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    Clinical Trial Results:
    A Phase 3 Multicenter, Randomized, Double-blinded, Active-controlled, Clinical Study to Evaluate the Safety and Efficacy of Lenvatinib (E7080/MK-7902) in Combination with Pembrolizumab (MK-3475) Versus Lenvatinib in First-line Therapy of Participants with Advanced Hepatocellular Carcinoma (LEAP-002)

    Summary
    EudraCT number
    		 2018-002983-26
    Trial protocol
    		 GB   IE   ES   DE   PL   IT  
    Global end of trial date
    24 Sep 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Oct 2025
    First version publication date
    23 Oct 2025
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    7902-002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03713593
    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@msd.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    21 Jun 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Jun 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Sep 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is to evaluate the safety and efficacy of lenvatinib (E7080/MK-7902) in combination with pembrolizumab (MK-3745) versus lenvatinib in combination with placebo as first-line therapy for the treatment of advanced hepatocellular carcinoma in adult participants. The primary hypotheses of this study are that lenvatinib plus pembrolizumab is superior to lenvatinib plus placebo with respect to progression-free survival (PFS) and overall survival (OS).
    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
    31 Dec 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 11
    Country: Number of subjects enrolled
    Canada: 7
    Country: Number of subjects enrolled
    Chile: 15
    Country: Number of subjects enrolled
    China: 150
    Country: Number of subjects enrolled
    Colombia: 19
    Country: Number of subjects enrolled
    France: 109
    Country: Number of subjects enrolled
    Germany: 31
    Country: Number of subjects enrolled
    Ireland: 5
    Country: Number of subjects enrolled
    Italy: 43
    Country: Number of subjects enrolled
    Japan: 80
    Country: Number of subjects enrolled
    Korea, Republic of: 50
    Country: Number of subjects enrolled
    Mexico: 39
    Country: Number of subjects enrolled
    New Zealand: 6
    Country: Number of subjects enrolled
    Poland: 27
    Country: Number of subjects enrolled
    Russian Federation: 31
    Country: Number of subjects enrolled
    Spain: 17
    Country: Number of subjects enrolled
    Taiwan: 31
    Country: Number of subjects enrolled
    Thailand: 13
    Country: Number of subjects enrolled
    Türkiye: 31
    Country: Number of subjects enrolled
    United Kingdom: 25
    Country: Number of subjects enrolled
    United States: 54
    Worldwide total number of subjects
    794
    EEA total number of subjects
    232
    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)
    370
    From 65 to 84 years
    416
    85 years and over
    8

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants with a radiologically, histologically- or cytologically-confirmed diagnosis of hepatocellular carcinoma (HCC) were recruited into this study.

    Pre-assignment
    Screening details
    		 794 participants were randomly assigned in a 1:1 ratio to either combination therapy, Pembrolizumab+Lenvatinib, or Lenvatinib+Placebo, to assess the safety and efficacy of Lenvatinib in combination with Pembrolizumab versus Lenvatinib in first-line therapy of participants with advanced hepatocellular carcinoma

    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
    		 Investigator, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Lenvatinib + Pembrolizumab
    Arm description
    		 Participants received lenvatinib 12 mg (for participants with screening body weight ≥60 kg) or 8 mg (for participants with screening body weight <60 kg) orally once a day (QD) plus pembrolizumab 200 mg by intravenous (IV) infusion on Day 1 of each 21-day cycle (Q3W). Pembrolizumab was administered for up to 35 cycles (approximately 24 months). Lenvatinib was administered until progressive disease or unacceptable toxicity.
    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

    Arm title
    		 Lenvatinib + Placebo
    Arm description
    		 Participants received lenvatinib 12 mg (for participants with screening body weight ≥60 kg) or 8 mg (for participants with screening body weight <60 kg) orally QD plus saline placebo by IV infusion on Day 1 Q3W. Saline placebo was administered for up to 35 cycles (approximately 24 months). Lenvatinib was administered until progressive disease or unacceptable toxicity.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Placebo matching pembrolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    0 mg via IV infusion on Day 1 of each 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

    Number of subjects in period 1
    		Lenvatinib + Pembrolizumab Lenvatinib + Placebo
    Started
    395
    399
    Completed
    0
    0
    Not completed
    395
    399
         Consent withdrawn by subject
    6
    8
         Death
    314
    349
         Sponsor Decision
    73
    41
         Lost to follow-up
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Lenvatinib + Pembrolizumab
    Reporting group description
    		 Participants received lenvatinib 12 mg (for participants with screening body weight ≥60 kg) or 8 mg (for participants with screening body weight <60 kg) orally once a day (QD) plus pembrolizumab 200 mg by intravenous (IV) infusion on Day 1 of each 21-day cycle (Q3W). Pembrolizumab was administered for up to 35 cycles (approximately 24 months). Lenvatinib was administered until progressive disease or unacceptable toxicity.

    Reporting group title
    Lenvatinib + Placebo
    Reporting group description
    		 Participants received lenvatinib 12 mg (for participants with screening body weight ≥60 kg) or 8 mg (for participants with screening body weight <60 kg) orally QD plus saline placebo by IV infusion on Day 1 Q3W. Saline placebo was administered for up to 35 cycles (approximately 24 months). Lenvatinib was administered until progressive disease or unacceptable toxicity.

