item 30) combined score is presented. The analysis population consisted of all randomized participants in Part 2 who received at least one dose of study treatment and have at least one EORTC-QLQ-C30 Items 29 and 30 assessment data available.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 27
    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: The statistical analysis planned for part 2 first course for this endpoint.
    End point values
    		 Part 2 First Course: Pembrolizumab+Chemotherapy+Lenvatinib Part 2 First Course: Pembrolizumab+Chemotherapy+Placebo
    Number of subjects analysed
    369
    371
    Units: Score on a Scale
        least squares mean (confidence interval 95%)
    0.65 (-1.55 to 2.84)
    1.66 (-0.53 to 3.85)
    Statistical analysis title
    		 Difference in Least Square Means (LS) Means
    Statistical analysis description
    Comparision based on a cLDA model with the PRO scores as the response variable with covariates for treatment by time interaction, stratification factors (baseline ECOG performance status (0 versus 1), geographic region of the enrolling site (East Asia versus non-East Asia), and baseline PD-L1 Status ( <50% versus ≥50%)) as covariates.
    Comparison groups
    Part 2 First Course: Pembrolizumab+Chemotherapy+Lenvatinib v Part 2 First Course: Pembrolizumab+Chemotherapy+Placebo
    Number of subjects included in analysis
    740
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.4805
    Method
    		 t-test, 2-sided
    Parameter type
    		 Difference in Least Square Means
    Point estimate
    -1.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.83
         upper limit
    		 1.8

    Secondary: Part 2: Change from Baseline in Chest Pain (EORTC QLQ-LC13 Item 40) Score

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    End point title
    		 Part 2: Change from Baseline in Chest Pain (EORTC QLQ-LC13 Item 40) Score [15]
    End point description
    The EORTC QLQ-LC13 is a lung cancer-specific supplemental questionnaire used in combination with the EORTC QLQ-C30. Participant responses to the question “Have you had pain in your chest?” are scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. The change from baseline in chest pain (EORTC QLQ-LC13 Item 40) score will be presented. A lower score indicates a better outcome. The analysis population consisted of all randomized participants in Part 2 who received at least one dose of study treatment and have at least one EORTC-QLQ-C30 Item 40 assessment data available.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 27
    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: The statistical analysis planned for part 2 first course for this endpoint.
    End point values
    		 Part 2 First Course: Pembrolizumab+Chemotherapy+Lenvatinib Part 2 First Course: Pembrolizumab+Chemotherapy+Placebo
    Number of subjects analysed
    368
    371
    Units: Score on a scale
        least squares mean (confidence interval 95%)
    -4.61 (-7.26 to -1.96)
    -3.70 (-6.34 to -1.06)
    Statistical analysis title
    		 Difference in LS Means
    Statistical analysis description
    Comparision based on a cLDA model with the PRO scores as the response variable with covariates for treatment by time interaction, stratification factors (baseline ECOG performance status (0 versus 1), geographic region of the enrolling site (East Asia versus non-East Asia), and baseline PD-L1 Status (<50% versus ≥50%)) as covariates.
    Comparison groups
    Part 2 First Course: Pembrolizumab+Chemotherapy+Lenvatinib v Part 2 First Course: Pembrolizumab+Chemotherapy+Placebo
    Number of subjects included in analysis
    739
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.5941
    Method
    		 t-test, 2-sided
    Parameter type
    		 Difference in Least Square Means
    Point estimate
    -0.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.24
         upper limit
    		 2.43

    Secondary: Part 2: Change from Baseline in Dyspnea (EORTC QLQ-C30 Item 8) Score

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    End point title
    		 Part 2: Change from Baseline in Dyspnea (EORTC QLQ-C30 Item 8) Score [16]
    End point description
    The EORTC QLQ-C30 is a questionnaire to assess the overall quality of life of cancer patients. Participant responses to the question “Were you short of breath?” are scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. The change from baseline in dyspnea (EORTC QLQ-C30 Item 8) score will be presented. A lower score indicates a better outcome. The analysis population consisted of all randomized participants in Part 2 who received at least one dose of study treatment and have at least one EORTC-QLQ-C30 Item 8 assessment data available.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 27
    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: The statistical analysis planned for part 2 first course for this endpoint.
    End point values
    		 Part 2 First Course: Pembrolizumab+Chemotherapy+Lenvatinib Part 2 First Course: Pembrolizumab+Chemotherapy+Placebo
    Number of subjects analysed
    369
    371
    Units: Score on a scale
        least squares mean (confidence interval 95%)
    -2.77 (-6.04 to 0.50)
    -0.61 (-3.86 to 2.65)
    Statistical analysis title
    		 Covariate
    Statistical analysis description
    Comparision based on a cLDA model with the PRO scores as the response variable with covariates for treatment by time interaction, stratification factors (baseline ECOG performance status (0 versus 1), geographic region of the enrolling site (East Asia versus non-East Asia), and baseline PD-L1 Status ( <50% versus ≥50%)) as covariates.
    Comparison groups
    Part 2 First Course: Pembrolizumab+Chemotherapy+Lenvatinib v Part 2 First Course: Pembrolizumab+Chemotherapy+Placebo
    Number of subjects included in analysis
    740
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.3115
    Method
    		 t-test, 2-sided
    Parameter type
    		 covariate
    Point estimate
    -2.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.36
         upper limit
    		 2.03

    Secondary: Part 2: Change from Baseline in Physical Functioning (EORTC QLQ-C30 Items 1-5) Score

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    End point title
    		 Part 2: Change from Baseline in Physical Functioning (EORTC QLQ-C30 Items 1-5) Score [17]
    End point description
    The EORTC QLQ-C30 is a questionnaire to assess the overall quality of life of cancer patients. Participant responses to 5 questions about their physical functioning are scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. The change from baseline in Physical Functioning (EORTC QLQ-C30 Items 1-5) score will be presented. A higher score indicates a better quality of life. The analysis population consisted of all randomized participants in Part 2 who received at least one dose of study treatment and have at least one EORTC-QLQ-C30 Items 1-5 assessment data available.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 27
    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: The statistical analysis planned for part 2 first course for this endpoint.
    End point values
    		 Part 2 First Course: Pembrolizumab+Chemotherapy+Lenvatinib Part 2 First Course: Pembrolizumab+Chemotherapy+Placebo
    Number of subjects analysed
    369
    371
    Units: Score on a scale
        least squares mean (confidence interval 95%)
    -4.11 (-6.37 to -1.84)
    -3.73 (-5.99 to -1.48)
    Statistical analysis title
    		 Covariate
    Statistical analysis description
    Comparision based on a cLDA model with the PRO scores as the response variable with covariates for treatment by time interaction, stratification factors (baseline ECOG performance status (0 versus 1), geographic region of the enrolling site (East Asia versus non-East Asia), and baseline PD-L1 Status ( <50% versus ≥50%)) as covariates.
    Comparison groups
    Part 2 First Course: Pembrolizumab+Chemotherapy+Lenvatinib v Part 2 First Course: Pembrolizumab+Chemotherapy+Placebo
    Number of subjects included in analysis
    740
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.8134
    Method
    		 t-test, 2-sided
    Parameter type
    		 covariate
    Point estimate
    -0.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.47
         upper limit
    		 2.72

    Secondary: Part 2: TTD Based on Change from Baseline in Cough EORTC QLQ-LC13 (Item 31) Score

