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    Clinical Trial Results:
    A Randomized, Open Label, Phase III Study of Overall Survival Comparing Pembrolizumab (MK-3475) versus Platinum Based Chemotherapy in Treatment Naïve Subjects with PD-L1 Positive Advanced or Metastatic Non-Small Cell Lung Cancer (Keynote 042)

    Summary
    EudraCT number
    		 2014-001473-14
    Trial protocol
    		 SE   CZ   LT   LV   PT   PL   EE   BG   HU  
    Global end of trial date
    02 Feb 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Sep 2023
    First version publication date
    23 Sep 2023
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    3475-042
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02220894
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme LLC
    Sponsor organisation address
    126 East Lincoln Avenue, P.O. Box 2000, Rahway, NJ, United States, 07065
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme LLC, ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme LLC, ClinicalTrialsDisclosure@merck.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    02 Feb 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Sep 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Feb 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the overall survival (OS) in subjects with TPS≥50%, advanced/metastatic NSCLC treated with pembrolizumab compared to standard of care (SOC) chemotherapies, to compare the OS in subjects with TPS≥20%, 1L advanced/metastatic NSCLC treated with pembrolizumab compared to standard of care (SOC) chemotherapies and to compare the OS in subjects with TPS≥1%, 1L advanced/metastatic NSCLC treated with pembrolizumab compared to SOC chemotherapies.
    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
    30 Oct 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 40
    Country: Number of subjects enrolled
    Brazil: 113
    Country: Number of subjects enrolled
    Bulgaria: 2
    Country: Number of subjects enrolled
    Canada: 25
    Country: Number of subjects enrolled
    Chile: 42
    Country: Number of subjects enrolled
    China: 92
    Country: Number of subjects enrolled
    Colombia: 8
    Country: Number of subjects enrolled
    Czechia: 39
    Country: Number of subjects enrolled
    Estonia: 12
    Country: Number of subjects enrolled
    Guatemala: 11
    Country: Number of subjects enrolled
    Hong Kong: 13
    Country: Number of subjects enrolled
    Hungary: 3
    Country: Number of subjects enrolled
    Japan: 93
    Country: Number of subjects enrolled
    Korea, Republic of: 39
    Country: Number of subjects enrolled
    Latvia: 49
    Country: Number of subjects enrolled
    Lithuania: 30
    Country: Number of subjects enrolled
    Malaysia: 35
    Country: Number of subjects enrolled
    Mexico: 32
    Country: Number of subjects enrolled
    Peru: 23
    Country: Number of subjects enrolled
    Philippines: 22
    Country: Number of subjects enrolled
    Poland: 90
    Country: Number of subjects enrolled
    Portugal: 12
    Country: Number of subjects enrolled
    Romania: 26
    Country: Number of subjects enrolled
    Russian Federation: 90
    Country: Number of subjects enrolled
    South Africa: 34
    Country: Number of subjects enrolled
    Sweden: 7
    Country: Number of subjects enrolled
    Switzerland: 16
    Country: Number of subjects enrolled
    Taiwan: 22
    Country: Number of subjects enrolled
    Thailand: 52
    Country: Number of subjects enrolled
    Turkey: 109
    Country: Number of subjects enrolled
    Ukraine: 91
    Country: Number of subjects enrolled
    Viet Nam: 2
    Worldwide total number of subjects
    1274
    EEA total number of subjects
    270
    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)
    707
    From 65 to 84 years
    554
    85 years and over
    13

    Subject disposition

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    Recruitment
    Recruitment details
    		 Of the 1275 participants randomized (pembrolizumab=638, chemotherapy=637), 1 participant assigned to receive pembrolizumab died prior to randomization and was randomized in error. The intent to treat population was defined as participants alive at the time of randomization, so the actual randomized population included 637 participants in each arm.

    Pre-assignment
    Screening details
    		 Pembrolizumab-treated participants, who attained a complete response (CR) or who stopped treatment after 35 administrations for reasons other than disease progression or intolerability may have been eligible for re-treatment with pembrolizumab after they had experienced radiographic disease as per protocol-defined criteria.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Pembrolizumab
    Arm description
    		 Participants received pembrolizumab 200 mg by intravenous (IV) infusion on Day 1 every 3 weeks (Q3W) for a maximum of 35 cycles (21-day cycles). Some participants may have been eligible for re-treatment with pembrolizumab monotherapy after they had experienced radiographic disease as per protocol-defined criteria.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    MK-3475 KEYTRUDA®
    Pharmaceutical forms
    Infusion, Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    200 mg on Day 1 of every 21-day cycle (every 3 weeks, or Q3W) for up to 35 treatments

    Arm title
    		 Chemotherapy (Standard of Care [SOC] Treatment)
    Arm description
    		 Participants received carboplatin at target dose Area Under Curve (AUC) 5 (maximum dose 750 mg) or AUC 6 (maximum dose 900 mg) + paclitaxel 200 mg/m^2 by IV infusion on Day 1 Q3W for a maximum of 6 cycles (21-day cycles) OR carboplatin target dose AUC 5 (maximum dose 750 mg) or AUC 6 (maximum dose 900 mg) + pemetrexed 500 mg/m^2 by IV infusion on Day 1 Q3W for a maximum of 6 cycles (21-day cycles). Participants with non-squamous histologies received optional additional maintenance treatment with pemetrexed 500 mg/m^2 by IV infusion on Day 1 Q3W
    Arm type
    		 Active comparator

    Investigational medicinal product name
    carboplatin
    Investigational medicinal product code
    Other name
    PARAPLATIN®
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Carboplatin target dose Area Under Curve (AUC) 5 (maximum dose 750 mg) or AUC 6 (maximum dose 900 mg)

    Investigational medicinal product name
    pemetrexed
    Investigational medicinal product code
    Other name
    ALIMTA®
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    500 mg/m^2 IV on Day 1 Q3W for a maximum of 6 cycles

    Investigational medicinal product name
    paclitaxel
    Investigational medicinal product code
    Other name
    TAXOL®
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    200 mg/m^2 IV on Day 1 of every 21-day cycle (Q3W) for a maximum of 6 cycles