    Reporting group values
    		 Lenvatinib + Pembrolizumab Lenvatinib + Placebo Total
    Number of subjects
    		 395 399 794
    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 ( 10.9 ) 64.1 ( 12.1 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 78 72 150
        Male
    		 317 327 644
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 13 8 21
        Asian
    		 172 173 345
        Native Hawaiian or Other Pacific Islander
    		 2 0 2
        Black or African American
    		 5 8 13
        White
    		 173 172 345
        More than one race
    		 12 10 22
        Unknown or Not Reported
    		 18 28 46
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 48 41 89
        Not Hispanic or Latino
    		 334 349 683
        Unknown or Not Reported
    		 13 9 22
    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) or 2 (Ambulatory but unable to work). The number of participants with missing ECOG performance status is indicated for each treatment arm.
    Units: Subjects
        ECOG = 0
    		 267 271 538
        ECOG = 1
    		 127 126 253
        ECOG = 2
    		 1 0 1
        Missing
    		 0 2 2
    Geographic Region
    Randomization of participants in this study was stratified by geographic region of the enrolling site (Asia without Japan versus Japan and Western regions).
    Units: Subjects
        Asia without Japan
    		 121 123 244
        Japan and Western regions
    		 274 276 550

    End points

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    End points reporting groups
    Reporting group title
    Lenvatinib + Pembrolizumab
    Reporting group description
    		 Participants received lenvatinib 12 mg (for participants with screening body weight ≥60 kg) or 8 mg (for participants with screening body weight <60 kg) orally once a day (QD) plus pembrolizumab 200 mg by intravenous (IV) infusion on Day 1 of each 21-day cycle (Q3W). Pembrolizumab was administered for up to 35 cycles (approximately 24 months). Lenvatinib was administered until progressive disease or unacceptable toxicity.

    Reporting group title
    Lenvatinib + Placebo
    Reporting group description
    		 Participants received lenvatinib 12 mg (for participants with screening body weight ≥60 kg) or 8 mg (for participants with screening body weight <60 kg) orally QD plus saline placebo by IV infusion on Day 1 Q3W. Saline placebo was administered for up to 35 cycles (approximately 24 months). Lenvatinib was administered until progressive disease or unacceptable toxicity.

    Primary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS was defined as the time from randomization until death from any cause
    End point type
    Primary
    End point timeframe
    Up to approximately 41 months
    End point values
    		 Lenvatinib + Pembrolizumab Lenvatinib + Placebo
    Number of subjects analysed
    395
    399
    Units: Months
        median (confidence interval 95%)
    21.2 (19.0 to 23.6)
    19.0 (17.2 to 21.7)
    Statistical analysis title
    		 Hazard Ratio (HR)
    Comparison groups
    Lenvatinib + Pembrolizumab v Lenvatinib + Placebo
    Number of subjects included in analysis
    794
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0227
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.708
         upper limit
    		 0.997

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

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    End point title
    		 Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
    End point description
    PFS was defined as the time from the date of the first documentation of disease progression, as determined by blinded independent central review (BICR) per RECIST 1.1 or death due to any cause (whichever occurred first). Disease progression was defined as at least 20 percent (%) increase (including an absolute increase of at least 5 millimeter [mm]) in the sum of diameter of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions. PFS was estimated and analyzed using Kaplan-Meier method.
    End point type
    Primary
    End point timeframe
    Up to approximately 41 months
    End point values
    		 Lenvatinib + Pembrolizumab Lenvatinib + Placebo
    Number of subjects analysed
    395
    399
    Units: Months
        median (confidence interval 95%)
    8.2 (6.3 to 8.3)
    8.1 (6.3 to 8.3)
    Statistical analysis title
    		 Hazard Ratio (HR)
    Comparison groups
    Lenvatinib + Pembrolizumab v Lenvatinib + Placebo
    Number of subjects included in analysis
    794
    Analysis specification
    Pre-specified
    Analysis type
    		 [1]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.834
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.712
         upper limit
    		 0.978
    Notes
    [1] - Descriptive assessment

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

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    End point title
    		 Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
    End point description
    ORR was defined as the percentage of participants who have a confirmed complete response (CR: disappearance of all target lesions) or partial response (PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters) per RECIST 1.1 as assessed by BICR. RECIST 1.1 has been modified for this study to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.
    End point type
    Secondary
    End point timeframe
    Up to approximately 41 months
    End point values
    		 Lenvatinib + Pembrolizumab Lenvatinib + Placebo
    Number of subjects analysed
    395
    399
    Units: Percentage of Participants
        number (confidence interval 95%)
    26.1 (21.8 to 30.7)
    17.5 (13.9 to 21.6)
    Statistical analysis title
    		 Difference in percentage
    Comparison groups
    Lenvatinib + Pembrolizumab v Lenvatinib + Placebo
    Number of subjects included in analysis
    794
    Analysis specification
    Pre-specified
    Analysis type
    		 [2]
    Method
    Parameter type
    		 Difference in percentage
    Point estimate
    8.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.8
         upper limit
    		 14.2
    Notes
    [2] - Descriptive assessment

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

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    End point title
    		 Duration of Response (DOR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
    End point description
    DOR was determined by disease assessment and is defined as the time from the first documented evidence of a response of CR or PR, per RECIST 1.1 as assessed by BICR, until the first documented disease progression or death due to any cause, whichever occurred first. RECIST 1.1 has been modified for this study to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.
    End point type
    Secondary
    End point timeframe
    Up to approximately 41 months
    End point values
    		 Lenvatinib + Pembrolizumab Lenvatinib + Placebo
    Number of subjects analysed
    103
    70
    Units: Months
        median (full range (min-max))
    4.1 (1.3 to 25.3)
    4.0 (0.3 to 18.6)
    No statistical analyses for this end point

