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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled Phase III Clinical Trial of Pembrolizumab (MK-3475) in Combination with Cisplatin and 5-Fluorouracil versus Placebo in Combination with Cisplatin and 5-Fluorouracil as First-Line Treatment in Subjects with Advanced/Metastatic Esophageal Carcinoma (KEYNOTE-590)

    Summary
    EudraCT number
    		 2017-000958-19
    Trial protocol
    		 DE   GB   ES   FR   DK   RO  
    Global end of trial date
    10 Jul 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 Jun 2024
    First version publication date
    19 Jun 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    3475-590
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03189719
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 MK-3475-590: Merck
    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
    10 Jul 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    02 Jul 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Jul 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this trial is to evaluate efficacy and safety of pembrolizumab plus standard of care (SOC) chemotherapy with cisplatin and 5-fluorouracil (5-FU) versus placebo plus SOC chemotherapy with cisplatin and 5-FU as first-line treatment in participants with locally advanced or metastatic esophageal carcinoma.
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    25 Jul 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 13
    Country: Number of subjects enrolled
    Australia: 20
    Country: Number of subjects enrolled
    Brazil: 29
    Country: Number of subjects enrolled
    Canada: 32
    Country: Number of subjects enrolled
    Chile: 16
    Country: Number of subjects enrolled
    China: 106
    Country: Number of subjects enrolled
    Colombia: 1
    Country: Number of subjects enrolled
    Costa Rica: 7
    Country: Number of subjects enrolled
    Germany: 19
    Country: Number of subjects enrolled
    Denmark: 7
    Country: Number of subjects enrolled
    Spain: 22
    Country: Number of subjects enrolled
    France: 30
    Country: Number of subjects enrolled
    United Kingdom: 22
    Country: Number of subjects enrolled
    Guatemala: 20
    Country: Number of subjects enrolled
    Hong Kong: 15
    Country: Number of subjects enrolled
    Japan: 141
    Country: Number of subjects enrolled
    Korea, Republic of: 59
    Country: Number of subjects enrolled
    Malaysia: 9
    Country: Number of subjects enrolled
    Peru: 9
    Country: Number of subjects enrolled
    Romania: 14
    Country: Number of subjects enrolled
    Russian Federation: 23
    Country: Number of subjects enrolled
    Thailand: 20
    Country: Number of subjects enrolled
    Türkiye: 25
    Country: Number of subjects enrolled
    Taiwan: 43
    Country: Number of subjects enrolled
    United States: 40
    Country: Number of subjects enrolled
    South Africa: 7
    Worldwide total number of subjects
    749
    EEA total number of subjects
    92
    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)
    427
    From 65 to 84 years
    319
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 749 participants were randomized 1:1 to receive either pembrolizumab plus standard of care (SOC) chemotherapy, or placebo plus SOC chemotherapy.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Pembrolizumab + SOC
    Arm description
    		 Participants received pembrolizumab 200 mg intravenously (IV) every 3 weeks (Q3W) plus standard of care (SOC) chemotherapy with cisplatin 80 mg/m^2 IV Q3W and 5-fluorouracil (5-FU) 800 mg/m^2/day continuous IV infusion on Days 1 to 5 (120 hours) Q3W. All treatments were administered on an outpatient basis beginning on Day 1 of each 3-week dosing cycle.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    KEYTRUDA®
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    200 mg administered IV Q3W on Day 1 of each 3-week cycle, up to 35 administrations.

    Investigational medicinal product name
    5-FU
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    800 mg/m^2/day (4000 mg/m^2 total per cycle) administered as continuous IV infusion on Days 1 to 5 (120 hours) of each 3-week cycle, or per local standard for 5-FU administration, up to 35 administrations.

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    80 mg/m^2 administered IV Q3W on Day 1 of each 3-week cycle. Duration of cisplatin treatment will be capped at 6 doses.

    Arm title
    		 Placebo + SOC
    Arm description
    		 Participants received placebo to pembrolizumab (saline) IV Q3W plus SOC chemotherapy with cisplatin 80 mg/m^2 IV Q3W and 5-FU 800 mg/m^2/day continuous IV infusion on Days 1 to 5 (120 hours) Q3W. All treatments were administered on an outpatient basis beginning on Day 1 of each 3-week dosing cycle.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo to pembrolizumab (saline) administered IV Q3W on Day 1 of each 3-week cycle, up to 35 administrations.

    Investigational medicinal product name
    5-FU
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    800 mg/m^2/day (4000 mg/m^2 total per cycle) administered as continuous IV infusion on Days 1 to 5 (120 hours) of each 3-week cycle, or per local standard for 5-FU administration, up to 35 administrations.

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    80 mg/m^2 administered IV Q3W on Day 1 of each 3-week cycle. Duration of cisplatin treatment will be capped at 6 doses.