    Number of subjects in period 1
    		Pembrolizumab Chemotherapy (Standard of Care [SOC] Treatment)
    Started
    637
    637
    Treated
    636
    615
    Completed
    0
    0
    Not completed
    637
    637
         Adverse event, serious fatal
    418
    508
         Consent withdrawn by subject
    10
    9
         Adverse event, non-fatal
    127
    74
         Withdrawal by Parent/Guardian
    -
    1
         Site Terminated by Sponsor
    2
    -
         Participation in Study Terminated by Sponsor
    80
    41
         Lost to follow-up
    -
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Pembrolizumab
    Reporting group description
    		 Participants received pembrolizumab 200 mg by intravenous (IV) infusion on Day 1 every 3 weeks (Q3W) for a maximum of 35 cycles (21-day cycles). Some participants may have been eligible for re-treatment with pembrolizumab monotherapy after they had experienced radiographic disease as per protocol-defined criteria.

    Reporting group title
    Chemotherapy (Standard of Care [SOC] Treatment)
    Reporting group description
    		 Participants received carboplatin at target dose Area Under Curve (AUC) 5 (maximum dose 750 mg) or AUC 6 (maximum dose 900 mg) + paclitaxel 200 mg/m^2 by IV infusion on Day 1 Q3W for a maximum of 6 cycles (21-day cycles) OR carboplatin target dose AUC 5 (maximum dose 750 mg) or AUC 6 (maximum dose 900 mg) + pemetrexed 500 mg/m^2 by IV infusion on Day 1 Q3W for a maximum of 6 cycles (21-day cycles). Participants with non-squamous histologies received optional additional maintenance treatment with pemetrexed 500 mg/m^2 by IV infusion on Day 1 Q3W

    Reporting group values
    		 Pembrolizumab Chemotherapy (Standard of Care [SOC] Treatment) Total
    Number of subjects
    		 637 637 1274
    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)
    		 62.5 ( 9.9 ) 63.1 ( 9.4 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 187 185 372
        Male
    		 450 452 902
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 10 5 15
        Asian
    		 189 187 376
        Native Hawaiian or Other Pacific Islander
    		 0 1 1
        Black or African American
    		 10 13 23
        White
    		 398 412 810
        More than one race
    		 30 19 49
    Eastern Cooperative Oncology Group (ECOG) Performance Status (PS)
    Participants were assessed for ECOG PS: Grade 0: Fully active, able to carry on all pre-disease performance without restriction; Grade 1: Restricted in physically strenuous activity but ambulatory & able to carry out work of a light or sedentary nature; Grade 2: Ambulatory & capable of all selfcare but unable to carry out any work activities, up & about more than 50% of waking hours; Grade 3: Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours; Grade 4: Completely disabled, cannot carry on any selfcare, totally confined to bed or chair or Grade 5: Dead.
    Units: Subjects
        ECOG PS=0
    		 197 192 389
        ECOG PS=1
    		 439 445 884
        ECOG PS=2
    		 1 0 1
    Programmed Cell Death-Ligand 1 (PD-L1) Tumor Status
    Participants were assessed for their PD-L1 tumor expression status by immunohistochemistry assay using tumor tissue from an archival or newly obtained biopsy. Participants with a tumor proportion score (TPS) were classified as follows: ≥50% = PD-L1 strongly positive; 1-49% = PD-L1 weakly positive; and <1% = PD-L1 negative.
    Units: Subjects
        TPS=≥50%
    		 299 300 599
        TPS=20-49%
    		 114 105 219
        TPS=1-19%
    		 224 232 456
        TPS=<1%
    		 0 0 0
    Tumor Histology
    Participants were classified according to tumor histology: Squamous or Non-squamous. The tumor histology determined potential treatment regimen.
    Units: Subjects
        Squamous
    		 242 249 491
        Non-squamous
    		 395 388 783

    End points

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    End points reporting groups
    Reporting group title
    Pembrolizumab
    Reporting group description
    		 Participants received pembrolizumab 200 mg by intravenous (IV) infusion on Day 1 every 3 weeks (Q3W) for a maximum of 35 cycles (21-day cycles). Some participants may have been eligible for re-treatment with pembrolizumab monotherapy after they had experienced radiographic disease as per protocol-defined criteria.

    Reporting group title
    Chemotherapy (Standard of Care [SOC] Treatment)
    Reporting group description
    		 Participants received carboplatin at target dose Area Under Curve (AUC) 5 (maximum dose 750 mg) or AUC 6 (maximum dose 900 mg) + paclitaxel 200 mg/m^2 by IV infusion on Day 1 Q3W for a maximum of 6 cycles (21-day cycles) OR carboplatin target dose AUC 5 (maximum dose 750 mg) or AUC 6 (maximum dose 900 mg) + pemetrexed 500 mg/m^2 by IV infusion on Day 1 Q3W for a maximum of 6 cycles (21-day cycles). Participants with non-squamous histologies received optional additional maintenance treatment with pemetrexed 500 mg/m^2 by IV infusion on Day 1 Q3W

    Primary: Overall Survival (OS) in Participants with a Tumor Proportion Score (TPS) of ≥50%

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    End point title
    		 Overall Survival (OS) in Participants with a Tumor Proportion Score (TPS) of ≥50%
    End point description
    OS was determined for participants with a TPS of ≥50% and was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the interim analysis were censored at the date of the last follow-up. The OS was calculated using the product-limit (Kaplan-Meier) method for censored data. The efficacy hypothesis was analyzed using a sequential testing strategy that involved testing a hypothesis only if the superiority of pembrolizumab over chemotherapy was established for all the preceding hypotheses. The order of testing was OS in participants with TPS≥50%, then with TPS≥20%, and finally with TPS≥1%. The OS for participants with a TPS ≥50% is presented. The analysis population included all participants who were alive at the time of randomization and had a TPS of ≥50%.
    End point type
    Primary
    End point timeframe
    Up to 45 months
    End point values
    		 Pembrolizumab Chemotherapy (Standard of Care [SOC] Treatment)
    Number of subjects analysed
    299
    300
    Units: Months
        median (confidence interval 95%)
    20.0 (15.9 to 24.2)
    12.2 (10.4 to 14.6)
    Statistical analysis title
    		 Pembrolizumab vs SOC
    Statistical analysis description
    Hazard ratio based on Cox regression model with treatment as a covariate stratified by geographic region (East Asia vs. non-East Asia), ECOG PS (0 vs. 1) and histology (squamous vs. non-squamous).
    Comparison groups
    Pembrolizumab v Chemotherapy (Standard of Care [SOC] Treatment)
    Number of subjects included in analysis
    599
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0003 [1]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.58
         upper limit
    		 0.86
    Notes
    [1] - One-sided p-value based on stratified log-rank test