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    End point title
    		 Part 2: TTD Based on Change from Baseline in Cough EORTC QLQ-LC13 (Item 31) Score [18]
    End point description
    TTD is defined as the time from Baseline to the first onset of a ≥10-point negative change (decrease) from Baseline cough (EORTC QLQ-LC30 Items 31) score. Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. The TTD, as assessed based on a ≥10-point negative change (decrease) from Baseline in physical functioning score, will be presented. A longer TTD indicates a better outcome. The analysis population consisted of all randomized participants in Part 2 who received at least one dose of study treatment and have at least one EORTC-QLQ-LC30 Item 31 assessment data available at baseline. 9999 indicates median, lower and upper range time to deterioration were not reached at time of data cut-off due to insufficient number of participants experiencing deterioration.
    End point type
    Secondary
    End point timeframe
    Baseline And Week 27
    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: The statistical analysis planned for part 2 first course for this endpoint.
    End point values
    		 Part 2 First Course: Pembrolizumab+Chemotherapy+Lenvatinib Part 2 First Course: Pembrolizumab+Chemotherapy+Placebo
    Number of subjects analysed
    356
    353
    Units: Months
        median (confidence interval 95%)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    Statistical analysis title
    		 Hazard Ratio (HR)
    Statistical analysis description
    Comparison based on Cox regression model with Efron’s method of tie handling with treatment as a covariate stratified by ECOG performance status (0 versus 1), geographic region of the enrolling site (East Asia versus non-East Asia), and Baseline PD-L1 Status (<50% versus >=50%).
    Comparison groups
    Part 2 First Course: Pembrolizumab+Chemotherapy+Lenvatinib v Part 2 First Course: Pembrolizumab+Chemotherapy+Placebo
    Number of subjects included in analysis
    709
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0377
    Method
    		 Stratified Log Rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.41
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.02
         upper limit
    		 1.94

    Secondary: Part 2: Time to True Deterioration (TTD) Based on Change from Baseline in Global Health Status (GHS)/Quality of Life (QoL) (EORTC QLQ-C30 Items 29 and 30) Score

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    End point title
    		 Part 2: Time to True Deterioration (TTD) Based on Change from Baseline in Global Health Status (GHS)/Quality of Life (QoL) (EORTC QLQ-C30 Items 29 and 30) Score [19]
    End point description
    TTD is defined as the time from Baseline to the first onset of a ≥10-point negative change (decrease) from Baseline in GHS/QoL (EORTC QLQ-C30 Items 29 and 30) score. Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. The TTD, as assessed based on a ≥10-point negative change (decrease) from Baseline in GHS/QoL score, will be presented. A longer TTD indicates a better outcome. The analysis population consisted of all randomized participants in Part 2 who received at least one dose of study treatment and have at least one EORTC-QLQ-C30 Items 29 and 30 assessment data available. 9999 indicates median and upper range time to deterioration was not reached at time of data cut-off due to insufficient number of participants experiencing deterioration.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 27
    Notes
    [19] - 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: The statistical analysis planned for part 2 first course for this endpoint.
    End point values
    		 Part 2 First Course: Pembrolizumab+Chemotherapy+Lenvatinib Part 2 First Course: Pembrolizumab+Chemotherapy+Placebo
    Number of subjects analysed
    358
    357
    Units: Months
        median (confidence interval 95%)
    15.70 (9.66 to 9999)
    9999 (21.32 to 9999)
    Statistical analysis title
    		 Hazard Ratio (HR)
    Statistical analysis description
    Comparison based on Cox regression model with Efron’s method of tie handling with treatment as a covariate stratified by ECOG performance status (0 versus 1), geographic region of the enrolling site (East Asia versus non-East Asia), and Baseline PD-L1 Status (<50% versus >=50%).
    Comparison groups
    Part 2 First Course: Pembrolizumab+Chemotherapy+Lenvatinib v Part 2 First Course: Pembrolizumab+Chemotherapy+Placebo
    Number of subjects included in analysis
    715
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.2133
    Method
    		 Stratified Log Rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.92
         upper limit
    		 1.47

    Secondary: Part 2: TTD Based on Change from Baseline in Chest Pain EORTC QLQ-LC13 (Item 40) Score

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    End point title
    		 Part 2: TTD Based on Change from Baseline in Chest Pain EORTC QLQ-LC13 (Item 40) Score [20]
    End point description
    TTD is defined as the time from Baseline to the first onset of a ≥10-point negative change (decrease) from Baseline chest pain (EORTC QLQ-C30 Item 40) score. Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. The TTD, as assessed based on a ≥10-point negative change (decrease) from Baseline in chest pains core, will be presented. A longer TTD indicates a better outcome. The analysis population consisted of all randomized participants in Part 2 who received at least one dose of study treatment and have at least one EORTC QLQ-LC13 chest pain Item 40 Score assessment data available at baseline. 9999 indicates median, lower and upper range time to deterioration were not reached at time of data cut-off due to insufficient number of participants experiencing deterioration.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 27
    Notes
    [20] - 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: The statistical analysis planned for part 2 first course for this endpoint.
    End point values
    		 Part 2 First Course: Pembrolizumab+Chemotherapy+Lenvatinib Part 2 First Course: Pembrolizumab+Chemotherapy+Placebo
    Number of subjects analysed
    356
    353
    Units: Months
        median (confidence interval 95%)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    Statistical analysis title
    		 Hazard Ratio (HR)
    Statistical analysis description
    Comparison based on Cox regression model with Efron’s method of tie handling with treatment as a covariate stratified by ECOG performance status (0 versus 1), geographic region of the enrolling site (East Asia versus non-East Asia), and Baseline PD-L1 Status (<50% versus >=50%).
    Comparison groups
    Part 2 First Course: Pembrolizumab+Chemotherapy+Lenvatinib v Part 2 First Course: Pembrolizumab+Chemotherapy+Placebo
    Number of subjects included in analysis
    709
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.4084
    Method
    		 Stratified Log Rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.62
         upper limit
    		 1.21

    Secondary: Part 2: TTD Based on Change from Baseline in Dyspnea EORTC QLQ-C30 (Item 8) Score

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    End point title
    		 Part 2: TTD Based on Change from Baseline in Dyspnea EORTC QLQ-C30 (Item 8) Score [21]
    End point description
    TTD is defined as the time from Baseline to the first onset of a ≥10-point negative change (decrease) from Baseline dyspnea (EORTC QLQ-C30 Item 8) score. Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. The TTD, as assessed based on a ≥10-point negative change (decrease) from Baseline in dyspnea score, will be presented. A longer TTD indicates a better outcome. The analysis population consisted of all randomized participants in Part 2 who received at least one dose of study treatment and have at least one EORTC-QLQ-C30 Item 8 assessment data available at baseline. 9999 indicates median, lower and upper range time to deterioration were not reached at time of data cut-off due to insufficient number of participants experiencing deterioration.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 27
    Notes
    [21] - 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: The statistical analysis planned for part 2 first course for this endpoint.
    End point values
    		 Part 2 First Course: Pembrolizumab+Chemotherapy+Lenvatinib Part 2 First Course: Pembrolizumab+Chemotherapy+Placebo
    Number of subjects analysed
    358
    357
    Units: Months
        median (confidence interval 95%)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    Statistical analysis title
    		 Hazard Ratio (HR)
    Statistical analysis description
    Comparison based on Cox regression model with Efron’s method of tie handling with treatment as a covariate stratified by ECOG performance status (0 versus 1), geographic region of the enrolling site (East Asia versus non-East Asia), and Baseline PD-L1 Status (<50% versus >=50%).
    Comparison groups
    Part 2 First Course: Pembrolizumab+Chemotherapy+Lenvatinib v Part 2 First Course: Pembrolizumab+Chemotherapy+Placebo
    Number of subjects included in analysis
    715
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.7955
    Method
    		 Stratified Log Rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.79
         upper limit
    		 1.36

    Secondary: Part 2: Time to True Deterioration (TTD) Based on Change from Baseline in the Composite Endpoint of Cough (EORTC QLQ-LC13 Item 31), Chest Pain (EORTC QLQ-LC13 Item 40), or Dyspnea (EORTC QLQ-C30 Item 8)