    Number of subjects in period 1
    		Pembrolizumab + SOC Placebo + SOC
    Started
    373
    376
    Treated
    370
    370
    Completed
    0
    0
    Not completed
    373
    376
         Adverse event, serious fatal
    325
    361
         Physician decision
    1
    -
         Consent withdrawn by subject
    7
    3
         Sponsor Decision
    40
    12

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Pembrolizumab + SOC
    Reporting group description
    		 Participants received pembrolizumab 200 mg intravenously (IV) every 3 weeks (Q3W) plus standard of care (SOC) chemotherapy with cisplatin 80 mg/m^2 IV Q3W and 5-fluorouracil (5-FU) 800 mg/m^2/day continuous IV infusion on Days 1 to 5 (120 hours) Q3W. All treatments were administered on an outpatient basis beginning on Day 1 of each 3-week dosing cycle.

    Reporting group title
    Placebo + SOC
    Reporting group description
    		 Participants received placebo to pembrolizumab (saline) IV Q3W plus SOC chemotherapy with cisplatin 80 mg/m^2 IV Q3W and 5-FU 800 mg/m^2/day continuous IV infusion on Days 1 to 5 (120 hours) Q3W. All treatments were administered on an outpatient basis beginning on Day 1 of each 3-week dosing cycle.

    Reporting group values
    		 Pembrolizumab + SOC Placebo + SOC Total
    Number of subjects
    		 373 376 749
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 201 226 427
        From 65-84 years
    		 171 148 319
        85 years and over
    		 1 2 3
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 62.8 ( 9.8 ) 62.0 ( 9.2 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 67 57 124
        Male
    		 306 319 625
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 9 12 21
        Asian
    		 201 199 400
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 5 2 7
        White
    		 139 139 278
        More than one race
    		 5 9 14
        Unknown or Not Reported
    		 14 15 29
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 42 57 99
        Not Hispanic or Latino
    		 315 296 611
        Unknown or Not Reported
    		 16 23 39
    Geographic Region
    Participants were stratified according to Geographic Region of enrolling site (Asia versus Rest of World)
    Units: Subjects
        Asia
    		 196 197 393
        Rest of World
    		 177 179 356
    Histology
    Participants were stratified according to baseline Histology (adenocarcinoma versus squamous cell carcinoma)
    Units: Subjects
        Adenocarcinoma
    		 99 102 201
        Squamous Cell Carcinoma
    		 274 274 548
    Eastern Cooperative Group Performance Status (ECOG PS)
    ECOG PS 0 = Fully active, able to carry on all pre-disease performance without restriction), ECOG PS 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, ECOG PS 2 = Ambulatory and capable of all selfcare but unable to carry out any work activities; up and about more than 50% of waking hours. Participants were stratified according to baseline ECOG PS (0 versus 1).
    Units: Subjects
        ECOG PS 0
    		 149 150 299
        ECOG PS 1
    		 223 225 448
        ECOG PS 2
    		 1 1 2

    End points

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    End points reporting groups
    Reporting group title
    Pembrolizumab + SOC
    Reporting group description
    		 Participants received pembrolizumab 200 mg intravenously (IV) every 3 weeks (Q3W) plus standard of care (SOC) chemotherapy with cisplatin 80 mg/m^2 IV Q3W and 5-fluorouracil (5-FU) 800 mg/m^2/day continuous IV infusion on Days 1 to 5 (120 hours) Q3W. All treatments were administered on an outpatient basis beginning on Day 1 of each 3-week dosing cycle.

    Reporting group title
    Placebo + SOC
    Reporting group description
    		 Participants received placebo to pembrolizumab (saline) IV Q3W plus SOC chemotherapy with cisplatin 80 mg/m^2 IV Q3W and 5-FU 800 mg/m^2/day continuous IV infusion on Days 1 to 5 (120 hours) Q3W. All treatments were administered on an outpatient basis beginning on Day 1 of each 3-week dosing cycle.

    Primary: OS in Participants With ESCC

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    End point title
    		 OS in Participants With ESCC
    End point description
    Overall survival was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last follow-up. Per protocol, OS is reported here for all participants of the ITT population (all randomized) who had ESCC.
    End point type
    Primary
    End point timeframe
    Up to approximately 34 months
    End point values
    		 Pembrolizumab + SOC Placebo + SOC
    Number of subjects analysed
    274
    274
    Units: Months
        median (confidence interval 95%)
    12.6 (10.2 to 14.3)
    9.8 (8.6 to 11.1)
    Statistical analysis title
    		 OS in ESCC
    Statistical analysis description
    OS in ESCC participants of the pembrolizumab + SOC arm was compared to OS in ESCC participants of the placebo + SOC arm based on a Cox regression model with Efron’s method of tie handling with treatment as a covariate stratified by geographic region (Asia versus Rest of the World) and ECOG performance status (0 versus 1).
    Comparison groups
    Pembrolizumab + SOC v Placebo + SOC
    Number of subjects included in analysis
    548
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0006
    Method
    		 Stratified Log-Rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6
         upper limit
    		 0.88