    Primary: Overall Survival (OS) in Participants with a Tumor Proportion Score (TPS) of ≥20%

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    End point title
    		 Overall Survival (OS) in Participants with a Tumor Proportion Score (TPS) of ≥20%
    End point description
    OS was determined for participants with a TPS of ≥20% and was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the interim analysis were censored at the date of the last follow-up. The OS was calculated using the product-limit (Kaplan-Meier) method for censored data. The efficacy hypothesis was analyzed using a sequential testing strategy that involved testing a hypothesis only if the superiority of pembrolizumab over chemotherapy was established for all the preceding hypotheses. The order of testing was OS in participants with TPS≥50%, then with TPS≥20%, and finally with TPS≥1%. The OS for participants with a TPS ≥20% is presented. The analysis population included all participants who were alive at the time of randomization and had a TPS of ≥20%.
    End point type
    Primary
    End point timeframe
    Up to 45 months
    End point values
    		 Pembrolizumab Chemotherapy (Standard of Care [SOC] Treatment)
    Number of subjects analysed
    413
    405
    Units: Months
        median (confidence interval 95%)
    18.0 (15.4 to 21.9)
    13.0 (11.6 to 15.3)
    Statistical analysis title
    		 Pembrolizumab vs SOC
    Statistical analysis description
    Hazard ratio based on Cox regression model with treatment as a covariate stratified by geographic region (East Asia vs. non-East Asia), ECOG PS (0 vs. 1) and histology (squamous vs. non-squamous).
    Comparison groups
    Pembrolizumab v Chemotherapy (Standard of Care [SOC] Treatment)
    Number of subjects included in analysis
    818
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0012 [2]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.65
         upper limit
    		 0.91
    Notes
    [2] - One-sided p-value based on stratified log-rank test

    Primary: Overall Survival (OS) in Participants with a Tumor Proportion Score (TPS) of ≥1%

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    End point title
    		 Overall Survival (OS) in Participants with a Tumor Proportion Score (TPS) of ≥1%
    End point description
    OS was determined for participants with a TPS of ≥1% and was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the interim analysis were censored at the date of the last follow-up. The OS was calculated using the product-limit (Kaplan-Meier) method for censored data. The efficacy hypothesis was analyzed using a sequential testing strategy that involved testing a hypothesis only if the superiority of pembrolizumab over chemotherapy was established for all the preceding hypotheses. The order of testing was OS in participants with TPS≥50%, then with TPS≥20%, and finally with TPS≥1%. The OS for participants with a TPS ≥1% is presented. The analysis population included all participants who were alive at the time of randomization and had a TPS of ≥1%.
    End point type
    Primary
    End point timeframe
    Up to 45 months
    End point values
    		 Pembrolizumab Chemotherapy (Standard of Care [SOC] Treatment)
    Number of subjects analysed
    637
    637
    Units: Months
        median (confidence interval 95%)
    16.4 (14.0 to 19.7)
    12.1 (11.3 to 13.3)
    Statistical analysis title
    		 Pembrolizumab vs SOC
    Statistical analysis description
    Hazard ratio based on Cox regression model with treatment as a covariate stratified by geographic region (East Asia vs. non-East Asia), ECOG PS (0 vs. 1) and histology (squamous vs. non-squamous).
    Comparison groups
    Pembrolizumab v Chemotherapy (Standard of Care [SOC] Treatment)
    Number of subjects included in analysis
    1274
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0013 [3]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.71
         upper limit
    		 0.93
    Notes
    [3] - One-sided p-value based on stratified log-rank test

    Secondary: Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) in Participants with a Tumor Proportion Score (TPS) of ≥50%

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    End point title
    		 Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) in Participants with a Tumor Proportion Score (TPS) of ≥50%
    End point description
    PFS was determined for participants with a TPS of ≥50% and was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first. PD was defined as ≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of 1 or more new lesions was also considered PD. The efficacy hypothesis was analyzed using a sequential testing strategy that involved testing a hypothesis only if the superiority of pembrolizumab over chemotherapy was established for all the preceding hypotheses. The order of testing was PFS in participants with TPS≥50%, then with TPS≥20%, and finally with TPS≥1%. The PFS for participants with a TPS ≥50% is presented. The analysis population included all participants who were alive at the time of randomization and had a TPS of ≥50%.
    End point type
    Secondary
    End point timeframe
    Up to 45 months
    End point values
    		 Pembrolizumab Chemotherapy (Standard of Care [SOC] Treatment)
    Number of subjects analysed
    299
    300
    Units: Months
        median (confidence interval 95%)
    6.5 (5.9 to 8.5)
    6.4 (6.2 to 7.2)
    Statistical analysis title
    		 Pembrolizumab vs SOC
    Statistical analysis description
    Hazard ratio based on Cox regression model with treatment as a covariate stratified by geographic region (East Asia vs. non-East Asia), ECOG PS (0 vs. 1) and histology (squamous vs. non-squamous).
    Comparison groups
    Pembrolizumab v Chemotherapy (Standard of Care [SOC] Treatment)
    Number of subjects included in analysis
    599
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.026 [4]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.69
         upper limit
    		 1
    Notes
    [4] - One-sided p-value based on stratified log-rank test

    Secondary: Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) in Participants with a Tumor Proportion Score (TPS) of ≥20%