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    End point title
    		 Part 2: Time to True Deterioration (TTD) Based on Change from Baseline in the Composite Endpoint of Cough (EORTC QLQ-LC13 Item 31), Chest Pain (EORTC QLQ-LC13 Item 40), or Dyspnea (EORTC QLQ-C30 Item 8) [22]
    End point description
    TTD is defined as the time from Baseline to the first onset of a ≥10-point negative change (decrease) from Baseline in the composite endpoint of cough (QLQ-LC13 item 31), chest pain (QLQ-LC13 item 40), or dyspnea (QLQ-C30 Item 8). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. The TTD, as assessed based on a ≥10-point negative change (decrease) from Baseline in the composite endpoint of cough, chest pain or dyspnea, will be presented. A longer TTD indicates a better outcome. The analysis population consisted of all randomized participants in Part 2 who received at least one dose of study treatment and have at least one EORTC-QLQ-LC13 Items 31 and 40 and EORTC-QLQ-C30 Item 8 assessment data available.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 27
    Notes
    [22] - 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: The statistical analysis planned for part 2 first course for this endpoint.
    End point values
    		 Part 2 First Course: Pembrolizumab+Chemotherapy+Lenvatinib Part 2 First Course: Pembrolizumab+Chemotherapy+Placebo
    Number of subjects analysed
    358
    358
    Units: Months
        median (confidence interval 95%)
    8.28 (5.98 to 11.07)
    9.33 (7.03 to 12.91)
    Statistical analysis title
    		 Hazard Ratio (HR)
    Statistical analysis description
    Comparison based on Cox regression model with Efron’s method of tie handling with treatment as a covariate stratified by ECOG performance status (0 versus 1), geographic region of the enrolling site (East Asia versus non-East Asia), and Baseline PD-L1 Status (<50% versus >=50%).
    Comparison groups
    Part 2 First Course: Pembrolizumab+Chemotherapy+Lenvatinib v Part 2 First Course: Pembrolizumab+Chemotherapy+Placebo
    Number of subjects included in analysis
    716
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.7191
    Method
    		 Stratified Log Rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.84
         upper limit
    		 1.28

    Secondary: Part 2: TTD Based on Change from Baseline in Physical Functioning EORTC QLQ-C30 (Items 1 through 5) Score

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    End point title
    		 Part 2: TTD Based on Change from Baseline in Physical Functioning EORTC QLQ-C30 (Items 1 through 5) Score [23]
    End point description
    TTD is defined as the time from Baseline to the first onset of a ≥10-point negative change (decrease) from Baseline physical functioning (EORTC QLQ-C30 Items 1 through 5) score. Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. The TTD, as assessed based on a ≥10-point negative change (decrease) from Baseline in physical functioning score, will be presented. A longer TTD indicates a better outcome. The analysis population consisted of all randomized participants in Part 2 who received at least one dose of study treatment and have at least one EORTC-QLQ-C30 Items 1 through 5 assessment data available at baseline. 9999 indicates median, lower and upper range time to deterioration were not reached at time of data cut-off due to insufficient number of participants experiencing deterioration.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 27
    Notes
    [23] - 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: The statistical analysis planned for part 2 first course for this endpoint.
    End point values
    		 Part 2 First Course: Pembrolizumab+Chemotherapy+Lenvatinib Part 2 First Course: Pembrolizumab+Chemotherapy+Placebo
    Number of subjects analysed
    358
    357
    Units: Months
        median (confidence interval 95%)
    16.82 (8.84 to 22.51)
    9999 (9999 to 9999)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to approximately 58 months
    Adverse event reporting additional description
    All-cause mortality was reported on all randomized participants (first and second course). Serious and non-serious AEs were reported among participants who received at least one dose of study treatment. MedDRA preferred terms 'Neoplasm progression', 'Malignant neoplasm progression' and 'Disease progression' not related to the drug were excluded.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    Part 1 First Course: Pembrolizumab+Chemotherapy+Lenvatinib
    Reporting group description
    		 Participants received carboplatin AUC5 or cisplatin 75 mg/m^2 via IV infusion Q3W for 4 cycles PLUS pemetrexed 500 mg/m^2 via IV infusion Q3W for 4 cycles PLUS pembrolizumab 200 mg via IV infusion Q3W for up to 35 cycles (up to 2 years) PLUS lenvatinib 8 mg via oral capsule once daily.

    Reporting group title
    Part 2 First Course: Pembrolizumab+Chemotherapy+Lenvatinib
    Reporting group description
    		 Participants received carboplatin Area Under Curve 5 mg/mL/min (AUC5) or cisplatin 75 mg/m^2 via intravenous (IV) infusion on Day 1 of each 3-week cycle (Q3W) for 4 cycles PLUS pemetrexed 500 mg/m^2 via IV infusion Q3W for 4 cycles PLUS pembrolizumab 200 mg via IV infusion Q3W for up to 35 cycles (up to 2 years) PLUS lenvatinib 8 mg via oral capsule once daily.

    Reporting group title
    Part 2 Second Course: Pembrolizumab+Chemotherapy+Lenvatinib
    Reporting group description
    		 Qualified participants who completed the first course of pembrolizumab plus chemotherapy plus lenvatinib for up to 35 cycles (up to 2 years), but experienced disease progression, initiated a second course of pembrolizumab at the investigator's discretion, at 200 mg IV Q2W for up to ~1 year. Participants previously receiving Lenvatinib could continue receiving lenvatinib at investigator's discretion.

    Reporting group title
    Part1 Second Course:Pembrolizumab Only→Chemotherapy+Lenvatinib
    Reporting group description
    		 Qualified participants who completed the first course of pembrolizumab plus chemotherapy plus lenvatinib for up to 35 cycles (up to 2 years), but experienced disease progression, initiated a second course of pembrolizumab at the investigator's discretion, at 200 mg IV Q2W for up to ~1 year, without chemotherapy plus lenvatinib.

    Reporting group title
    Part 2 Second Course: Pembrolizumab+Chemotherapy+Placebo
    Reporting group description
    		 Qualified participants who completed the first course of pembrolizumab plus chemotherapy plus lenvatinib for up to 35 cycles (up to 2 years), but experienced disease progression, initiated a second course of pembrolizumab at the investigator's discretion, at 200 mg IV Q2W for up to ~1 year. Participants previously receiving Lenvatinib could continue receiving lenvatinib at investigator's discretion.

    Reporting group title
    Part 2 First Course: Pembrolizumab+Chemotherapy+Placebo
    Reporting group description
    		 Participants received carboplatin AUC5 or cisplatin 75 mg/m^2 via IV infusion Q3W for 4 cycles PLUS pemetrexed 500 mg/m^2 via IV infusion Q3W for 4 cycles PLUS pembrolizumab 200 mg via IV infusion Q3W for up to 35 cycles (up to 2 years) PLUS placebo matching lenvatinib via oral capsule once daily.