    Primary: Overall Survival (OS) in Participants With Esophageal Squamous Cell Carcinoma (ESCC) Whose Tumors Are Programmed Cell Death-Ligand 1 (PD-L1) Biomarker-Positive (Combined Positive Score [CPS] ≥10)

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    End point title
    		 Overall Survival (OS) in Participants With Esophageal Squamous Cell Carcinoma (ESCC) Whose Tumors Are Programmed Cell Death-Ligand 1 (PD-L1) Biomarker-Positive (Combined Positive Score [CPS] ≥10)
    End point description
    Overall survival was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last follow-up. Per protocol, OS is reported here for all participants of the Intent-To-Treat (ITT) population (all randomized) who had ESCC and who were PD-L1 CPS ≥10.
    End point type
    Primary
    End point timeframe
    Up to approximately 34 months
    End point values
    		 Pembrolizumab + SOC Placebo + SOC
    Number of subjects analysed
    143
    143
    Units: Months
        median (confidence interval 95%)
    13.9 (11.1 to 17.7)
    8.8 (7.8 to 10.5)
    Statistical analysis title
    		 OS in ESCC PD-L1 CPS ≥10
    Statistical analysis description
    OS in ESCC PD-L1 CPS ≥10 participants of the pembrolizumab + SOC arm was compared to OS in ESCC PD-L1 CPS ≥10 participants of the placebo + SOC arm based on a Cox regression model with Efron’s method of tie handling with treatment as a covariate stratified by geographic region (Asia versus Rest of the World) and ECOG performance status (0 versus 1).
    Comparison groups
    Pembrolizumab + SOC v Placebo + SOC
    Number of subjects included in analysis
    286
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Stratified Log-Rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.57
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.43
         upper limit
    		 0.75

    Primary: OS in Participants Whose Tumors Are PD-L1 Biomarker-Positive (CPS ≥10)

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    End point title
    		 OS in Participants Whose Tumors Are PD-L1 Biomarker-Positive (CPS ≥10)
    End point description
    Overall survival was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last follow-up. Per protocol, OS is reported here for all participants of the ITT population (all randomized) who were PD-L1 CPS ≥10.
    End point type
    Primary
    End point timeframe
    Up to approximately 34 months
    End point values
    		 Pembrolizumab + SOC Placebo + SOC
    Number of subjects analysed
    186
    197
    Units: Months
        median (confidence interval 95%)
    13.5 (11.1 to 15.6)
    9.4 (8.0 to 10.7)
    Statistical analysis title
    		 OS in PD-L1 CPS ≥10
    Statistical analysis description
    OS in PD-L1 CPS ≥10 participants of the pembrolizumab + SOC arm was compared to OS in PD-L1 CPS ≥10 participants of the placebo + SOC arm based on a Cox regression model with Efron’s method of tie handling with treatment as a covariate stratified by geographic region (Asia versus Rest of the World) and tumor histology (Adenocarcinoma versus Squamous Cell Carcinoma).
    Comparison groups
    Pembrolizumab + SOC v Placebo + SOC
    Number of subjects included in analysis
    383
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Stratified Log-Rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.49
         upper limit
    		 0.78

    Primary: OS in All Participants

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    End point title
    		 OS in All Participants
    End point description
    Overall survival was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last follow-up. Per protocol, OS is reported here for all participants of the ITT population (all randomized).
    End point type
    Primary
    End point timeframe
    Up to approximately 34 months
    End point values
    		 Pembrolizumab + SOC Placebo + SOC
    Number of subjects analysed
    373
    376
    Units: Months
        median (confidence interval 95%)
    12.4 (10.5 to 14.0)
    9.8 (8.8 to 10.8)
    Statistical analysis title
    		 OS in all participants
    Statistical analysis description
    OS in all participants of the pembrolizumab + SOC arm was compared to OS in all participants of the placebo + SOC arm based on a Cox regression model with Efron’s method of tie handling with treatment as a covariate stratified by geographic region (Asia versus Rest of the World), tumor histology (Adenocarcinoma versus Squamous Cell Carcinoma), and ECOG performance status (0 versus 1).
    Comparison groups
    Pembrolizumab + SOC v Placebo + SOC
    Number of subjects included in analysis
    749
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Stratified Log-Rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.62
         upper limit
    		 0.86

    Primary: Progression-free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) As Assessed By Investigator in Participants With ESCC