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    End point title
    		 Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) in Participants with a Tumor Proportion Score (TPS) of ≥20%
    End point description
    PFS was determined for participants with a TPS of ≥20% and was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first. PD was defined as ≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of 1 or more new lesions was also considered PD. The efficacy hypothesis was analyzed using a sequential testing strategy that involved testing a hypothesis only if the superiority of pembrolizumab over chemotherapy was established for all the preceding hypotheses. The order of testing was PFS in participants with TPS≥50%, then with TPS≥20%, and finally with TPS≥1%. The PFS for participants with a TPS ≥20% is presented. The analysis population included all participants who were alive at the time of randomization and had a TPS of ≥20%.
    End point type
    Secondary
    End point timeframe
    Up to 45 months
    End point values
    		 Pembrolizumab Chemotherapy (Standard of Care [SOC] Treatment)
    Number of subjects analysed
    413
    405
    Units: Months
        median (confidence interval 95%)
    6.2 (5.1 to 7.4)
    6.7 (6.3 to 8.0)
    Statistical analysis title
    		 Pembrolizumab vs SOC
    Statistical analysis description
    Hazard ratio based on Cox regression model with treatment as a covariate stratified by geographic region (East Asia vs. non-East Asia), ECOG PS (0 vs. 1) and histology (squamous vs. non-squamous).
    Comparison groups
    Pembrolizumab v Chemotherapy (Standard of Care [SOC] Treatment)
    Number of subjects included in analysis
    818
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.2134 [5]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 1.1
    Notes
    [5] - One-sided p-value based on stratified log-rank test

    Secondary: Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) in Participants with a Tumor Proportion Score (TPS) of ≥1%

    		 Close Top of page
    End point title
    		 Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) in Participants with a Tumor Proportion Score (TPS) of ≥1%
    End point description
    PFS was determined for participants with a TPS of ≥1% and was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first. PD was defined as ≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of 1 or more new lesions was also considered PD. The efficacy hypothesis was analyzed using a sequential testing strategy that involved testing a hypothesis only if the superiority of pembrolizumab over chemotherapy was established for all the preceding hypotheses. The order of testing was PFS in participants with TPS≥50%, then with TPS≥20%, and finally with TPS≥1%. The PFS for participants with a TPS ≥1% is presented. The analysis population included all participants who were alive at the time of randomization and had a TPS of ≥1%.
    End point type
    Secondary
    End point timeframe
    Up to 45 months
    End point values
    		 Pembrolizumab Chemotherapy (Standard of Care [SOC] Treatment)
    Number of subjects analysed
    637
    637
    Units: Months
        median (confidence interval 95%)
    5.4 (4.3 to 6.2)
    6.6 (6.3 to 7.3)
    Statistical analysis title
    		 Pembrolizumab vs SOC
    Statistical analysis description
    Hazard ratio based on Cox regression model with treatment as a covariate stratified by geographic region (East Asia vs. non-East Asia), ECOG PS (0 vs. 1), PD-L1 expression status (TPS=≥50% vs. TPS=1-49%) and histology (squamous vs. non-squamous).
    Comparison groups
    Pembrolizumab v Chemotherapy (Standard of Care [SOC] Treatment)
    Number of subjects included in analysis
    1274
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.7964 [6]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.93
         upper limit
    		 1.19
    Notes
    [6] - One-sided p-value based on stratified log-rank test

    Secondary: Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) in Participants with a Tumor Proportion Score (TPS) of ≥50%

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    End point title
    		 Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) in Participants with a Tumor Proportion Score (TPS) of ≥50%
    End point description
    ORR was determined for participants with a TPS of ≥50%. ORR was determined per RECIST 1.1 and was defined as the percentage of participants in the analysis population who had a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters) per RECIST 1.1. The efficacy hypothesis was analyzed using a sequential testing strategy that involved testing a hypothesis only if the superiority of pembrolizumab over chemotherapy was established for all the preceding hypotheses. The order of testing was ORR in participants with TPS≥50%, then with TPS≥20%, and finally with TPS≥1%. The percentage of participants who had a TPS ≥50% and who experienced a CR or PR is presented. The analysis population included all participants who were alive at the time of randomization and had a TPS of ≥50%.
    End point type
    Secondary
    End point timeframe
    Up to 45 months
    End point values
    		 Pembrolizumab Chemotherapy (Standard of Care [SOC] Treatment)
    Number of subjects analysed
    299
    300
    Units: Percentage of participants
        number (confidence interval 95%)
    39.1 (33.6 to 44.9)
    32.0 (26.8 to 37.6)
    Statistical analysis title
    		 Pembrolizumab vs SOC
    Statistical analysis description
    Difference in Percentage (DP) for pembrolizumab vs. chemotherapy based on Miettinen & Nurminen method stratified by geographic region (East Asia vs. non-East Asia), ECOG PS (0 vs. 1) and histology (squamous vs. nonsquamous).
    Comparison groups
    Pembrolizumab v Chemotherapy (Standard of Care [SOC] Treatment)
    Number of subjects included in analysis
    599
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0353 [7]
    Method
    		 Stratified Miettinen and Nurminen
    Parameter type
    		 Difference in Percentage (DP)
    Point estimate
    7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.6
         upper limit
    		 14.6
    Notes
    [7] - One-sided p-value for testing. H0: difference in percentages=0 vs. H1: difference in percentages >0

    Secondary: Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) in Participants with a Tumor Proportion Score (TPS) of ≥20%