    Serious adverse events
    		 Part 1 First Course: Pembrolizumab+Chemotherapy+Lenvatinib Part 2 First Course: Pembrolizumab+Chemotherapy+Lenvatinib Part 2 Second Course: Pembrolizumab+Chemotherapy+Lenvatinib Part1 Second Course:Pembrolizumab Only→Chemotherapy+Lenvatinib Part 2 Second Course: Pembrolizumab+Chemotherapy+Placebo Part 2 First Course: Pembrolizumab+Chemotherapy+Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 13 (53.85%)
    232 / 373 (62.20%)
    1 / 3 (33.33%)
    1 / 1 (100.00%)
    3 / 7 (42.86%)
    189 / 372 (50.81%)
         number of deaths (all causes)
    9
    278
    3
    0
    3
    266
         number of deaths resulting from adverse events
    3
    57
    1
    0
    1
    44
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer metastatic
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cancer pain
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 373 (0.54%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Liposarcoma
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Neoplasm malignant
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour associated fever
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arterial disorder
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arterial thrombosis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    2 / 372 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 373 (0.54%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    4 / 372 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Superior vena cava syndrome
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery thrombosis
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Jugular vein thrombosis
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 13 (0.00%)
    4 / 373 (1.07%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    2 / 372 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest discomfort
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 13 (0.00%)
    10 / 373 (2.68%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    5 / 372 (1.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 10
    0 / 0
    0 / 0
    0 / 0
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 10
    0 / 0
    0 / 0
    0 / 0
    2 / 5
    Fatigue
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 373 (0.54%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    2 / 372 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 373 (0.54%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 373 (0.54%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oedema
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral swelling
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 13 (7.69%)
    5 / 373 (1.34%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    3 / 372 (0.81%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 5
    0 / 0
    0 / 0
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic shock
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 373 (0.54%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anaphylactic reaction
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostatitis
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 13 (0.00%)
    3 / 373 (0.80%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Emphysema
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 373 (0.54%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchopneumopathy
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    2 / 372 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pharyngeal haemorrhage
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung infiltration
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 13 (0.00%)
    3 / 373 (0.80%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    4 / 372 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    0 / 0
    0 / 0
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune-mediated lung disease
         subjects affected / exposed
    0 / 13 (0.00%)
    5 / 373 (1.34%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    2 / 372 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 5
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hydrothorax
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 13 (7.69%)
    4 / 373 (1.07%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    2 / 372 (0.54%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 5
    0 / 0
    0 / 0
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Pleural effusion
         subjects affected / exposed
    1 / 13 (7.69%)
    10 / 373 (2.68%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    1 / 7 (14.29%)
    9 / 372 (2.42%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 10
    0 / 0
    0 / 0
    0 / 1
    1 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Epistaxis
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary artery thrombosis
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax spontaneous
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    2 / 372 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 13 (7.69%)
    14 / 373 (3.75%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    15 / 372 (4.03%)
         occurrences causally related to treatment / all
    1 / 1
    12 / 14
    0 / 0
    0 / 0
    0 / 0
    15 / 16
         deaths causally related to treatment / all
    0 / 0
    5 / 5
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    Pleurisy
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 13 (0.00%)
    11 / 373 (2.95%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    1 / 7 (14.29%)
    8 / 372 (2.15%)
         occurrences causally related to treatment / all
    0 / 0
    6 / 11
    0 / 0
    0 / 0
    0 / 1
    4 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    Pulmonary fibrosis
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary infarction
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Psychiatric disorders
    Behaviour disorder
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Completed suicide
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Disorientation
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 373 (0.54%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 13 (0.00%)
    3 / 373 (0.80%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    5 / 372 (1.34%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    0 / 0
    0 / 0
    0 / 0
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Amylase increased
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 13 (0.00%)
    3 / 373 (0.80%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    7 / 372 (1.88%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    0 / 0
    0 / 0
    0 / 0
    6 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lipase increased
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 373 (0.54%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 13 (0.00%)
    3 / 373 (0.80%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    1 / 13 (7.69%)
    3 / 373 (0.80%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    6 / 372 (1.61%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 3
    0 / 0
    0 / 0
    0 / 0
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    0 / 13 (0.00%)
    10 / 373 (2.68%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    8 / 372 (2.15%)
         occurrences causally related to treatment / all
    0 / 0
    10 / 10
    0 / 0
    0 / 0
    0 / 0
    7 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SARS-CoV-2 test positive
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    1 / 13 (7.69%)
    2 / 373 (0.54%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    4 / 372 (1.08%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fracture
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Procedural pneumothorax
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tracheal haemorrhage
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Synovial rupture
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 373 (0.54%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    2 / 372 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Acute myocardial infarction
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Arteriosclerosis coronary artery
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 13 (7.69%)
    2 / 373 (0.54%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    2 / 372 (0.54%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial thrombosis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Cardiac tamponade
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Coronary artery disease
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune-mediated myocarditis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 13 (0.00%)
    6 / 373 (1.61%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 6
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    2 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocarditis
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    2 / 372 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Brain oedema
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Basal ganglia infarction
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    2 / 372 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    Dysarthria
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cognitive disorder
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 13 (0.00%)
    5 / 373 (1.34%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    4 / 372 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 5
    0 / 0
    0 / 0
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral thrombosis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Cerebral infarction
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 373 (0.54%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lethargy
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 373 (0.54%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    2 / 372 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Ischaemic cerebral infarction
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Intracranial aneurysm
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune-mediated encephalopathy
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 373 (0.54%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 13 (0.00%)
    3 / 373 (0.80%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spondylitic myelopathy
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    2 / 372 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sensory disturbance
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    1 / 7 (14.29%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 13 (7.69%)
    17 / 373 (4.56%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    9 / 372 (2.42%)
         occurrences causally related to treatment / all
    1 / 1
    16 / 19
    0 / 0
    0 / 0
    0 / 0
    7 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 13 (0.00%)
    12 / 373 (3.22%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    5 / 372 (1.34%)
         occurrences causally related to treatment / all
    0 / 0
    13 / 13
    0 / 0
    0 / 0
    0 / 0
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    3 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone marrow failure
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 13 (0.00%)
    4 / 373 (1.07%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 5
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spontaneous haematoma
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vertigo positional
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Retinal detachment
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cataract
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    2 / 372 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ulcerative keratitis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vitreous haemorrhage
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coeliac artery stenosis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal fistula
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    2 / 372 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 13 (7.69%)
    2 / 373 (0.54%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    5 / 372 (1.34%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Duodenitis
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 13 (0.00%)
    7 / 373 (1.88%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    4 / 372 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    7 / 9
    0 / 0
    0 / 0
    0 / 0
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Faecaloma
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer haemorrhage
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 373 (0.54%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal inflammation
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    2 / 372 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune-mediated enterocolitis
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oral pain
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    5 / 372 (1.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenic colitis
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Obstruction gastric