    Secondary: Disease Control Rate (DCR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)

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    End point title
    		 Disease Control Rate (DCR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
    End point description
    DCR was defined as the percentage of participants who have a best overall response of CR, PR, or stable disease (SD) per RECIST 1.1 as assessed by BICR. SD must be achieved at ≥6 weeks after randomization to be considered best overall response. RECIST 1.1 has been modified for this study to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.
    End point type
    Secondary
    End point timeframe
    Up to approximately 41 months
    End point values
    		 Lenvatinib + Pembrolizumab Lenvatinib + Placebo
    Number of subjects analysed
    395
    399
    Units: Percentage of Participants
        number (confidence interval 95%)
    81.3 (77.1 to 85.0)
    78.4 (74.1 to 82.4)
    No statistical analyses for this end point

    Secondary: Progression-free Survival (PFS) per Modified Response Evaluation Criteria in Solid Tumors (mRECIST)

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    End point title
    		 Progression-free Survival (PFS) per Modified Response Evaluation Criteria in Solid Tumors (mRECIST)
    End point description
    PFS was defined as the time from the first dose of study intervention to the first documented progressive disease (PD) per mRECIST by BICR or death due to any cause, whichever occurred first. mRECIST for HCC allowed evaluation of treatment effects that were not reflected in simple total size changes of lesions. Per mRECIST, PD was defined as an increase of at least 20% in the sum of diameters (SODs) of viable (enhancing) target lesions, taking as reference the smallest SODs of viable (enhancing) target lesions recorded since the treatment started.
    End point type
    Secondary
    End point timeframe
    Up to approximately 41 months
    End point values
    		 Lenvatinib + Pembrolizumab Lenvatinib + Placebo
    Number of subjects analysed
    395
    399
    Units: Months
        median (confidence interval 95%)
    8.4 (8.2 to 10.2)
    8.1 (6.5 to 8.3)
    Statistical analysis title
    		 Hazard Ratio (HR)
    Comparison groups
    Lenvatinib + Pembrolizumab v Lenvatinib + Placebo
    Number of subjects included in analysis
    794
    Analysis specification
    Pre-specified
    Analysis type
    		 [3]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.68
         upper limit
    		 0.94
    Notes
    [3] - Descriptive assessment

    Secondary: Time to Disease Progression (TTP) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)

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    End point title
    		 Time to Disease Progression (TTP) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
    End point description
    TTP was defined as the time from randomization to the first documented disease progression per RECIST 1.1 as assessed by BICR. RECIST 1.1 was modified for this study to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ were followed.
    End point type
    Secondary
    End point timeframe
    Up to approximately 41 months
    End point values
    		 Lenvatinib + Pembrolizumab Lenvatinib + Placebo
    Number of subjects analysed
    395
    399
    Units: Months
        median (confidence interval 95%)
    8.3 (8.1 to 10.3)
    8.2 (7.0 to 8.4)
    Statistical analysis title
    		 Hazard Ratio (HR)
    Comparison groups
    Lenvatinib + Pembrolizumab v Lenvatinib + Placebo
    Number of subjects included in analysis
    794
    Analysis specification
    Pre-specified
    Analysis type
    		 [4]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.66
         upper limit
    		 0.93
    Notes
    [4] - Descriptive assessment

    Secondary: Objective Response Rate (ORR) per Modified Response Evaluation Criteria in Solid Tumors (mRECIST)

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    End point title
    		 Objective Response Rate (ORR) per Modified Response Evaluation Criteria in Solid Tumors (mRECIST)
    End point description
    ORR wass defined as the percentage of participants who have a confirmed complete response (CR: disappearance of any intratumoral arterial enhancement in all target lesions) or partial response (PR: at least a 30% decrease in the sum of diameters of viable [enhancement in the arterial phase] target lesions, taking as reference the baseline sum of the diameters of target lesions) per mRECIST as assessed by BICR. mRECIST for hepatocellular carcinoma evaluates lesions within the liver parenchyma showing increased contrast enhancement in the arterial phase. A maximum of 10 target lesions and a maximum of 5 target lesions per organ were followed.
    End point type
    Secondary
    End point timeframe
    Up to approximately 41 months
    End point values
    		 Lenvatinib + Pembrolizumab Lenvatinib + Placebo
    Number of subjects analysed
    395
    399
    Units: Percentage of Participants
        number (confidence interval 95%)
    40.8 (35.9 to 45.8)
    34.1 (29.4 to 39.0)
    Statistical analysis title
    		 Difference in percentage
    Comparison groups
    Lenvatinib + Pembrolizumab v Lenvatinib + Placebo
    Number of subjects included in analysis
    794
    Analysis specification
    Pre-specified
    Analysis type
    		 [5]
    Method
    Parameter type
    		 Difference in percentage
    Point estimate
    6.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 13.4
    Notes
    [5] - Descriptive assessment

    Secondary: Duration of Response (DOR) per Modified Response Evaluation Criteria in Solid Tumors (mRECIST)