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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 Investigator in Participants With ESCC
    End point description
    PFS was defined as the time from randomization to the first documented progressive disease (PD) per RECIST 1.1 as assessed by the investigator, or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. The sponsor allowed a maximum of 10 target lesions in total and 5 per organ on this study. Per protocol, PFS is reported here for all participants of the ITT population (all randomized) who had ESCC.
    End point type
    Primary
    End point timeframe
    Up to approximately 34 months
    End point values
    		 Pembrolizumab + SOC Placebo + SOC
    Number of subjects analysed
    274
    274
    Units: Months
        median (confidence interval 95%)
    6.3 (6.2 to 6.9)
    5.8 (5.0 to 6.1)
    Statistical analysis title
    		 PFS in ESCC
    Statistical analysis description
    PFS in ESCC participants of the pembrolizumab + SOC arm was compared to PFS in ESCC participants of the placebo + SOC arm based on a Cox regression model with Efron’s method of tie handling with treatment as a covariate stratified by geographic region (Asia versus Rest of the World) and ECOG performance status (0 versus 1).
    Comparison groups
    Pembrolizumab + SOC v Placebo + SOC
    Number of subjects included in analysis
    548
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Stratified Log-Rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.54
         upper limit
    		 0.78

    Primary: PFS Per RECIST 1.1 As Assessed By Investigator in All Participants

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    End point title
    		 PFS Per RECIST 1.1 As Assessed By Investigator in All Participants
    End point description
    PFS was defined as the time from randomization to the first documented progressive disease (PD) per RECIST 1.1 as assessed by the investigator, or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. The sponsor allowed a maximum of 10 target lesions in total and 5 per organ on this study. Per protocol, PFS is reported here for all participants of the ITT population (all randomized).
    End point type
    Primary
    End point timeframe
    Up to approximately 34 months
    End point values
    		 Pembrolizumab + SOC Placebo + SOC
    Number of subjects analysed
    373
    376
    Units: Months
        median (confidence interval 95%)
    6.3 (6.2 to 6.9)
    5.8 (5.0 to 6.0)
    Statistical analysis title
    		 PFS in all participants
    Statistical analysis description
    PFS in all participants of the pembrolizumab + SOC arm was compared to PFS in all participants of the placebo + SOC arm based on a Cox regression model with Efron’s method of tie handling with treatment as a covariate stratified by geographic region (Asia versus Rest of the World), tumor histology (Adenocarcinoma versus Squamous Cell Carcinoma), and ECOG performance status (0 versus 1).
    Comparison groups
    Pembrolizumab + SOC v Placebo + SOC
    Number of subjects included in analysis
    749
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Stratified Log-Rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.55
         upper limit
    		 0.76

    Primary: PFS Per RECIST 1.1 As Assessed By Investigator in Participants Whose Tumors Are PD-L1 Biomarker-Positive (CPS ≥10)

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    End point title
    		 PFS Per RECIST 1.1 As Assessed By Investigator in Participants Whose Tumors Are PD-L1 Biomarker-Positive (CPS ≥10)
    End point description
    PFS was defined as the time from randomization to the first documented progressive disease (PD) per RECIST 1.1 as assessed by the investigator, or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. The sponsor allowed a maximum of 10 target lesions in total and 5 per organ on this study. Per protocol, PFS is reported here for all participants of the ITT population (all randomized) who were PD-L1 CPS ≥10.
    End point type
    Primary
    End point timeframe
    Up to approximately 34 months
    End point values
    		 Pembrolizumab + SOC Placebo + SOC
    Number of subjects analysed
    186
    197
    Units: Months
        median (confidence interval 95%)
    7.5 (6.2 to 8.2)
    5.5 (4.3 to 6.0)
    Statistical analysis title
    		 PFS in PD-L1 CPS ≥10
    Statistical analysis description
    PFS in PD-L1 CPS ≥10 participants of the pembrolizumab + SOC arm was compared to PFS in PD-L1 CPS ≥10 participants of the placebo + SOC arm based on a Cox regression model with Efron’s method of tie handling with treatment as a covariate stratified by geographic region (Asia versus Rest of the World) and tumor histology (Adenocarcinoma versus Squamous Cell Carcinoma).
    Comparison groups
    Pembrolizumab + SOC v Placebo + SOC
    Number of subjects included in analysis
    383
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Stratified Log-Rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.41
         upper limit
    		 0.65

    Secondary: ORR per RECIST 1.1 As Assessed By Investigator in Participants With ESCC Whose Tumors Are PD-L1 Biomarker-Positive (CPS ≥10)

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    End point title
    		 ORR per RECIST 1.1 As Assessed By Investigator in Participants With ESCC Whose Tumors Are PD-L1 Biomarker-Positive (CPS ≥10)
    End point description
    ORR 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) per RECIST 1.1. as assessed by the investigator. The sponsor allowed a maximum of 10 target lesions in total and 5 per organ on this study. Per protocol, the percentage of participants who experienced CR or PR is reported here as the ORR for all participants of the ITT population (all randomized) who had ESCC and who were PD-L1 CPS ≥10.
    End point type
    Secondary
    End point timeframe
    Up to approximately 34 months
    End point values
    		 Pembrolizumab + SOC Placebo + SOC
    Number of subjects analysed
    143
    143
    Units: Percentage of Participants
        number (confidence interval 95%)
    51.0 (42.6 to 59.5)
    28.0 (20.8 to 36.1)
    Statistical analysis title
    		 ORR in ESCC PD-L1 CPS ≥10
    Statistical analysis description
    ORR in ESCC PD-L1 CPS ≥10 participants of the pembrolizumab + SOC arm was compared to ORR in ESCC PD-L1 CPS ≥10 participants of the placebo + SOC arm based on the Miettinen & Nurminen method stratified by geographic region (Asia versus Rest of the World) and ECOG performance status (0 versus 1).
    Comparison groups
    Pembrolizumab + SOC v Placebo + SOC
    Number of subjects included in analysis
    286
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 One-sided p-value
    Parameter type
    		 Difference in Percentage
    Point estimate
    22.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 11.6
         upper limit
    		 33.4