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    End point title
    		 Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) in Participants with a Tumor Proportion Score (TPS) of ≥20%
    End point description
    ORR was determined for participants with a TPS of ≥20%. ORR was determined per RECIST 1.1 and was defined as the percentage of participants in the analysis population who had a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters) per RECIST 1.1. The efficacy hypothesis was analyzed using a sequential testing strategy that involved testing a hypothesis only if the superiority of pembrolizumab over chemotherapy was established for all the preceding hypotheses. The order of testing was ORR in participants with TPS≥50%, then with TPS≥20%, and finally with TPS≥1%. The percentage of participants who had a TPS ≥20% and who experienced a CR or PR is presented. The analysis population included all participants who were alive at the time of randomization and had a TPS of ≥20%.
    End point type
    Secondary
    End point timeframe
    Up to 45 months
    End point values
    		 Pembrolizumab Chemotherapy (Standard of Care [SOC] Treatment)
    Number of subjects analysed
    413
    405
    Units: Percentage of participants
        number (confidence interval 95%)
    33.2 (28.6 to 37.9)
    28.9 (24.5 to 33.6)
    Statistical analysis title
    		 Pembrolizumab vs SOC
    Statistical analysis description
    DP for pembrolizumab vs. chemotherapy based on Miettinen & Nurminen method stratified by geographic region (East Asia vs. non-East Asia), ECOG PS (0 vs. 1), PD-L1 expression status (TPS=≥50% vs. TPS=1- 49%) and histology (squamous vs. non-squamous).
    Comparison groups
    Pembrolizumab v Chemotherapy (Standard of Care [SOC] Treatment)
    Number of subjects included in analysis
    818
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0744 [8]
    Method
    		 Stratified Miettinen and Nurminen
    Parameter type
    		 Difference in Percentage (DP)
    Point estimate
    4.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.7
         upper limit
    		 10.9
    Notes
    [8] - One-sided p-value for testing. H0: difference in percentages=0 vs. H1: difference in percentages >0

    Secondary: Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) in Participants with a Tumor Proportion Score (TPS) of ≥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) as Assessed by Blinded Independent Central Review (BICR) in Participants with a Tumor Proportion Score (TPS) of ≥1%
    End point description
    ORR was determined for participants with a TPS of ≥1%. ORR was determined per RECIST 1.1 and was defined as the percentage of participants in the analysis population who had a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters) per RECIST 1.1. The efficacy hypothesis was analyzed using a sequential testing strategy that involved testing a hypothesis only if the superiority of pembrolizumab over chemotherapy was established for all the preceding hypotheses. The order of testing was ORR in participants with TPS≥50%, then with TPS≥20%, and finally with TPS≥1%. The percentage of participants who had a TPS ≥1% and who experienced a CR or PR is presented. The analysis population included all participants who were alive at the time of randomization and had a TPS of ≥1%.
    End point type
    Secondary
    End point timeframe
    Up to 45 months
    End point values
    		 Pembrolizumab Chemotherapy (Standard of Care [SOC] Treatment)
    Number of subjects analysed
    637
    637
    Units: Percentage of participants
        number (confidence interval 95%)
    27.2 (23.7 to 30.8)
    26.5 (23.1 to 30.1)
    Statistical analysis title
    		 Pembrolizumab vs SOC
    Statistical analysis description
    DP for pembrolizumab vs. chemotherapy based on Miettinen & Nurminen method stratified by geographic region (East Asia vs. non-East Asia), ECOG PS (0 vs. 1), PD-L1 expression status (TPS=≥50% vs. TPS=1-49%) and histology (squamous vs. non-squamous).
    Comparison groups
    Pembrolizumab v Chemotherapy (Standard of Care [SOC] Treatment)
    Number of subjects included in analysis
    1274
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.406 [9]
    Method
    		 Stratified Miettinen and Nurminen
    Parameter type
    		 Difference in Percentage (DP)
    Point estimate
    0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.2
         upper limit
    		 5.4
    Notes
    [9] - One-sided p-value for testing. H0: difference in percentages=0 vs. H1: difference in percentages >0

    Secondary: Number of Participants Who Experienced At Least One Adverse Event (AE)

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    End point title
    		 Number of Participants Who Experienced At Least One Adverse Event (AE)
    End point description
    An AE was defined as any untoward medical occurrence in a participant administered a study treatment and which does not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the study treatment or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that was temporally associated with the use of study treatment, was also an AE. The number of participants who experienced at least one AE is presented. The analysis population consisted of all participants who received ≥1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Up to 93 months
    End point values
    		 Pembrolizumab Chemotherapy (Standard of Care [SOC] Treatment)
    Number of subjects analysed
    636
    615
    Units: Participants
    608
    606
    No statistical analyses for this end point

    Secondary: Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE)

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    End point title
    		 Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE)
    End point description
    An AE was defined as any untoward medical occurrence in a participant administered a study treatment and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the study treatment or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that was temporally associated with the use of study treatment, was also an AE. The number of participants who discontinued study treatment due to an AE is presented. The analysis population consisted of all participants who received ≥1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Up to 93 months
    End point values
    		 Pembrolizumab Chemotherapy (Standard of Care [SOC] Treatment)
    Number of subjects analysed
    636
    615
    Units: Participants
    126
    93
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 93 months
    Adverse event reporting additional description
    Population: All participants receiving ≥1 dose of study treatment. Per protocol, progression of cancer under study was not considered an AE unless related to study drug. Therefore, MedDRA preferred terms "Neoplasm progression", "Malignant neoplasm progression" & "Disease progression" not related to study drug are excluded as AEs.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Pembrolizumab
    Reporting group description
    		 Participants received pembrolizumab 200 mg by IV infusion on Day 1 Q3W for a maximum of 35 cycles (21-day cycles)

    Reporting group title
    Pembrolizumab Second Course
    Reporting group description
    		 Eligible participants who stopped the initial course of pembrolizumab with Stable Disease (SD) or better but progressed after discontinuation may have been able to initiate a second course of pembrolizumab for up to 17 cycles (up to approximately 1 additional year) at the investigator's discretion.

    Reporting group title
    Chemotherapy (SOC Treatment)
    Reporting group description
    		 Participants received carboplatin at target dose AUC 5 (maximum dose 750 mg) or AUC 6 (maximum dose 900 mg) + paclitaxel 200 mg/m^2 by IV infusion on Day 1 Q3W for a maximum of 6 cycles (21-day cycles) OR carboplatin target dose AUC 5 (maximum dose 750 mg) or AUC 6 (maximum dose 900 mg) + pemetrexed 500 mg/m^2 by IV infusion on Day 1 Q3W for a maximum of 6 cycles (21-day cycles). Participants with non-squamous histologies received optional additional maintenance treatment with pemetrexed 500 mg/m^2 by IV infusion on Day 1 Q3W.