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    2 / 372 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    2 / 372 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Stomatitis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Proctitis
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    4 / 372 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 13 (0.00%)
    3 / 373 (0.80%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic cirrhosis
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic haematoma
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic cytolysis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    1 / 13 (7.69%)
    3 / 373 (0.80%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune-mediated hepatitis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    2 / 372 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Perforation bile duct
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis herpetiformis
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pseudocellulitis
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 373 (0.54%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Superficial inflammatory dermatosis
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Immune-mediated nephritis
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Autoimmune nephritis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    1 / 13 (7.69%)
    6 / 373 (1.61%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    3 / 372 (0.81%)
         occurrences causally related to treatment / all
    1 / 1
    4 / 7
    0 / 0
    0 / 0
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephritis
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 373 (0.54%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephropathy
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Proteinuria
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    2 / 372 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Urinary tract obstruction
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tubulointerstitial nephritis
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 373 (0.54%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal haematoma
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Adrenal insufficiency
         subjects affected / exposed
    1 / 13 (7.69%)
    3 / 373 (0.80%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperthyroidism
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypophysitis
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypothyroidism
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    2 / 372 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Myositis
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    2 / 372 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteonecrosis of jaw
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 373 (0.54%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Anorectal infection
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal sepsis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 373 (0.54%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Biliary sepsis
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 13 (7.69%)
    2 / 373 (0.54%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Catheter site infection
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    0 / 13 (0.00%)
    7 / 373 (1.88%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    4 / 372 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 7
    0 / 0
    0 / 0
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    0 / 13 (0.00%)
    5 / 373 (1.34%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    10 / 372 (2.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
    0 / 0
    0 / 0
    0 / 0
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 5
    Campylobacter gastroenteritis
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis viral
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 373 (0.54%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 373 (0.54%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalitis
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile infection
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 13 (0.00%)
    4 / 373 (1.07%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myelitis
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Parainfluenzae virus infection
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritonsillar abscess
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Pneumonia
         subjects affected / exposed
    2 / 13 (15.38%)
    28 / 373 (7.51%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    1 / 7 (14.29%)
    36 / 372 (9.68%)
         occurrences causally related to treatment / all
    3 / 3
    13 / 37
    0 / 0
    0 / 0
    0 / 1
    6 / 40
         deaths causally related to treatment / all
    0 / 0
    3 / 7
    0 / 0
    0 / 0
    0 / 0
    0 / 9
    Pneumonia aspiration
         subjects affected / exposed
    0 / 13 (0.00%)
    3 / 373 (0.80%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 373 (0.54%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    2 / 372 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Pneumonia fungal
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia klebsiella
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Pulmonary sepsis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Pyelonephritis
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 13 (0.00%)
    4 / 373 (1.07%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 13 (0.00%)
    7 / 373 (1.88%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    4 / 372 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 7
    0 / 0
    0 / 0
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    Septic shock
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tuberculosis
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 373 (0.54%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Varicella zoster virus infection
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 373 (0.54%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 373 (0.54%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 13 (0.00%)
    3 / 373 (0.80%)
    0 / 3 (0.00%)
    1 / 1 (100.00%)
    0 / 7 (0.00%)
    3 / 372 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
    0 / 0
    0 / 1
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 373 (0.54%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Part 1 First Course: Pembrolizumab+Chemotherapy+Lenvatinib Part 2 First Course: Pembrolizumab+Chemotherapy+Lenvatinib Part 2 Second Course: Pembrolizumab+Chemotherapy+Lenvatinib Part1 Second Course:Pembrolizumab Only→Chemotherapy+Lenvatinib Part 2 Second Course: Pembrolizumab+Chemotherapy+Placebo Part 2 First Course: Pembrolizumab+Chemotherapy+Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 13 (100.00%)
    366 / 373 (98.12%)
    2 / 3 (66.67%)
    1 / 1 (100.00%)
    4 / 7 (57.14%)
    363 / 372 (97.58%)
    Vascular disorders
    Orthostatic hypotension
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences all number
    1
    1
    0
    0
    0
    1
    Hot flush
         subjects affected / exposed
    1 / 13 (7.69%)
    2 / 373 (0.54%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    3 / 372 (0.81%)
         occurrences all number
    1
    2
    0
    0
    0
    3
    Hypertension
         subjects affected / exposed
    9 / 13 (69.23%)
    110 / 373 (29.49%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
    1 / 7 (14.29%)
    44 / 372 (11.83%)
         occurrences all number
    10
    158
    1
    0
    1
    46
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 13 (15.38%)
    108 / 373 (28.95%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    110 / 372 (29.57%)
         occurrences all number
    2
    167
    0
    0
    0
    175
    Chest pain
         subjects affected / exposed
    1 / 13 (7.69%)
    21 / 373 (5.63%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    1 / 7 (14.29%)
    25 / 372 (6.72%)
         occurrences all number
    2
    23
    0
    0
    1
    29
    Gait disturbance
         subjects affected / exposed
    1 / 13 (7.69%)
    3 / 373 (0.80%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    4 / 372 (1.08%)
         occurrences all number
    1
    5
    0
    0
    0
    4
    Fatigue
         subjects affected / exposed
    8 / 13 (61.54%)
    116 / 373 (31.10%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    86 / 372 (23.12%)
         occurrences all number
    15
    182
    0
    0
    0
    114
    Oedema
         subjects affected / exposed
    1 / 13 (7.69%)
    7 / 373 (1.88%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    9 / 372 (2.42%)
         occurrences all number
    1
    7
    0
    0
    0
    11
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 13 (7.69%)
    5 / 373 (1.34%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    9 / 372 (2.42%)
         occurrences all number
    1
    6
    0
    0
    0
    13
    Mucosal inflammation
         subjects affected / exposed
    2 / 13 (15.38%)
    47 / 373 (12.60%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    28 / 372 (7.53%)
         occurrences all number
    3
    62
    0
    0
    0
    35
    Malaise
         subjects affected / exposed
    1 / 13 (7.69%)
    15 / 373 (4.02%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    15 / 372 (4.03%)
         occurrences all number
    2
    24
    0
    0
    0
    18
    Influenza like illness
         subjects affected / exposed
    1 / 13 (7.69%)
    7 / 373 (1.88%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    6 / 372 (1.61%)
         occurrences all number
    1
    11
    0
    0
    0
    6
    General physical health deterioration
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences all number
    1
    1
    0
    0
    0
    1
    Extravasation
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Pyrexia
         subjects affected / exposed
    1 / 13 (7.69%)
    57 / 373 (15.28%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    1 / 7 (14.29%)
    61 / 372 (16.40%)
         occurrences all number
    3
    98
    0
    0
    1
    83
    Pain
         subjects affected / exposed
    1 / 13 (7.69%)
    7 / 373 (1.88%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    6 / 372 (1.61%)
         occurrences all number
    1
    7
    0
    0
    0
    6
    Oedema peripheral
         subjects affected / exposed
    3 / 13 (23.08%)
    61 / 373 (16.35%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    49 / 372 (13.17%)
         occurrences all number
    4
    81
    1
    0
    0
    70
    Reproductive system and breast disorders
    Erectile dysfunction
         subjects affected / exposed
    1 / 13 (7.69%)
    2 / 373 (0.54%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences all number
    1
    2
    0
    0
    0
    1
    Pelvic pain
         subjects affected / exposed
    1 / 13 (7.69%)
    3 / 373 (0.80%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    2 / 372 (0.54%)
         occurrences all number
    1
    3
    0
    0
    0
    2
    Breast pain
         subjects affected / exposed
    1 / 13 (7.69%)
    3 / 373 (0.80%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences all number
    1
    3
    0
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 13 (30.77%)
    65 / 373 (17.43%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    1 / 7 (14.29%)
    50 / 372 (13.44%)
         occurrences all number
    6
    82
    0
    0
    1
    60
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 13 (7.69%)
    3 / 373 (0.80%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    2 / 372 (0.54%)
         occurrences all number
    1
    3
    0
    0
    0
    4
    Dysphonia
         subjects affected / exposed
    3 / 13 (23.08%)
    31 / 373 (8.31%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    12 / 372 (3.23%)
         occurrences all number
    10
    36
    0
    0
    0
    12
    Dyspnoea
         subjects affected / exposed
    3 / 13 (23.08%)
    63 / 373 (16.89%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    1 / 7 (14.29%)
    66 / 372 (17.74%)
         occurrences all number
    5
    78
    0
    0
    1
    68
    Dyspnoea exertional
         subjects affected / exposed
    1 / 13 (7.69%)
    5 / 373 (1.34%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    4 / 372 (1.08%)
         occurrences all number
    1
    5
    0
    0
    0
    7
    Oropharyngeal pain
         subjects affected / exposed
    3 / 13 (23.08%)
    20 / 373 (5.36%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    5 / 372 (1.34%)
         occurrences all number
    4
    21
    0
    0
    0
    5
    Haemoptysis
         subjects affected / exposed
    1 / 13 (7.69%)
    20 / 373 (5.36%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    14 / 372 (3.76%)
         occurrences all number
    2
    23
    0
    0
    0
    20
    Hiccups
         subjects affected / exposed
    4 / 13 (30.77%)
    18 / 373 (4.83%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    21 / 372 (5.65%)
         occurrences all number
    8
    21
    0
    0
    0
    30
    Immune-mediated lung disease
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Epistaxis