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    End point title
    		 Duration of Response (DOR) per Modified Response Evaluation Criteria in Solid Tumors (mRECIST)
    End point description
    DOR was determined by disease assessment and is defined as the time from the first documented evidence of a response of CR or PR, per mRECIST as assessed by BICR, until the first documented disease progression or death due to any cause, whichever occurs first. mRECIST for hepatocellular carcinoma evaluates lesions within the liver parenchyma showing increased contrast enhancement in the arterial phase. A maximum of 10 target lesions and a maximum of 5 target lesions per organ were followed.
    End point type
    Secondary
    End point timeframe
    Up to approximately 41 months
    End point values
    		 Lenvatinib + Pembrolizumab Lenvatinib + Placebo
    Number of subjects analysed
    151
    136
    Units: Months
        median (full range (min-max))
    2.1 (1.2 to 16.6)
    2.1 (0.2 to 14.5)
    No statistical analyses for this end point

    Secondary: Disease Control Rate (DCR) per Modified Response Evaluation Criteria in Solid Tumors (mRECIST)

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    End point title
    		 Disease Control Rate (DCR) per Modified Response Evaluation Criteria in Solid Tumors (mRECIST)
    End point description
    DCR was defined as the percentage of participants who have a best overall response of CR, PR, or SD per mRECIST as assessed by BICR. mRECIST for hepatocellular carcinoma evaluates lesions within the liver parenchyma showing increased contrast enhancement in the arterial phase. SD must be achieved at ≥6 weeks after randomization to be considered best overall response. A maximum of 10 target lesions and a maximum of 5 target lesions per organ were followed.
    End point type
    Secondary
    End point timeframe
    Up to approximately 41 months
    End point values
    		 Lenvatinib + Pembrolizumab Lenvatinib + Placebo
    Number of subjects analysed
    395
    399
    Units: Percentage of Participants
        number (confidence interval 95%)
    84.3 (80.3 to 87.7)
    83.2 (79.2 to 86.7)
    No statistical analyses for this end point

    Secondary: Time to Disease Progression (TTP) per Modified Response Evaluation Criteria in Solid Tumors (mRECIST)

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    End point title
    		 Time to Disease Progression (TTP) per Modified Response Evaluation Criteria in Solid Tumors (mRECIST)
    End point description
    TTP was defined as the time from randomization to the first documented disease progression per mRECIST as assessed by BICR. mRECIST for hepatocellular carcinoma evaluates lesions within the liver parenchyma showing increased contrast enhancement in the arterial phase. A maximum of 10 target lesions and a maximum of 5 target lesions per organ were followed.
    End point type
    Secondary
    End point timeframe
    Up to approximately 41 months
    End point values
    		 Lenvatinib + Pembrolizumab Lenvatinib + Placebo
    Number of subjects analysed
    395
    399
    Units: Months
        median (confidence interval 95%)
    10.4 (8.5 to 11.7)
    8.3 (8.1 to 8.9)
    Statistical analysis title
    		 Hazard Ratio (HR)
    Comparison groups
    Lenvatinib + Pembrolizumab v Lenvatinib + Placebo
    Number of subjects included in analysis
    794
    Analysis specification
    Pre-specified
    Analysis type
    		 [6]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.61
         upper limit
    		 0.88
    Notes
    [6] - Descriptive assessment

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

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    End point title
    		 Number of Participants Who Experienced an Adverse Event (AE)
    End point description
    Number of participants who experienced an AE defined as any unfavorable and unintended sign, symptom, disease, or worsening of preexisting condition temporally associated with study therapy and irrespective of causality to study treatment
    End point type
    Secondary
    End point timeframe
    Up to approximately 68 months
    End point values
    		 Lenvatinib + Pembrolizumab Lenvatinib + Placebo
    Number of subjects analysed
    395
    395
    Units: Participants
    394
    392
    No statistical analyses for this end point

    Secondary: Number of Participants Who Experienced an Serious Adverse Event (SAE)

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    End point title
    		 Number of Participants Who Experienced an Serious Adverse Event (SAE)
    End point description
    Number of participants who experienced a SAE defined as an AE that resulted in death, was life threatening, resulting in persistent or significant disability or incapacity, resulting in or prolonged a hospitalization, was a congenital anomaly or birth defect, was a cancer, was associated with an overdose, or was another important medical event
    End point type
    Secondary
    End point timeframe
    Up to approximately 68 months
    End point values
    		 Lenvatinib + Pembrolizumab Lenvatinib + Placebo
    Number of subjects analysed
    395
    395
    Units: Participants
    185
    159
    No statistical analyses for this end point

    Secondary: Number of Participants Who Experienced an Immune-related Adverse Event (irAE) of Clinical Interest

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    End point title
    		 Number of Participants Who Experienced an Immune-related Adverse Event (irAE) of Clinical Interest
    End point description
    Number of participants who experienced an AE representing an immunologic etiology and considered to be causally related to drug exposure
    End point type
    Secondary
    End point timeframe
    Up to approximately 41 months
    End point values
    		 Lenvatinib + Pembrolizumab Lenvatinib + Placebo
    Number of subjects analysed
    395
    395
    Units: Participants
    210
    184
    No statistical analyses for this end point

    Secondary: Number of Participants Who Experienced an Hepatic Event of Clinical Interest (HECI)