    Serious adverse events
    		 Pembrolizumab Pembrolizumab Second Course Chemotherapy (SOC Treatment)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    261 / 636 (41.04%)
    8 / 34 (23.53%)
    193 / 615 (31.38%)
         number of deaths (all causes)
    528
    18
    582
         number of deaths resulting from adverse events
    13
    0
    14
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant neoplasm progression
         subjects affected / exposed
    2 / 636 (0.31%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    Metastases to bone
         subjects affected / exposed
    2 / 636 (0.31%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal carcinoma
         subjects affected / exposed
    3 / 636 (0.47%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Adenocarcinoma gastric
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Keratoacanthoma
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cancer pain
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric cancer
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infected neoplasm
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anogenital warts
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung cancer metastatic
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of the tongue
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tumour necrosis
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tumour associated fever
         subjects affected / exposed
    1 / 636 (0.16%)
    1 / 34 (2.94%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Superior vena cava syndrome
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Aortic aneurysm
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arterial thrombosis
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Jugular vein thrombosis
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery occlusion
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    2 / 636 (0.31%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    2 / 615 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    9 / 636 (1.42%)
    0 / 34 (0.00%)
    5 / 615 (0.81%)
         occurrences causally related to treatment / all
    1 / 9
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    1 / 9
    0 / 0
    0 / 5
    Fatigue
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    2 / 615 (0.33%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    4 / 636 (0.63%)
    1 / 34 (2.94%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Accidental death
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    4 / 615 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ill-defined disorder
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Performance status decreased
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prosthetic cardiac valve thrombosis
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    2 / 615 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Contrast media allergy
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ovarian cyst torsion
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Interstitial lung disease
         subjects affected / exposed
    4 / 636 (0.63%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    6 / 6
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    2 / 636 (0.31%)
    0 / 34 (0.00%)
    5 / 615 (0.81%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    1 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    7 / 636 (1.10%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    1 / 7
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Pleural effusion
         subjects affected / exposed
    14 / 636 (2.20%)
    0 / 34 (0.00%)
    5 / 615 (0.81%)
         occurrences causally related to treatment / all
    8 / 16
    0 / 0
    0 / 7
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Pulmonary embolism
         subjects affected / exposed
    13 / 636 (2.04%)
    0 / 34 (0.00%)
    11 / 615 (1.79%)
         occurrences causally related to treatment / all
    2 / 13
    0 / 0
    5 / 11
         deaths causally related to treatment / all
    1 / 5
    0 / 0
    1 / 5
    Respiratory failure
         subjects affected / exposed
    4 / 636 (0.63%)
    0 / 34 (0.00%)
    4 / 615 (0.65%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    1 / 3
    0 / 0
    0 / 3
    Acute respiratory failure
         subjects affected / exposed
    2 / 636 (0.31%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    2 / 636 (0.31%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atelectasis
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis chronic
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic respiratory failure
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hydrothorax
         subjects affected / exposed
    2 / 636 (0.31%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophagobronchial fistula
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    7 / 636 (1.10%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    2 / 8
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
    Pneumonitis
         subjects affected / exposed
    25 / 636 (3.93%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    26 / 26
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    3 / 636 (0.47%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary artery thrombosis
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Pulmonary fistula
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    2 / 615 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    Pulmonary thrombosis
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    2 / 615 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Tracheal stenosis
         subjects affected / exposed
    2 / 636 (0.31%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    4 / 636 (0.63%)
    0 / 34 (0.00%)
    2 / 615 (0.33%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 4
    0 / 0
    0 / 2
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    2 / 636 (0.31%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    2 / 636 (0.31%)
    0 / 34 (0.00%)
    2 / 615 (0.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    2 / 636 (0.31%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Completed suicide
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    5 / 615 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    2 / 615 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 636 (0.47%)
    0 / 34 (0.00%)
    2 / 615 (0.33%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    3 / 636 (0.47%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood prolactin increased
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    2 / 636 (0.31%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood calcium decreased
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood pressure increased
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bilirubin conjugated increased
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Subdural haematoma
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cervical vertebral fracture
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    2 / 636 (0.31%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subdural haemorrhage
         subjects affected / exposed
    0 / 636 (0.00%)
    1 / 34 (2.94%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Coronary artery disease
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    3 / 636 (0.47%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    3 / 615 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Acute myocardial infarction
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 636 (0.31%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    3 / 636 (0.47%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    Aortic valve stenosis
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    2 / 636 (0.31%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Cardiac tamponade
         subjects affected / exposed
    3 / 636 (0.47%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    3 / 636 (0.47%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Myocarditis
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    2 / 636 (0.31%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    6 / 636 (0.94%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    4 / 6
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral infarction
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    2 / 636 (0.31%)
    0 / 34 (0.00%)
    3 / 615 (0.49%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Altered state of consciousness