         subjects affected / exposed
    3 / 13 (23.08%)
    55 / 373 (14.75%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    17 / 372 (4.57%)
         occurrences all number
    3
    86
    0
    0
    0
    21
    Pneumonitis
         subjects affected / exposed
    0 / 13 (0.00%)
    10 / 373 (2.68%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    22 / 372 (5.91%)
         occurrences all number
    0
    10
    0
    0
    0
    22
    Productive cough
         subjects affected / exposed
    2 / 13 (15.38%)
    15 / 373 (4.02%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    23 / 372 (6.18%)
         occurrences all number
    3
    19
    0
    0
    0
    25
    Rhinitis allergic
         subjects affected / exposed
    1 / 13 (7.69%)
    7 / 373 (1.88%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences all number
    1
    7
    0
    0
    0
    1
    Rhinorrhoea
         subjects affected / exposed
    1 / 13 (7.69%)
    11 / 373 (2.95%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    11 / 372 (2.96%)
         occurrences all number
    1
    14
    0
    0
    0
    12
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    2 / 372 (0.54%)
         occurrences all number
    1
    1
    0
    0
    0
    2
    Anxiety
         subjects affected / exposed
    1 / 13 (7.69%)
    9 / 373 (2.41%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    9 / 372 (2.42%)
         occurrences all number
    1
    9
    0
    0
    0
    12
    Insomnia
         subjects affected / exposed
    2 / 13 (15.38%)
    26 / 373 (6.97%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    32 / 372 (8.60%)
         occurrences all number
    5
    28
    0
    0
    0
    43
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 13 (0.00%)
    132 / 373 (35.39%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    119 / 372 (31.99%)
         occurrences all number
    0
    271
    0
    0
    0
    251
    Amylase increased
         subjects affected / exposed
    2 / 13 (15.38%)
    55 / 373 (14.75%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    1 / 7 (14.29%)
    55 / 372 (14.78%)
         occurrences all number
    2
    108
    0
    0
    1
    95
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 13 (0.00%)
    127 / 373 (34.05%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    108 / 372 (29.03%)
         occurrences all number
    0
    311
    0
    0
    0
    240
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 13 (0.00%)
    31 / 373 (8.31%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    31 / 372 (8.33%)
         occurrences all number
    0
    52
    0
    0
    0
    44
    Blood bilirubin increased
         subjects affected / exposed
    0 / 13 (0.00%)
    20 / 373 (5.36%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    9 / 372 (2.42%)
         occurrences all number
    0
    31
    0
    0
    0
    18
    Blood creatinine increased
         subjects affected / exposed
    5 / 13 (38.46%)
    66 / 373 (17.69%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
    1 / 7 (14.29%)
    69 / 372 (18.55%)
         occurrences all number
    7
    122
    1
    0
    1
    104
    Blood glucose increased
         subjects affected / exposed
    0 / 13 (0.00%)
    21 / 373 (5.63%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    22 / 372 (5.91%)
         occurrences all number
    0
    31
    0
    0
    0
    28
    Blood magnesium decreased
         subjects affected / exposed
    0 / 13 (0.00%)
    23 / 373 (6.17%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    17 / 372 (4.57%)
         occurrences all number
    0
    31
    0
    0
    0
    29
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    0 / 13 (0.00%)
    38 / 373 (10.19%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    9 / 372 (2.42%)
         occurrences all number
    0
    51
    0
    0
    0
    12
    Blood urea increased
         subjects affected / exposed
    0 / 13 (0.00%)
    13 / 373 (3.49%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    12 / 372 (3.23%)
         occurrences all number
    0
    18
    1
    0
    0
    21
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 13 (0.00%)
    49 / 373 (13.14%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    30 / 372 (8.06%)
         occurrences all number
    0
    73
    0
    0
    0
    39
    Lactescent serum
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Lipase increased
         subjects affected / exposed
    1 / 13 (7.69%)
    47 / 373 (12.60%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    43 / 372 (11.56%)
         occurrences all number
    1
    94
    0
    0
    0
    82
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 13 (0.00%)
    29 / 373 (7.77%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    18 / 372 (4.84%)
         occurrences all number
    0
    54
    0
    0
    0
    31
    Neutrophil count decreased
         subjects affected / exposed
    4 / 13 (30.77%)
    188 / 373 (50.40%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    154 / 372 (41.40%)
         occurrences all number
    6
    526
    0
    0
    0
    436
    Platelet count decreased
         subjects affected / exposed
    1 / 13 (7.69%)
    148 / 373 (39.68%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    98 / 372 (26.34%)
         occurrences all number
    4
    348
    0
    0
    0
    203
    SARS-CoV-2 test positive
         subjects affected / exposed
    1 / 13 (7.69%)
    5 / 373 (1.34%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    4 / 372 (1.08%)
         occurrences all number
    1
    5
    0
    0
    0
    4
    Urinary occult blood positive
         subjects affected / exposed
    0 / 13 (0.00%)
    4 / 373 (1.07%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    1 / 7 (14.29%)
    3 / 372 (0.81%)
         occurrences all number
    0
    6
    0
    0
    1
    4
    Weight increased
         subjects affected / exposed
    0 / 13 (0.00%)
    20 / 373 (5.36%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    7 / 372 (1.88%)
         occurrences all number
    0
    30
    0
    0
    0
    8
    White blood cell count decreased
         subjects affected / exposed
    0 / 13 (0.00%)
    119 / 373 (31.90%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    95 / 372 (25.54%)
         occurrences all number
    0
    372
    0
    0
    0
    306
    Weight decreased
         subjects affected / exposed
    1 / 13 (7.69%)
    69 / 373 (18.50%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    29 / 372 (7.80%)
         occurrences all number
    2
    82
    0
    0
    0
    31
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 13 (7.69%)
    5 / 373 (1.34%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    6 / 372 (1.61%)
         occurrences all number
    1
    5
    0
    0
    0
    6
    Contusion
         subjects affected / exposed
    1 / 13 (7.69%)
    2 / 373 (0.54%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences all number
    1
    2
    0
    0
    0
    0
    Head injury
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 373 (0.00%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Ligament injury
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 13 (7.69%)
    4 / 373 (1.07%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences all number
    1
    9
    0
    0
    0
    1
    Degenerative aortic valve disease
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    1 / 7 (14.29%)
    0 / 372 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    Nervous system disorders
    Cognitive disorder
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    Headache
         subjects affected / exposed
    2 / 13 (15.38%)
    45 / 373 (12.06%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    35 / 372 (9.41%)
         occurrences all number
    2
    64
    0
    0
    0
    44
    Dizziness postural
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Dysgeusia
         subjects affected / exposed
    4 / 13 (30.77%)
    26 / 373 (6.97%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    19 / 372 (5.11%)
         occurrences all number
    4
    28
    0
    0
    0
    22
    Encephalitis autoimmune
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Dizziness
         subjects affected / exposed
    3 / 13 (23.08%)
    39 / 373 (10.46%)
    0 / 3 (0.00%)
    1 / 1 (100.00%)
    0 / 7 (0.00%)
    36 / 372 (9.68%)
         occurrences all number
    4
    50
    0
    1
    0
    42
    Lethargy
         subjects affected / exposed
    3 / 13 (23.08%)
    4 / 373 (1.07%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    3 / 372 (0.81%)
         occurrences all number
    5
    4
    0
    0
    0
    3
    Neuropathy peripheral
         subjects affected / exposed
    0 / 13 (0.00%)
    20 / 373 (5.36%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    18 / 372 (4.84%)
         occurrences all number
    0
    23
    0
    0
    0
    19
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 13 (7.69%)
    6 / 373 (1.61%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    8 / 372 (2.15%)
         occurrences all number
    1
    7
    0
    0
    0
    10
    Tremor
         subjects affected / exposed
    1 / 13 (7.69%)
    2 / 373 (0.54%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    4 / 372 (1.08%)
         occurrences all number
    1
    2
    0
    0
    0
    4
    Vocal cord paralysis
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Post herpetic neuralgia
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 13 (7.69%)
    192 / 373 (51.47%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    220 / 372 (59.14%)
         occurrences all number
    1
    394
    1
    0
    0
    419
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 13 (7.69%)
    9 / 373 (2.41%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    7 / 372 (1.88%)
         occurrences all number
    2
    10
    0
    0
    0
    7
    Dry eye
         subjects affected / exposed
    1 / 13 (7.69%)
    9 / 373 (2.41%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    1 / 7 (14.29%)
    14 / 372 (3.76%)
         occurrences all number
    1
    9
    0
    0
    1
    14
    Eye pain
         subjects affected / exposed
    1 / 13 (7.69%)
    2 / 373 (0.54%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences all number
    1
    2
    0
    0
    0
    1
    Eye pruritus
         subjects affected / exposed
    1 / 13 (7.69%)
    4 / 373 (1.07%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    3 / 372 (0.81%)
         occurrences all number
    1
    4
    0
    0
    0
    3
    Glaucoma
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    1 / 7 (14.29%)
    0 / 372 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Lacrimation increased
         subjects affected / exposed
    2 / 13 (15.38%)
    24 / 373 (6.43%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    24 / 372 (6.45%)
         occurrences all number
    3
    25
    0
    0
    0
    28
    Vision blurred
         subjects affected / exposed
    1 / 13 (7.69%)
    5 / 373 (1.34%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    5 / 372 (1.34%)
         occurrences all number
    1
    5
    0
    0
    0
    6
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 13 (15.38%)
    33 / 373 (8.85%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    20 / 372 (5.38%)
         occurrences all number
    2
    47
    0
    0
    0
    27
    Anal incontinence
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    1 / 13 (7.69%)
    30 / 373 (8.04%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    18 / 372 (4.84%)
         occurrences all number
    2
    33
    0
    0
    0
    20
    Constipation
         subjects affected / exposed
    7 / 13 (53.85%)
    120 / 373 (32.17%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    110 / 372 (29.57%)
         occurrences all number
    9
    169
    2
    0
    0
    143
    Dyspepsia
         subjects affected / exposed
    3 / 13 (23.08%)
    23 / 373 (6.17%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    11 / 372 (2.96%)
         occurrences all number
    3
    25
    0
    0
    0
    11
    Dry mouth
         subjects affected / exposed
    3 / 13 (23.08%)
    10 / 373 (2.68%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    10 / 372 (2.69%)
         occurrences all number
    3
    10
    0
    0
    0
    12
    Diarrhoea
         subjects affected / exposed
    7 / 13 (53.85%)
    127 / 373 (34.05%)
    0 / 3 (0.00%)
    1 / 1 (100.00%)
    0 / 7 (0.00%)
    69 / 372 (18.55%)
         occurrences all number
    10
    245
    0
    2
    0
    107
    Lip dry
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Glossodynia
         subjects affected / exposed
    1 / 13 (7.69%)
    2 / 373 (0.54%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences all number
    3
    2
    0
    0
    0
    0
    Gingival pain
         subjects affected / exposed
    1 / 13 (7.69%)
    11 / 373 (2.95%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    3 / 372 (0.81%)
         occurrences all number
    1
    15
    0
    0
    0
    6
    Gingival bleeding