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    End point title
    		 Number of Participants Who Experienced an Hepatic Event of Clinical Interest (HECI)
    End point description
    Number of participants who experienced a hepatic ECI not due to disease progression as judged by the investigator.
    End point type
    Secondary
    End point timeframe
    Up to approximately 68 months
    End point values
    		 Lenvatinib + Pembrolizumab Lenvatinib + Placebo
    Number of subjects analysed
    395
    395
    Units: Participants
    71
    77
    No statistical analyses for this end point

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

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    End point title
    		 Number of Participants Who Discontinued Study Drug Due to an Adverse Event
    End point description
    Number of participants who discontinued study treatment due to an AE
    End point type
    Secondary
    End point timeframe
    Up to approximately 68 months
    End point values
    		 Lenvatinib + Pembrolizumab Lenvatinib + Placebo
    Number of subjects analysed
    395
    395
    Units: Participants
    51
    41
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to ~ 68 months
    Adverse event reporting additional description
    AE additional description
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    27.0
    Reporting groups
    Reporting group title
    Lenvatinib + Placebo
    Reporting group description
    		 Participants received lenvatinib 12 mg (for participants with screening body weight ≥60 kg) or 8 mg (for participants with screening body weight <60 kg) orally QD plus saline placebo by IV infusion on Day 1 Q3W. Saline placebo was administered for up to 35 cycles (approximately 24 months). Lenvatinib was administered until progressive disease or unacceptable toxicity.

    Reporting group title
    Lenvatinib + Pembrolizumab
    Reporting group description
    		 Participants received lenvatinib 12 mg (for participants with screening body weight ≥60 kg) or 8 mg (for participants with screening body weight <60 kg) orally once a day (QD) plus pembrolizumab 200 mg by intravenous (IV) infusion on Day 1 of each 21-day cycle (Q3W). Pembrolizumab was administered for up to 35 cycles (approximately 24 months). Lenvatinib was administered until progressive disease or unacceptable toxicity.