    Secondary: Objective Response Rate (ORR) Per RECIST 1.1 As Assessed By Investigator in All Participants

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    End point title
    		 Objective Response Rate (ORR) Per RECIST 1.1 As Assessed By Investigator in All Participants
    End point description
    ORR 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) per RECIST 1.1. as assessed by the investigator. The sponsor allowed a maximum of 10 target lesions in total and 5 per organ on this study. Per protocol, the percentage of participants who experienced CR or PR is reported here as the ORR for all participants of the ITT population (all randomized).
    End point type
    Secondary
    End point timeframe
    Up to approximately 34 months
    End point values
    		 Pembrolizumab + SOC Placebo + SOC
    Number of subjects analysed
    373
    376
    Units: Percentage of Participants
        number (confidence interval 95%)
    45.0 (39.9 to 50.2)
    29.3 (24.7 to 34.1)
    Statistical analysis title
    		 ORR in all participants
    Statistical analysis description
    ORR in all participants of the pembrolizumab + SOC arm was compared to ORR in all participants of the placebo + SOC arm based on the Miettinen & Nurminen method stratified by geographic region (Asia versus Rest of the World), tumor histology (Adenocarcinoma versus Squamous Cell Carcinoma), and ECOG performance status (0 versus 1).
    Comparison groups
    Pembrolizumab + SOC v Placebo + SOC
    Number of subjects included in analysis
    749
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 One-sided p-value
    Parameter type
    		 Difference in Percentage
    Point estimate
    15.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 9
         upper limit
    		 22.5

    Secondary: ORR per RECIST 1.1 As Assessed By Investigator in Participants With ESCC

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    End point title
    		 ORR per RECIST 1.1 As Assessed By Investigator in Participants With ESCC
    End point description
    ORR 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) per RECIST 1.1. as assessed by the investigator. The sponsor allowed a maximum of 10 target lesions in total and 5 per organ on this study. Per protocol, the percentage of participants who experienced CR or PR is reported here as the ORR for all participants of the ITT population (all randomized) who had ESCC.
    End point type
    Secondary
    End point timeframe
    Up to approximately 34 months
    End point values
    		 Pembrolizumab + SOC Placebo + SOC
    Number of subjects analysed
    274
    274
    Units: Percentage of Participants
        number (confidence interval 95%)
    43.8 (37.8 to 49.9)
    31.0 (25.6 to 36.9)
    Statistical analysis title
    		 ORR in ESCC
    Statistical analysis description
    ORR in ESCC participants of the pembrolizumab + SOC arm was compared to ORR in ESCC participants of the placebo + SOC arm based on the Miettinen & Nurminen method stratified by geographic region (Asia versus Rest of the World) and ECOG performance status (0 versus 1).
    Comparison groups
    Pembrolizumab + SOC v Placebo + SOC
    Number of subjects included in analysis
    548
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0009
    Method
    		 One-sided p-value
    Parameter type
    		 Difference in Percentage
    Point estimate
    12.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.7
         upper limit
    		 20.7

    Secondary: Duration of Response (DOR) per RECIST 1.1 As Assessed By Investigator in All Participants

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    End point title
    		 Duration of Response (DOR) per RECIST 1.1 As Assessed By Investigator in All Participants
    End point description
    For participants who demonstrated a confirmed CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1 as assessed by the investigator, DOR was defined as the time from first documented evidence of confirmed CR or PR until PD or death due to any cause, whichever occurred first. DOR for participants who had not progressed or died at the time of analysis was censored at the date of their last tumor assessment. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. Per protocol, DOR is reported here for all participants of the ITT population (all randomized) who had CR or PR.
    End point type
    Secondary
    End point timeframe
    Up to approximately 34 months
    End point values
    		 Pembrolizumab + SOC Placebo + SOC
    Number of subjects analysed
    168
    110
    Units: Months
        median (confidence interval 95%)
    8.3 (6.4 to 10.4)
    6.0 (4.4 to 6.4)
    No statistical analyses for this end point

    Secondary: ORR per RECIST 1.1 As Assessed By Investigator in Participants Whose Tumors are PD-L1 Biomarker-Positive (CPS ≥10)