         subjects affected / exposed
    1 / 13 (7.69%)
    7 / 373 (1.88%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    2 / 372 (0.54%)
         occurrences all number
    2
    9
    0
    0
    0
    2
    Gastrointestinal pain
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Flatulence
         subjects affected / exposed
    1 / 13 (7.69%)
    3 / 373 (0.80%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    4 / 372 (1.08%)
         occurrences all number
    1
    3
    0
    0
    0
    5
    Dysphagia
         subjects affected / exposed
    1 / 13 (7.69%)
    13 / 373 (3.49%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    1 / 7 (14.29%)
    7 / 372 (1.88%)
         occurrences all number
    1
    14
    0
    0
    1
    7
    Toothache
         subjects affected / exposed
    1 / 13 (7.69%)
    13 / 373 (3.49%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    7 / 372 (1.88%)
         occurrences all number
    1
    17
    0
    0
    0
    10
    Vomiting
         subjects affected / exposed
    5 / 13 (38.46%)
    69 / 373 (18.50%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    62 / 372 (16.67%)
         occurrences all number
    7
    133
    0
    0
    0
    99
    Stomatitis
         subjects affected / exposed
    2 / 13 (15.38%)
    47 / 373 (12.60%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    21 / 372 (5.65%)
         occurrences all number
    3
    64
    0
    0
    0
    30
    Rectal ulcer
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Oral pain
         subjects affected / exposed
    1 / 13 (7.69%)
    15 / 373 (4.02%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    2 / 372 (0.54%)
         occurrences all number
    1
    16
    0
    0
    0
    4
    Nausea
         subjects affected / exposed
    10 / 13 (76.92%)
    148 / 373 (39.68%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    137 / 372 (36.83%)
         occurrences all number
    17
    264
    0
    0
    0
    246
    Skin and subcutaneous tissue disorders
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    2 / 13 (15.38%)
    13 / 373 (3.49%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    3 / 372 (0.81%)
         occurrences all number
    2
    13
    0
    0
    0
    3
    Decubitus ulcer
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Dry skin
         subjects affected / exposed
    4 / 13 (30.77%)
    14 / 373 (3.75%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    13 / 372 (3.49%)
         occurrences all number
    4
    14
    0
    0
    0
    14
    Pain of skin
         subjects affected / exposed
    1 / 13 (7.69%)
    2 / 373 (0.54%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences all number
    1
    2
    0
    0
    0
    1
    Alopecia
         subjects affected / exposed
    2 / 13 (15.38%)
    16 / 373 (4.29%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    15 / 372 (4.03%)
         occurrences all number
    2
    19
    0
    0
    0
    15
    Pruritus
         subjects affected / exposed
    3 / 13 (23.08%)
    45 / 373 (12.06%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    48 / 372 (12.90%)
         occurrences all number
    6
    56
    0
    0
    0
    68
    Rash
         subjects affected / exposed
    4 / 13 (30.77%)
    64 / 373 (17.16%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    57 / 372 (15.32%)
         occurrences all number
    7
    86
    0
    0
    0
    64
    Rash vesicular
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Skin lesion
         subjects affected / exposed
    1 / 13 (7.69%)
    4 / 373 (1.07%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    4 / 372 (1.08%)
         occurrences all number
    1
    4
    0
    0
    0
    4
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    1 / 13 (7.69%)
    10 / 373 (2.68%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    9 / 372 (2.42%)
         occurrences all number
    1
    11
    0
    0
    0
    10
    Proteinuria
         subjects affected / exposed
    3 / 13 (23.08%)
    55 / 373 (14.75%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    26 / 372 (6.99%)
         occurrences all number
    8
    114
    0
    0
    0
    37
    Urinary incontinence
         subjects affected / exposed
    1 / 13 (7.69%)
    2 / 373 (0.54%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    2 / 372 (0.54%)
         occurrences all number
    1
    2
    0
    0
    0
    2
    Endocrine disorders
    Thyroid mass
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Hypothyroidism
         subjects affected / exposed
    5 / 13 (38.46%)
    84 / 373 (22.52%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    42 / 372 (11.29%)
         occurrences all number
    6
    104
    0
    0
    0
    46
    Hyperthyroidism
         subjects affected / exposed
    1 / 13 (7.69%)
    26 / 373 (6.97%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    23 / 372 (6.18%)
         occurrences all number
    1
    30
    0
    0
    0
    27
    Adrenal insufficiency
         subjects affected / exposed
    1 / 13 (7.69%)
    10 / 373 (2.68%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    3 / 372 (0.81%)
         occurrences all number
    1
    10
    0
    0
    0
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 13 (7.69%)
    54 / 373 (14.48%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    33 / 372 (8.87%)
         occurrences all number
    2
    72
    0
    0
    0
    38
    Arthritis
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    6 / 372 (1.61%)
         occurrences all number
    2
    2
    0
    0
    0
    6
    Back pain
         subjects affected / exposed
    6 / 13 (46.15%)
    44 / 373 (11.80%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    42 / 372 (11.29%)
         occurrences all number
    8
    52
    0
    0
    0
    47
    Myalgia
         subjects affected / exposed
    0 / 13 (0.00%)
    20 / 373 (5.36%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    16 / 372 (4.30%)
         occurrences all number
    0
    21
    0
    0
    0
    19
    Muscle spasms
         subjects affected / exposed
    1 / 13 (7.69%)
    3 / 373 (0.80%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    6 / 372 (1.61%)
         occurrences all number
    1
    4
    0
    0
    0
    7
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 13 (0.00%)
    19 / 373 (5.09%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    7 / 372 (1.88%)
         occurrences all number
    0
    20
    0
    0
    0
    7
    Joint swelling
         subjects affected / exposed
    1 / 13 (7.69%)
    4 / 373 (1.07%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences all number
    1
    4
    0
    0
    0
    1
    Myositis
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Neck pain
         subjects affected / exposed
    0 / 13 (0.00%)
    10 / 373 (2.68%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    8 / 372 (2.15%)
         occurrences all number
    0
    11
    1
    0
    0
    9
    Pain in extremity
         subjects affected / exposed
    2 / 13 (15.38%)
    32 / 373 (8.58%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    17 / 372 (4.57%)
         occurrences all number
    2
    43
    0
    0
    0
    18
    Infections and infestations
    Eye infection
         subjects affected / exposed
    2 / 13 (15.38%)
    2 / 373 (0.54%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences all number
    2
    2
    0
    0
    0
    0
    Device related infection
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences all number
    1
    2
    0
    0
    0
    0
    Conjunctivitis
         subjects affected / exposed
    0 / 13 (0.00%)
    24 / 373 (6.43%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    18 / 372 (4.84%)
         occurrences all number
    0
    27
    0
    0
    0
    21
    COVID-19
         subjects affected / exposed
    1 / 13 (7.69%)
    32 / 373 (8.58%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    23 / 372 (6.18%)
         occurrences all number
    2
    32
    0
    0
    0
    24
    Fungal skin infection
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Herpes zoster
         subjects affected / exposed
    1 / 13 (7.69%)
    6 / 373 (1.61%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    7 / 372 (1.88%)
         occurrences all number
    1
    6
    0
    0
    0
    7
    Gastroenteritis viral
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Gastroenteritis
         subjects affected / exposed
    1 / 13 (7.69%)
    4 / 373 (1.07%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences all number
    1
    4
    0
    0
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    2 / 13 (15.38%)
    10 / 373 (2.68%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    5 / 372 (1.34%)
         occurrences all number
    3
    13
    0
    0
    0
    5
    Pneumonia
         subjects affected / exposed
    1 / 13 (7.69%)
    23 / 373 (6.17%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    21 / 372 (5.65%)
         occurrences all number
    1
    27
    0
    0
    0
    22
    Otitis externa
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Oral infection
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences all number
    4
    0
    0
    0
    0
    0
    Oral herpes
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences all number
    1
    1
    0
    0
    0
    1
    Oral candidiasis
         subjects affected / exposed
    1 / 13 (7.69%)
    6 / 373 (1.61%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    4 / 372 (1.08%)
         occurrences all number
    1
    8
    0
    0
    0
    5
    Pneumonia bacterial
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 373 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Sepsis
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 373 (0.27%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    Viral pharyngitis
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 373 (0.27%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    0 / 372 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Urinary tract infection
         subjects affected / exposed
    5 / 13 (38.46%)
    30 / 373 (8.04%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    29 / 372 (7.80%)
         occurrences all number
    11
    41
    0
    0
    0
    35
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 13 (15.38%)
    22 / 373 (5.90%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    15 / 372 (4.03%)
         occurrences all number
    2
    31
    0
    0
    0
    21
    Tooth infection
         subjects affected / exposed
    1 / 13 (7.69%)
    7 / 373 (1.88%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    1 / 372 (0.27%)
         occurrences all number
    1
    9
    0
    0
    0
    1
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    2 / 13 (15.38%)
    11 / 373 (2.95%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    5 / 372 (1.34%)
         occurrences all number
    6
    14
    1
    0
    0
    6
    Decreased appetite
         subjects affected / exposed
    3 / 13 (23.08%)
    130 / 373 (34.85%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    1 / 7 (14.29%)
    112 / 372 (30.11%)
         occurrences all number
    4
    218
    0
    0
    1
    150
    Hyperglycaemia
         subjects affected / exposed
    0 / 13 (0.00%)
    39 / 373 (10.46%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    33 / 372 (8.87%)
         occurrences all number
    0
    69
    0
    0
    0
    56
    Hyperkalaemia
         subjects affected / exposed
    0 / 13 (0.00%)
    20 / 373 (5.36%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    19 / 372 (5.11%)
         occurrences all number
    0
    28
    0
    0
    0
    26
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 13 (7.69%)
    39 / 373 (10.46%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    28 / 372 (7.53%)
         occurrences all number
    1
    81
    0
    0
    0
    51
    Hypocalcaemia
         subjects affected / exposed
    1 / 13 (7.69%)
    19 / 373 (5.09%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    18 / 372 (4.84%)
         occurrences all number
    1
    26
    0
    0
    0
    22
    Hypomagnesaemia
         subjects affected / exposed
    1 / 13 (7.69%)
    36 / 373 (9.65%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    29 / 372 (7.80%)
         occurrences all number
    2
    59
    0
    0
    0
    42
    Hyponatraemia
         subjects affected / exposed
    2 / 13 (15.38%)
    44 / 373 (11.80%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    31 / 372 (8.33%)
         occurrences all number
    3
    72
    0
    0
    0
    64
    Hypoproteinaemia
         subjects affected / exposed
    0 / 13 (0.00%)
    11 / 373 (2.95%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    1 / 7 (14.29%)
    9 / 372 (2.42%)
         occurrences all number
    0
    11
    0
    0
    1
    20
    Hypokalaemia
         subjects affected / exposed
    1 / 13 (7.69%)
    39 / 373 (10.46%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 7 (0.00%)
    27 / 372 (7.26%)
         occurrences all number
    1
    59
    0
    0
    0
    41