    Serious adverse events
    		 Lenvatinib + Placebo Lenvatinib + Pembrolizumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    159 / 395 (40.25%)
    185 / 395 (46.84%)
         number of deaths (all causes)
    352
    314
         number of deaths resulting from adverse events
    21
    29
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    1 / 395 (0.25%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cancer pain
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver carcinoma ruptured
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Malignant neoplasm of unknown primary site
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 395 (0.25%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin squamous cell carcinoma recurrent
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    2 / 395 (0.51%)
    3 / 395 (0.76%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Vasculitis
         subjects affected / exposed
    1 / 395 (0.25%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive emergency
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    2 / 395 (0.51%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    2 / 395 (0.51%)
    3 / 395 (0.76%)
         occurrences causally related to treatment / all
    1 / 2
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic aneurysm
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Drowning
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Asthenia
         subjects affected / exposed
    0 / 395 (0.00%)
    3 / 395 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    3 / 395 (0.76%)
    5 / 395 (1.27%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 3
    0 / 5
    Fatigue
         subjects affected / exposed
    2 / 395 (0.51%)
    3 / 395 (0.76%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 395 (0.00%)
    7 / 395 (1.77%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperthermia malignant
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 395 (0.00%)
    2 / 395 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Oedema peripheral
         subjects affected / exposed
    2 / 395 (0.51%)
    2 / 395 (0.51%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    4 / 395 (1.01%)
    3 / 395 (0.76%)
         occurrences causally related to treatment / all
    3 / 5
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stent-graft endoleak
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Scrotal inflammation
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostatitis
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign prostatic hyperplasia
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal spasm
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract congestion
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Idiopathic pulmonary fibrosis
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hiccups
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    2 / 395 (0.51%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 395 (0.00%)
    4 / 395 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic respiratory failure
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pulmonary embolism
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Completed suicide
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Confusional state
         subjects affected / exposed
    1 / 395 (0.25%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    False positive investigation result
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood thyroid stimulating hormone decreased
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood glucose decreased
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 395 (0.25%)
    5 / 395 (1.27%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 395 (0.25%)
    3 / 395 (0.76%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Amylase increased
         subjects affected / exposed
    0 / 395 (0.00%)
    2 / 395 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 395 (0.25%)
    4 / 395 (1.01%)
         occurrences causally related to treatment / all
    1 / 1
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    2 / 395 (0.51%)
    2 / 395 (0.51%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Troponin T increased
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    1 / 395 (0.25%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Limb injury
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament rupture
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint injury
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    1 / 395 (0.25%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrioventricular block complete
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 395 (0.00%)
    2 / 395 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 395 (0.25%)
    2 / 395 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    2 / 395 (0.51%)
    3 / 395 (0.76%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Atrioventricular block second degree
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    2 / 395 (0.51%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Coronary artery disease
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    2 / 395 (0.51%)
    3 / 395 (0.76%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial injury
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocarditis
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus node dysfunction
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nervous system disorders
    Cerebral infarction
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 395 (0.25%)
    2 / 395 (0.51%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    0 / 395 (0.00%)
    3 / 395 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolic stroke
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic encephalopathy
         subjects affected / exposed
    11 / 395 (2.78%)
    21 / 395 (5.32%)
         occurrences causally related to treatment / all
    6 / 12
    14 / 27
         deaths causally related to treatment / all
    0 / 0
    2 / 2
    Ischaemic stroke
         subjects affected / exposed
    1 / 395 (0.25%)
    2 / 395 (0.51%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myasthenia gravis
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Posterior reversible encephalopathy syndrome
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ruptured cerebral aneurysm
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 395 (0.00%)
    2 / 395 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient global amnesia
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Agranulocytosis
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    1 / 395 (0.25%)
    5 / 395 (1.27%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune thrombocytopenia
         subjects affected / exposed
    0 / 395 (0.00%)
    2 / 395 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Diabetic retinopathy
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cataract
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glaucoma
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pterygium
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Dysphagia
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal distension
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal hernia
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    4 / 395 (1.01%)
    8 / 395 (2.03%)
         occurrences causally related to treatment / all
    3 / 4
    3 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal fistula
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    10 / 395 (2.53%)
    5 / 395 (1.27%)
         occurrences causally related to treatment / all
    3 / 10
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 395 (0.25%)
    2 / 395 (0.51%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 395 (0.25%)
    2 / 395 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    5 / 395 (1.27%)
    13 / 395 (3.29%)
         occurrences causally related to treatment / all
    5 / 5
    13 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer perforation, obstructive
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 395 (0.25%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mesenteric vein thrombosis
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    1 / 395 (0.25%)
    2 / 395 (0.51%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer haemorrhage
         subjects affected / exposed
    1 / 395 (0.25%)
    2 / 395 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric varices haemorrhage
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 395 (0.51%)
    3 / 395 (0.76%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 3
         deaths causally related to treatment / all
    1 / 1
    1 / 1
    Gastrointestinal inflammation
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoperitoneum
         subjects affected / exposed
    2 / 395 (0.51%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    1 / 395 (0.25%)
    3 / 395 (0.76%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    2 / 395 (0.51%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    1 / 395 (0.25%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mechanical ileus
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 395 (0.25%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal ulcer haemorrhage