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    End point title
    		 ORR per RECIST 1.1 As Assessed By Investigator in Participants Whose Tumors are PD-L1 Biomarker-Positive (CPS ≥10)
    End point description
    ORR 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) per RECIST 1.1. as assessed by the investigator. The sponsor allowed a maximum of 10 target lesions in total and 5 per organ on this study. Per protocol, the percentage of participants who experienced CR or PR is reported here as the ORR for all participants of the ITT population (all randomized) who were PD-L1 CPS ≥10.
    End point type
    Secondary
    End point timeframe
    Up to approximately 34 months
    End point values
    		 Pembrolizumab + SOC Placebo + SOC
    Number of subjects analysed
    186
    197
    Units: Percentage of Participants
        number (confidence interval 95%)
    51.1 (43.7 to 58.5)
    26.9 (20.8 to 33.7)
    Statistical analysis title
    		 ORR in PD-L1 CPS ≥10
    Statistical analysis description
    ORR in PD-L1 CPS ≥10 participants of the pembrolizumab + SOC arm was compared to ORR in PD-L1 CPS ≥10 participants of the placebo + SOC arm based on the Miettinen & Nurminen method stratified by geographic region (Asia versus Rest of the World) and tumor histology (Adenocarcinoma versus Squamous Cell Carcinoma).
    Comparison groups
    Pembrolizumab + SOC v Placebo + SOC
    Number of subjects included in analysis
    383
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 One-sided p-value
    Parameter type
    		 Difference in Percentage
    Point estimate
    24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 14.3
         upper limit
    		 33.2

    Secondary: DOR per RECIST 1.1 As Assessed By Investigator in Participants With ESCC Whose Tumors are PD-L1 Biomarker-Positive (CPS ≥10)

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    End point title
    		 DOR per RECIST 1.1 As Assessed By Investigator in Participants With ESCC Whose Tumors are PD-L1 Biomarker-Positive (CPS ≥10)
    End point description
    For participants who demonstrated a confirmed CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1 as assessed by the investigator, DOR was defined as the time from first documented evidence of confirmed CR or PR until PD or death due to any cause, whichever occurred first. DOR for participants who had not progressed or died at the time of analysis was censored at the date of their last tumor assessment. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. Per protocol, DOR is reported here for all participants of the ITT population (all randomized) who had CR or PR, and who had ESCC and were PD-L1 CPS ≥10.
    End point type
    Secondary
    End point timeframe
    Up to approximately 34 months
    End point values
    		 Pembrolizumab + SOC Placebo + SOC
    Number of subjects analysed
    73
    40
    Units: Months
        median (confidence interval 95%)
    10.4 (8.0 to 16.2)
    4.4 (4.1 to 6.2)
    No statistical analyses for this end point

    Secondary: DOR per RECIST 1.1 As Assessed By Investigator in Participants Whose Tumors are PD-L1 Biomarker-Positive (CPS ≥10)

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    End point title
    		 DOR per RECIST 1.1 As Assessed By Investigator in Participants Whose Tumors are PD-L1 Biomarker-Positive (CPS ≥10)
    End point description
    For participants who demonstrated a confirmed CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1 as assessed by the investigator, DOR was defined as the time from first documented evidence of confirmed CR or PR until PD or death due to any cause, whichever occurred first. DOR for participants who had not progressed or died at the time of analysis was censored at the date of their last tumor assessment. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. Per protocol, DOR is reported here for all participants of the ITT population (all randomized) who had CR or PR, and were PD-L1 CPS ≥10.
    End point type
    Secondary
    End point timeframe
    Up to approximately 34 months
    End point values
    		 Pembrolizumab + SOC Placebo + SOC
    Number of subjects analysed
    95
    53
    Units: Months
        median (confidence interval 95%)
    10.4 (6.7 to 14.5)
    5.6 (4.3 to 6.5)
    No statistical analyses for this end point

    Secondary: DOR per RECIST 1.1 As Assessed By Investigator in Participants With ESCC

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    End point title
    		 DOR per RECIST 1.1 As Assessed By Investigator in Participants With ESCC
    End point description
    For participants who demonstrated a confirmed CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1 as assessed by the investigator, DOR was defined as the time from first documented evidence of confirmed CR or PR until PD or death due to any cause, whichever occurred first. DOR for participants who had not progressed or died at the time of analysis was censored at the date of their last tumor assessment. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. Per protocol, DOR is reported here for all participants of the ITT population (all randomized) who had CR or PR, and who had ESCC.
    End point type
    Secondary
    End point timeframe
    Up to approximately 34 months
    End point values
    		 Pembrolizumab + SOC Placebo + SOC
    Number of subjects analysed
    120
    85
    Units: Months
        median (confidence interval 95%)
    9.1 (6.6 to 12.3)
    6.1 (4.4 to 6.4)
    No statistical analyses for this end point

    Secondary: Number of Participants with an Adverse Event (AE)