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ataxia
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    3 / 636 (0.47%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coma
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Embolic stroke
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychomotor hyperactivity
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolic encephalopathy
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    2 / 615 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    2 / 615 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Agranulocytosis
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    3 / 636 (0.47%)
    0 / 34 (0.00%)
    16 / 615 (2.60%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    21 / 23
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    8 / 615 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    8 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    6 / 615 (0.98%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Leukopenia
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    2 / 615 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    16 / 615 (2.60%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    14 / 17
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
    Normochromic anaemia
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Splenic infarction
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    2 / 636 (0.31%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    5 / 636 (0.79%)
    1 / 34 (2.94%)
    3 / 615 (0.49%)
         occurrences causally related to treatment / all
    3 / 5
    1 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    6 / 636 (0.94%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    5 / 6
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Duodenal perforation
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer haemorrhage
         subjects affected / exposed
    2 / 636 (0.31%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Incarcerated inguinal hernia
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal ulcer
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Glossitis
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 636 (0.00%)
    1 / 34 (2.94%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Ileus paralytic
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    2 / 615 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    3 / 636 (0.47%)
    0 / 34 (0.00%)
    2 / 615 (0.33%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 636 (0.00%)
    1 / 34 (2.94%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal fistula
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatic mass
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal ulcer
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    2 / 636 (0.31%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenic colitis
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Volvulus
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 636 (0.31%)
    0 / 34 (0.00%)
    2 / 615 (0.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Autoimmune hepatitis
         subjects affected / exposed
    3 / 636 (0.47%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    2 / 636 (0.31%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatitis acute
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatitis toxic
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune-mediated hepatitis
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Drug eruption
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    1 / 636 (0.16%)
    1 / 34 (2.94%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    3 / 636 (0.47%)
    0 / 34 (0.00%)
    4 / 615 (0.65%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Glomerulonephritis membranous
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephritis
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephropathy
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal tubular necrosis
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    2 / 636 (0.31%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperthyroidism
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypophysitis
         subjects affected / exposed
    2 / 636 (0.31%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypopituitarism
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypothyroidism
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bone pain
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteitis
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteoporotic fracture
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Lung abscess
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    2 / 615 (0.33%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    49 / 636 (7.70%)
    2 / 34 (5.88%)
    34 / 615 (5.53%)
         occurrences causally related to treatment / all
    1 / 54
    0 / 2
    14 / 41
         deaths causally related to treatment / all
    0 / 10
    0 / 0
    4 / 7
    Septic shock
         subjects affected / exposed
    3 / 636 (0.47%)
    0 / 34 (0.00%)
    4 / 615 (0.65%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    2 / 2
    Lymph gland infection
         subjects affected / exposed
    0 / 636 (0.00%)
    1 / 34 (2.94%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Biliary sepsis
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Abscess jaw
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Amoebiasis
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Amoebic dysentery
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal sepsis
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Bronchitis
         subjects affected / exposed
    8 / 636 (1.26%)
    0 / 34 (0.00%)
    3 / 615 (0.49%)
         occurrences causally related to treatment / all
    1 / 8
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Candida infection
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    2 / 615 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Enterocolitis infectious
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infective exacerbation of bronchiectasis
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal candidiasis
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    2 / 636 (0.31%)
    0 / 34 (0.00%)
    2 / 615 (0.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Laryngitis
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    3 / 615 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    2 / 615 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Infective exacerbation of chronic obstructive airways disease
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    2 / 615 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural infection
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    2 / 636 (0.31%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    3 / 636 (0.47%)
    1 / 34 (2.94%)
    2 / 615 (0.33%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    4 / 636 (0.63%)
    0 / 34 (0.00%)
    3 / 615 (0.49%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
    3 / 4
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    Post procedural cellulitis
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pseudomembranous colitis
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    2 / 615 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    1 / 2
    Respiratory tract infection
         subjects affected / exposed
    2 / 636 (0.31%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Pneumonia klebsiella
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    2 / 615 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular access site infection
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    4 / 636 (0.63%)
    0 / 34 (0.00%)
    3 / 615 (0.49%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    2 / 615 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperuricaemia
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    2 / 615 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    3 / 636 (0.47%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ketoacidosis
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Diabetes mellitus
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 636 (0.00%)
    0 / 34 (0.00%)
    1 / 615 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    2 / 615 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    2 / 636 (0.31%)
    0 / 34 (0.00%)
    2 / 615 (0.33%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    0 / 615 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 636 (0.16%)