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Jan 2019
    The major changes for amendment 1 (AM 1) was in in response to the feedback from the regulatory agency (FDA) regarding a potential hold comment related to permanent discontinuation of lenvatinib for Grade 3 thromboembolic events since CTCAE V5 classifies Grade 3 as “Urgent medical intervention indicated”.
    02 Jul 2019
    The major changes for AM2 was to address health authority feedback and to align with the Sponsor’s newly released lenvatinib and pembrolizumab (LEAP) program protocol template.
    09 Aug 2019
    The major changes for AM 3 were to correct significant clerical errors inadvertently introduced into study amendment 02 that altered the study protocol inclusion/exclusion criteria and contraceptive language.
    03 Mar 2020
    The major changes for AM 4 were to extend the enrollment period beyond the global study to achieve required exposure and number of events to investigate efficacy and safety in participants with Front-line (or first-line) (1L) NSCLC enrolled in China.
    30 Apr 2021
    The major changes for AM 5 was to update the assumptions and timing of the analyses in the SAP to allow sufficient duration of follow-up based on updated enrollment period and the long-term survival data from the reference study KEYNOTE-189.
    03 Sep 2021
    The major changes for AM6 were country specific clarifications added to address the sourcing of pembrolizumab in the UK and to clarify pembrolizumab dose modification and toxicity management in Canada.
    06 Oct 2022
    The major changes for AM 7 was Merck Sharp & Dohme Corp. entity name and address change to Merck Sharp & Dohme LLC, Rahway, NJ, USA.
    27 Oct 2023
    The major changes for AM 8 were the study to be discontinued based on the observation that the combination of pembrolizumab + platinum chemotherapy + lenvatinib versus pembrolizumab + platinum chemotherapy did not meet the prespecified criteria for the primary endpoint of OS at the final analysis and the second dual primary endpoint of PFS.

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

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