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    End point title
    		 Number of Participants with an Adverse Event (AE)
    End point description
    An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavourable 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 medicinal product or protocol-specified procedure. Any worsening of a pre-existing condition that was temporally associated with the use of the Sponsor’s product was also an AE. The number of participants that experienced at least one AE was reported for each treatment arm. All randomized participants who received at least one dose of study treatment were analyzed.
    End point type
    Secondary
    End point timeframe
    Up to approximately 28 months
    End point values
    		 Pembrolizumab + SOC Placebo + SOC
    Number of subjects analysed
    370
    370
    Units: Participants
    370
    368
    No statistical analyses for this end point

    Secondary: Number of Participants Discontinuing Study Treatment Due to an AE

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    End point title
    		 Number of Participants Discontinuing Study Treatment Due to an AE
    End point description
    An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavourable 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 medicinal product or protocol-specified procedure. Any worsening of a pre-existing condition that was temporally associated with the use of the Sponsor’s product was also an AE. The number of participants that discontinued any study drug due to an AE was reported for each treatment arm. All randomized participants who received at least one dose of study treatment were analyzed.
    End point type
    Secondary
    End point timeframe
    Up to approximately 27 months
    End point values
    		 Pembrolizumab + SOC Placebo + SOC
    Number of subjects analysed
    370
    370
    Units: Participants
    90
    74
    No statistical analyses for this end point

    Secondary: Change from Baseline To Week 18 in the European Organization for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 (QLQ-C30) Global Health Status/Quality of Life (GHS/QoL) Combined Score in All Participants

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    End point title
    		 Change from Baseline To Week 18 in the European Organization for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 (QLQ-C30) Global Health Status/Quality of Life (GHS/QoL) Combined Score in All Participants
    End point description
    The EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. Participant responses to the Global Health Status (GHS) question "How would you rate your overall health during the past week?" (Item 29) and the Quality of Life (QoL) question "How would you rate your overall quality of life during the past week?" (Item 30) were scored on a 7-point scale (1=Very Poor to 7=Excellent). Using linear transformation, raw scores were standardized so that scores ranged from 0 to 100, with a higher score indicating a better overall outcome. Per protocol, change from baseline to Week 18 in the GHS/QoL combined score was reported by treatment arm as a pre-specified secondary analysis for all participants. All randomized participants who received at least one dose of study treatment and completed at least 1 EORTC-QLQ-C30 assessment were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 18
    End point values
    		 Pembrolizumab + SOC Placebo + SOC
    Number of subjects analysed
    366
    363
    Units: Score on a Scale
        least squares mean (confidence interval 95%)
    -1.74 (-4.24 to 0.75)
    -1.64 (-4.21 to 0.92)
    Statistical analysis title
    		 EORTC-QLQ-C30 GHS/QoL combined score
    Statistical analysis description
    Change from baseline to Week 18 in EORTC-QLQ-C30 GHS/QoL combined score was compared between treatment arms based on a constrained longitudinal data analysis (cLDA) model with the EORTC-QLQ-C30 GHS/QoL scores as the response variable with covariates for treatment by study visit interaction, and stratification factors including geographic region (Asia versus Rest of the World) and tumor histology (Adenocarcinoma versus Squamous Cell Carcinoma) and ECOG performance status (0 versus 1).
    Comparison groups
    Pembrolizumab + SOC v Placebo + SOC
    Number of subjects included in analysis
    729
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.953
    Method
    		 constrained Longitudinal Data Analysis
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.4
         upper limit
    		 3.2

    Secondary: Change from Baseline To Week 18 in the EORTC QLQ-C30 GHS/QoL Combined Score in Participants With ESCC Whose Tumors are PD-L1 Biomarker-Positive (CPS ≥10)

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    End point title
    		 Change from Baseline To Week 18 in the EORTC QLQ-C30 GHS/QoL Combined Score in Participants With ESCC Whose Tumors are PD-L1 Biomarker-Positive (CPS ≥10)
    End point description
    The EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. Participant responses to the Global Health Status (GHS) question "How would you rate your overall health during the past week?" (Item 29) and the Quality of Life (QoL) question "How would you rate your overall quality of life during the past week?" (Item 30) were scored on a 7-point scale (1=Very Poor to 7=Excellent). Using linear transformation, raw scores were standardized so that scores ranged from 0 to 100, with a higher score indicating a better overall outcome. Per protocol, change from baseline to Week 18 in the GHS/QoL combined score was reported by treatment arm as a pre-specified secondary analysis for all participants who had ESCC and who were PD-L1 CPS ≥10. All randomized participants who received at least one dose of study treatment, completed at least 1 EORTC-QLQ-C30 assessment, who had ESCC, and who were PD-L1 CPS ≥10 were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 18
    End point values
    		 Pembrolizumab + SOC Placebo + SOC
    Number of subjects analysed
    142
    138
    Units: Score on a Scale
        least squares mean (confidence interval 95%)
    -2.36 (-6.58 to 1.87)
    -0.40 (-4.86 to 4.05)
    Statistical analysis title
    		 EORTC-QLQ-C30 GHS/QoL combined score
    Statistical analysis description
    Change from baseline to Week 18 in EORTC-QLQ-C30 GHS/QoL combined score was compared between treatment arms based on a cLDA model with the EORTC-QLQ-C30 GHS/QoL scores as the response variable with covariates for treatment by study visit interaction, and stratification factors including geographic region (Asia versus Rest of the World) and ECOG performance status (0 versus 1).
    Comparison groups
    Pembrolizumab + SOC v Placebo + SOC
    Number of subjects included in analysis
    280
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.5053
    Method
    		 constrained Longitudinal Data Analysis
    Parameter type
    		 Difference in LS Means
    Point estimate
    -1.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.72
         upper limit
    		 3.82