    0 / 34 (0.00%)
    2 / 615 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Pembrolizumab Pembrolizumab Second Course Chemotherapy (SOC Treatment)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    535 / 636 (84.12%)
    21 / 34 (61.76%)
    577 / 615 (93.82%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    41 / 636 (6.45%)
    1 / 34 (2.94%)
    14 / 615 (2.28%)
         occurrences all number
    49
    1
    17
    General disorders and administration site conditions
    Malaise
         subjects affected / exposed
    15 / 636 (2.36%)
    1 / 34 (2.94%)
    32 / 615 (5.20%)
         occurrences all number
    15
    1
    49
    Asthenia
         subjects affected / exposed
    69 / 636 (10.85%)
    2 / 34 (5.88%)
    81 / 615 (13.17%)
         occurrences all number
    92
    3
    110
    Chest pain
         subjects affected / exposed
    56 / 636 (8.81%)
    1 / 34 (2.94%)
    43 / 615 (6.99%)
         occurrences all number
    61
    1
    52
    Fatigue
         subjects affected / exposed
    101 / 636 (15.88%)
    0 / 34 (0.00%)
    129 / 615 (20.98%)
         occurrences all number
    129
    0
    193
    Pyrexia
         subjects affected / exposed
    64 / 636 (10.06%)
    1 / 34 (2.94%)
    52 / 615 (8.46%)
         occurrences all number
    82
    1
    63
    Oedema peripheral
         subjects affected / exposed
    32 / 636 (5.03%)
    1 / 34 (2.94%)
    36 / 615 (5.85%)
         occurrences all number
    33
    1
    50
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    107 / 636 (16.82%)
    2 / 34 (5.88%)
    66 / 615 (10.73%)
         occurrences all number
    128
    2
    72
    Dyspnoea
         subjects affected / exposed
    105 / 636 (16.51%)
    1 / 34 (2.94%)
    72 / 615 (11.71%)
         occurrences all number
    120
    1
    81
    Haemoptysis
         subjects affected / exposed
    45 / 636 (7.08%)
    3 / 34 (8.82%)
    23 / 615 (3.74%)
         occurrences all number
    62
    4
    25
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    34 / 636 (5.35%)
    0 / 34 (0.00%)
    45 / 615 (7.32%)
         occurrences all number
    38
    0
    51
    Investigations
    Weight decreased
         subjects affected / exposed
    67 / 636 (10.53%)
    4 / 34 (11.76%)
    48 / 615 (7.80%)
         occurrences all number
    71
    4
    49
    Platelet count decreased
         subjects affected / exposed
    7 / 636 (1.10%)
    0 / 34 (0.00%)
    65 / 615 (10.57%)
         occurrences all number
    7
    0
    144
    Neutrophil count decreased
         subjects affected / exposed
    6 / 636 (0.94%)
    0 / 34 (0.00%)
    89 / 615 (14.47%)
         occurrences all number
    6
    0
    239
    Aspartate aminotransferase increased
         subjects affected / exposed
    62 / 636 (9.75%)
    3 / 34 (8.82%)
    57 / 615 (9.27%)
         occurrences all number
    83
    3
    87
    Alanine aminotransferase increased
         subjects affected / exposed
    66 / 636 (10.38%)
    3 / 34 (8.82%)
    72 / 615 (11.71%)
         occurrences all number
    89
    4
    97
    White blood cell count decreased
         subjects affected / exposed
    5 / 636 (0.79%)
    1 / 34 (2.94%)
    77 / 615 (12.52%)
         occurrences all number
    7
    1
    228
    Blood alkaline phosphatase increased
         subjects affected / exposed
    39 / 636 (6.13%)
    2 / 34 (5.88%)
    30 / 615 (4.88%)
         occurrences all number
    46
    2
    35
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    25 / 636 (3.93%)
    0 / 34 (0.00%)
    39 / 615 (6.34%)
         occurrences all number
    28
    0
    49
    Headache
         subjects affected / exposed
    44 / 636 (6.92%)
    2 / 34 (5.88%)
    51 / 615 (8.29%)
         occurrences all number
    58
    2
    62
    Neuropathy peripheral
         subjects affected / exposed
    5 / 636 (0.79%)
    0 / 34 (0.00%)
    52 / 615 (8.46%)
         occurrences all number
    6
    0
    62
    Peripheral sensory neuropathy
         subjects affected / exposed
    4 / 636 (0.63%)
    0 / 34 (0.00%)
    43 / 615 (6.99%)
         occurrences all number
    5
    0
    55
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    6 / 636 (0.94%)
    0 / 34 (0.00%)
    59 / 615 (9.59%)
         occurrences all number
    7
    0
    86
    Neutropenia
         subjects affected / exposed
    6 / 636 (0.94%)
    0 / 34 (0.00%)
    85 / 615 (13.82%)
         occurrences all number
    9
    0
    177
    Anaemia
         subjects affected / exposed
    102 / 636 (16.04%)
    2 / 34 (5.88%)
    253 / 615 (41.14%)
         occurrences all number
    124
    2
    332
    Leukopenia
         subjects affected / exposed
    10 / 636 (1.57%)
    1 / 34 (2.94%)
    35 / 615 (5.69%)
         occurrences all number
    17
    1
    63
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    74 / 636 (11.64%)
    3 / 34 (8.82%)
    78 / 615 (12.68%)
         occurrences all number
    94
    5
    107
    Constipation
         subjects affected / exposed
    78 / 636 (12.26%)
    3 / 34 (8.82%)
    131 / 615 (21.30%)
         occurrences all number
    98
    3
    168
    Nausea
         subjects affected / exposed
    73 / 636 (11.48%)
    1 / 34 (2.94%)
    195 / 615 (31.71%)
         occurrences all number
    98
    1
    407
    Vomiting
         subjects affected / exposed
    50 / 636 (7.86%)
    0 / 34 (0.00%)
    106 / 615 (17.24%)
         occurrences all number
    62
    0
    167
    Stomatitis
         subjects affected / exposed
    16 / 636 (2.52%)
    0 / 34 (0.00%)
    33 / 615 (5.37%)
         occurrences all number
    18
    0
    40
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    3 / 636 (0.47%)
    0 / 34 (0.00%)
    138 / 615 (22.44%)
         occurrences all number
    4
    0
    139
    Pruritus
         subjects affected / exposed
    67 / 636 (10.53%)
    2 / 34 (5.88%)
    22 / 615 (3.58%)
         occurrences all number
    83
    4
    23
    Rash
         subjects affected / exposed
    72 / 636 (11.32%)
    1 / 34 (2.94%)
    43 / 615 (6.99%)
         occurrences all number
    82
    4
    52
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    76 / 636 (11.95%)
    3 / 34 (8.82%)
    10 / 615 (1.63%)
         occurrences all number
    99
    5
    10
    Hyperthyroidism
         subjects affected / exposed
    37 / 636 (5.82%)
    1 / 34 (2.94%)
    4 / 615 (0.65%)
         occurrences all number
    38
    1
    4
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    31 / 636 (4.87%)
    0 / 34 (0.00%)
    34 / 615 (5.53%)
         occurrences all number
    36
    0
    40
    Myalgia
         subjects affected / exposed
    32 / 636 (5.03%)
    1 / 34 (2.94%)
    70 / 615 (11.38%)
         occurrences all number
    37
    1
    135
    Back pain
         subjects affected / exposed
    61 / 636 (9.59%)
    1 / 34 (2.94%)
    43 / 615 (6.99%)
         occurrences all number
    70
    1
    51
    Arthralgia
         subjects affected / exposed
    86 / 636 (13.52%)
    3 / 34 (8.82%)
    87 / 615 (14.15%)
         occurrences all number
    109
    3
    162
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    46 / 636 (7.23%)
    1 / 34 (2.94%)
    32 / 615 (5.20%)
         occurrences all number
    62
    1
    41
    Pneumonia
         subjects affected / exposed
    39 / 636 (6.13%)
    1 / 34 (2.94%)
    30 / 615 (4.88%)
         occurrences all number
    40
    1
    35
    Nasopharyngitis
         subjects affected / exposed
    26 / 636 (4.09%)
    3 / 34 (8.82%)
    21 / 615 (3.41%)
         occurrences all number
    37
    4
    26
    Bronchitis
         subjects affected / exposed
    30 / 636 (4.72%)
    3 / 34 (8.82%)
    23 / 615 (3.74%)
         occurrences all number
    34
    4
    25
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    21 / 636 (3.30%)
    1 / 34 (2.94%)
    32 / 615 (5.20%)
         occurrences all number
    26
    1
    43
    Decreased appetite
         subjects affected / exposed
    108 / 636 (16.98%)
    3 / 34 (8.82%)
    134 / 615 (21.79%)
         occurrences all number
    127
    3
    209

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Jan 2016
    Updated Statistical Analysis Plan and Inclusion/Exclusion Criteria
    11 May 2017
    Updates to the primary, secondary, and exploratory objectives/hypothesis
    01 Mar 2018
    Expanded dose modification guidelines
    20 Apr 2021
    Added language regarding the enrollment of participants in a pembrolizumab extension study

    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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