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Oesophageal varices haemorrhage
         subjects affected / exposed
    5 / 395 (1.27%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    3 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 395 (0.00%)
    2 / 395 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    2 / 395 (0.51%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumatosis intestinalis
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctitis
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal perforation
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    4 / 395 (1.01%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    5 / 5
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Varices oesophageal
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 395 (0.00%)
    2 / 395 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal haemorrhage
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Biliary obstruction
         subjects affected / exposed
    2 / 395 (0.51%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bile duct stone
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    2 / 395 (0.51%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis acute
         subjects affected / exposed
    1 / 395 (0.25%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis chronic
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic cirrhosis
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    8 / 395 (2.03%)
    4 / 395 (1.01%)
         occurrences causally related to treatment / all
    1 / 8
    1 / 5
         deaths causally related to treatment / all
    0 / 5
    0 / 2
    Immune-mediated hepatitis
         subjects affected / exposed
    1 / 395 (0.25%)
    2 / 395 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic haemorrhage
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic necrosis
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic pain
         subjects affected / exposed
    1 / 395 (0.25%)
    2 / 395 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatorenal syndrome
         subjects affected / exposed
    2 / 395 (0.51%)
    2 / 395 (0.51%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 3
         deaths causally related to treatment / all
    1 / 2
    1 / 2
    Hepatic function abnormal
         subjects affected / exposed
    3 / 395 (0.76%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Portal vein thrombosis
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver injury
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin ulcer
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psoriasis
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pemphigoid
         subjects affected / exposed
    0 / 395 (0.00%)
    2 / 395 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parapsoriasis
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lichenoid keratosis
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hidradenitis
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Henoch-Schonlein purpura
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Chronic kidney disease
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    2 / 395 (0.51%)
    3 / 395 (0.76%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nephritis
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrotic syndrome
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal tubular necrosis
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal infarct
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prerenal failure
         subjects affected / exposed
    1 / 395 (0.25%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    0 / 395 (0.00%)
    2 / 395 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperthyroidism
         subjects affected / exposed
    1 / 395 (0.25%)
    2 / 395 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypophysitis
         subjects affected / exposed
    0 / 395 (0.00%)
    2 / 395 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thyroiditis
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    2 / 395 (0.51%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tenosynovitis
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 395 (0.25%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fistula
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc degeneration
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteolysis
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis of jaw
         subjects affected / exposed
    2 / 395 (0.51%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Cytomegalovirus colitis
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal infection
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal sepsis
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    1 / 395 (0.25%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anorectal infection
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 395 (0.25%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis perforated
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    3 / 395 (0.76%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary tract infection
         subjects affected / exposed
    2 / 395 (0.51%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Bronchitis
         subjects affected / exposed
    3 / 395 (0.76%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    3 / 395 (0.76%)
    5 / 395 (1.27%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    COVID-19 pneumonia
         subjects affected / exposed
    1 / 395 (0.25%)
    3 / 395 (0.76%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    2 / 395 (0.51%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cryptococcosis
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalitis
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis infectious
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia bacteraemia
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fungaemia
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 395 (0.25%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine infection
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed
    1 / 395 (0.25%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periodontitis
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    2 / 395 (0.51%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis bacterial
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleurisy bacterial
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    7 / 395 (1.77%)
    8 / 395 (2.03%)
         occurrences causally related to treatment / all
    1 / 7
    2 / 8
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    3 / 395 (0.76%)
    3 / 395 (0.76%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Salmonellosis
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    2 / 395 (0.51%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostatic abscess
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia klebsiella
         subjects affected / exposed
    0 / 395 (0.00%)
    2 / 395 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia cryptococcal
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord infection
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal sepsis
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 395 (0.51%)
    4 / 395 (1.01%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 395 (0.51%)
    3 / 395 (0.76%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    3 / 395 (0.76%)
    2 / 395 (0.51%)
         occurrences causally related to treatment / all
    2 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    4 / 395 (1.01%)
    2 / 395 (0.51%)
         occurrences causally related to treatment / all
    2 / 4
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 395 (0.00%)
    2 / 395 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 395 (0.00%)
    2 / 395 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Type 1 diabetes mellitus
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    0 / 395 (0.00%)
    2 / 395 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hyponatraemia
         subjects affected / exposed
    2 / 395 (0.51%)
    2 / 395 (0.51%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 395 (0.25%)
    3 / 395 (0.76%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 395 (0.00%)
    3 / 395 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 395 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypervolaemia
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 395 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Lenvatinib + Placebo Lenvatinib + Pembrolizumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    388 / 395 (98.23%)
    390 / 395 (98.73%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    200 / 395 (50.63%)
    180 / 395 (45.57%)
         occurrences all number
    258
    248
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    61 / 395 (15.44%)
    73 / 395 (18.48%)
         occurrences all number
    85
    90
    Fatigue
         subjects affected / exposed
    98 / 395 (24.81%)
    126 / 395 (31.90%)
         occurrences all number
    124
    148
    Malaise
         subjects affected / exposed
    30 / 395 (7.59%)
    20 / 395 (5.06%)
         occurrences all number
    35
    24
    Mucosal inflammation
         subjects affected / exposed
    19 / 395 (4.81%)
    25 / 395 (6.33%)
         occurrences all number
    25
    30
    Oedema peripheral
         subjects affected / exposed
    54 / 395 (13.67%)
    63 / 395 (15.95%)
         occurrences all number
    68
    86
    Pyrexia
         subjects affected / exposed
    45 / 395 (11.39%)
    48 / 395 (12.15%)
         occurrences all number
    66
    60
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    29 / 395 (7.34%)
    25 / 395 (6.33%)
         occurrences all number
    42
    28
    Dyspnoea
         subjects affected / exposed
    24 / 395 (6.08%)
    44 / 395 (11.14%)
         occurrences all number
    32
    47
    Dysphonia
         subjects affected / exposed
    79 / 395 (20.00%)
    83 / 395 (21.01%)
         occurrences all number
    92
    94
    Cough
         subjects affected / exposed
    43 / 395 (10.89%)
    55 / 395 (13.92%)
         occurrences all number
    49
    66
    Oropharyngeal pain
         subjects affected / exposed
    15 / 395 (3.80%)
    23 / 395 (5.82%)
         occurrences all number
    17
    24
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    43 / 395 (10.89%)
    35 / 395 (8.86%)
         occurrences all number
    49
    40
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    89 / 395 (22.53%)
    93 / 395 (23.54%)
         occurrences all number
    155
    162
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    56 / 395 (14.18%)
    65 / 395 (16.46%)
         occurrences all number
    72
    78
    Blood creatinine increased
         subjects affected / exposed
    25 / 395 (6.33%)
    39 / 395 (9.87%)
         occurrences all number
    41
    60
    Blood bilirubin increased
         subjects affected / exposed
    108 / 395 (27.34%)
    101 / 395 (25.57%)
         occurrences all number
    216
    222
    Blood alkaline phosphatase increased
         subjects affected / exposed
    35 / 395 (8.86%)
    50 / 395 (12.66%)
         occurrences all number
    54
    64
    Aspartate aminotransferase increased
         subjects affected / exposed
    105 / 395 (26.58%)
    117 / 395 (29.62%)
         occurrences all number
    179
    195
    Amylase increased
         subjects affected / exposed
    18 / 395 (4.56%)
    40 / 395 (10.13%)
         occurrences all number
    30
    64
    Lipase increased
         subjects affected / exposed
    37 / 395 (9.37%)
    57 / 395 (14.43%)
         occurrences all number
    59
    79
    Neutrophil count decreased
         subjects affected / exposed
    39 / 395 (9.87%)
    34 / 395 (8.61%)
         occurrences all number
    85
    73
    Platelet count decreased
         subjects affected / exposed
    110 / 395 (27.85%)
    101 / 395 (25.57%)
         occurrences all number
    198
    170
    Weight decreased
         subjects affected / exposed
    90 / 395 (22.78%)
    121 / 395 (30.63%)
         occurrences all number
    105
    139
    White blood cell count decreased
         subjects affected / exposed
    45 / 395 (11.39%)
    29 / 395 (7.34%)
         occurrences all number
    105
    75
    Nervous system disorders
    Headache
         subjects affected / exposed
    43 / 395 (10.89%)
    51 / 395 (12.91%)
         occurrences all number
    58
    67
    Dysgeusia
         subjects affected / exposed
    19 / 395 (4.81%)
    22 / 395 (5.57%)
         occurrences all number
    21
    26
    Dizziness
         subjects affected / exposed
    28 / 395 (7.09%)
    26 / 395 (6.58%)
         occurrences all number
    30
    30
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    64 / 395 (16.20%)
    51 / 395 (12.91%)
         occurrences all number
    88
    61
    Neutropenia
         subjects affected / exposed
    22 / 395 (5.57%)
    19 / 395 (4.81%)
         occurrences all number
    38
    54
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    73 / 395 (18.48%)
    67 / 395 (16.96%)
         occurrences all number
    81
    81
    Diarrhoea
         subjects affected / exposed
    167 / 395 (42.28%)
    187 / 395 (47.34%)
         occurrences all number
    352
    359
    Dry mouth
         subjects affected / exposed
    14 / 395 (3.54%)
    20 / 395 (5.06%)
         occurrences all number
    14
    20
    Dyspepsia
         subjects affected / exposed
    14 / 395 (3.54%)
    33 / 395 (8.35%)
         occurrences all number
    18
    41
    Nausea
         subjects affected / exposed
    82 / 395 (20.76%)
    89 / 395 (22.53%)
         occurrences all number
    120
    123
    Stomatitis
         subjects affected / exposed
    35 / 395 (8.86%)
    41 / 395 (10.38%)
         occurrences all number
    47
    55
    Toothache
         subjects affected / exposed
    18 / 395 (4.56%)
    24 / 395 (6.08%)
         occurrences all number
    23
    28
    Vomiting
         subjects affected / exposed
    61 / 395 (15.44%)
    54 / 395 (13.67%)
         occurrences all number
    93
    93
    Ascites
         subjects affected / exposed
    29 / 395 (7.34%)
    28 / 395 (7.09%)
         occurrences all number
    34
    35
    Abdominal pain upper
         subjects affected / exposed
    40 / 395 (10.13%)
    46 / 395 (11.65%)
         occurrences all number
    53
    52
    Abdominal pain
         subjects affected / exposed
    74 / 395 (18.73%)
    74 / 395 (18.73%)
         occurrences all number
    91
    88
    Abdominal distension
         subjects affected / exposed
    18 / 395 (4.56%)
    27 / 395 (6.84%)
         occurrences all number
    20
    33
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    35 / 395 (8.86%)
    63 / 395 (15.95%)
         occurrences all number
    46
    79
    Pruritus
         subjects affected / exposed
    44 / 395 (11.14%)
    67 / 395 (16.96%)
         occurrences all number
    57
    79
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    125 / 395 (31.65%)
    133 / 395 (33.67%)
         occurrences all number
    141
    155
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    24 / 395 (6.08%)
    27 / 395 (6.84%)
         occurrences all number
    55
    43
    Proteinuria
         subjects affected / exposed
    153 / 395 (38.73%)
    136 / 395 (34.43%)
         occurrences all number
    268
    280
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    15 / 395 (3.80%)
    31 / 395 (7.85%)
         occurrences all number
    16
    32
    Hypothyroidism
         subjects affected / exposed
    159 / 395 (40.25%)
    167 / 395 (42.28%)
         occurrences all number
    202
    207
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    23 / 395 (5.82%)
    19 / 395 (4.81%)
         occurrences all number
    27
    22
    Myalgia
         subjects affected / exposed
    14 / 395 (3.54%)
    25 / 395 (6.33%)
         occurrences all number
    15
    27
    Back pain
         subjects affected / exposed
    43 / 395 (10.89%)
    60 / 395 (15.19%)
         occurrences all number
    49
    72
    Arthralgia
         subjects affected / exposed
    77 / 395 (19.49%)
    89 / 395 (22.53%)
         occurrences all number
    93
    114
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    14 / 395 (3.54%)
    20 / 395 (5.06%)
         occurrences all number
    16
    27
    Urinary tract infection
         subjects affected / exposed
    42 / 395 (10.63%)
    35 / 395 (8.86%)
         occurrences all number
    65
    48
    Metabolism and nutrition disorders
    Hypophosphataemia
         subjects affected / exposed
    23 / 395 (5.82%)
    19 / 395 (4.81%)
         occurrences all number
    43
    24
    Hyponatraemia
         subjects affected / exposed
    39 / 395 (9.87%)
    43 / 395 (10.89%)
         occurrences all number
    64
    69
    Hypomagnesaemia
         subjects affected / exposed
    28 / 395 (7.09%)
    27 / 395 (6.84%)
         occurrences all number
    56
    46
    Hypokalaemia
         subjects affected / exposed
    36 / 395 (9.11%)
    39 / 395 (9.87%)
         occurrences all number
    60
    75
    Decreased appetite
         subjects affected / exposed
    120 / 395 (30.38%)
    146 / 395 (36.96%)
         occurrences all number
    167
    183
    Hyperglycaemia
         subjects affected / exposed
    25 / 395 (6.33%)
    24 / 395 (6.08%)
         occurrences all number
    46
    33
    Hyperkalaemia
         subjects affected / exposed
    20 / 395 (5.06%)
    14 / 395 (3.54%)
         occurrences all number
    26
    22
    Hypertriglyceridaemia
         subjects affected / exposed
    31 / 395 (7.85%)
    24 / 395 (6.08%)
         occurrences all number
    64
    51
    Hypoalbuminaemia
         subjects affected / exposed
    61 / 395 (15.44%)
    62 / 395 (15.70%)
         occurrences all number
    99
    85

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 May 2019
    The major changes for AM1 was to address feedback from regulatory authorities and align with MK-7902 program standard updates.
    11 May 2021
    The major changes for AM2 was to remove pharmacokinetic (PK) objective and update pembrolizumab dose modification table.
    08 Dec 2022
    The major changes for AM3 was to space out clinic visits to every 6 weeks and imaging scans to every 12 weeks.
    17 Oct 2023
    The major changes for AM4 was to add Study extension.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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