    Secondary: Change from Baseline To Week 18 in the EORTC QLQ-C30 GHS/QoL Combined Score in Participants Whose Tumors are PD-L1 Biomarker-Positive (CPS ≥10)

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    End point title
    		 Change from Baseline To Week 18 in the EORTC QLQ-C30 GHS/QoL Combined Score in Participants Whose Tumors are PD-L1 Biomarker-Positive (CPS ≥10)
    End point description
    The EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. Participant responses to the Global Health Status (GHS) question "How would you rate your overall health during the past week?" (Item 29) and the Quality of Life (QoL) question "How would you rate your overall quality of life during the past week?" (Item 30) were scored on a 7-point scale (1=Very Poor to 7=Excellent). Using linear transformation, raw scores were standardized so that scores ranged from 0 to 100, with a higher score indicating a better overall outcome. Per protocol, change from baseline to Week 18 in the GHS/QoL combined score was reported by treatment arm as a pre-specified secondary analysis for all participants who were PD-L1 CPS ≥10. All randomized participants who received at least one dose of study treatment, completed at least 1 EORTC-QLQ-C30 assessment, and who were PD-L1 CPS ≥10 were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 18
    End point values
    		 Pembrolizumab + SOC Placebo + SOC
    Number of subjects analysed
    184
    191
    Units: Score on a Scale
        least squares mean (confidence interval 95%)
    -1.73 (-5.50 to 2.04)
    0.04 (-3.77 to 3.85)
    Statistical analysis title
    		 EORTC-QLQ-C30 GHS/QoL combined score
    Statistical analysis description
    Change from baseline to Week 18 in EORTC-QLQ-C30 GHS/QoL combined score was compared between treatment arms based on a cLDA model with the EORTC-QLQ-C30 GHS/QoL scores as the response variable with covariates for treatment by study visit interaction, and stratification factors including geographic region (Asia versus Rest of the World) and tumor histology (Adenocarcinoma versus Squamous Cell Carcinoma).
    Comparison groups
    Pembrolizumab + SOC v Placebo + SOC
    Number of subjects included in analysis
    375
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.481
    Method
    		 constrained Longitudinal Data Analysis
    Parameter type
    		 Difference in LS Means
    Point estimate
    -1.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.71
         upper limit
    		 3.17

    Secondary: Change from Baseline To Week 18 in the EORTC QLQ-C30 GHS/QoL Combined Score in Participants With ESCC

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    End point title
    		 Change from Baseline To Week 18 in the EORTC QLQ-C30 GHS/QoL Combined Score in Participants With ESCC
    End point description
    The EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. Participant responses to the Global Health Status (GHS) question "How would you rate your overall health during the past week?" (Item 29) and the Quality of Life (QoL) question "How would you rate your overall quality of life during the past week?" (Item 30) were scored on a 7-point scale (1=Very Poor to 7=Excellent). Using linear transformation, raw scores were standardized so that scores ranged from 0 to 100, with a higher score indicating a better overall outcome. Per protocol, change from baseline to Week 18 in the GHS/QoL combined score was reported by treatment arm as a pre-specified secondary analysis for all participants who had ESCC. All randomized participants who received at least one dose of study treatment, completed at least 1 EORTC-QLQ-C30 assessment, and who had ESCC were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 18
    End point values
    		 Pembrolizumab + SOC Placebo + SOC
    Number of subjects analysed
    270
    264
    Units: Score on a Scale
        least squares mean (confidence interval 95%)
    -2.00 (-4.90 to 0.89)
    -1.94 (-4.93 to 1.06)
    Statistical analysis title
    		 EORTC-QLQ-C30 GHS/QoL combined score
    Statistical analysis description
    Change from baseline to Week 18 in EORTC-QLQ-C30 GHS/QoL combined score was compared between treatment arms based on a cLDA model with the EORTC-QLQ-C30 GHS/QoL scores as the response variable with covariates for treatment by study visit interaction, and stratification factors including geographic region (Asia versus Rest of the World) and ECOG performance status (0 versus 1).
    Comparison groups
    Pembrolizumab + SOC v Placebo + SOC
    Number of subjects included in analysis
    534
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.9742
    Method
    		 constrained Longitudinal Data Analysis
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.93
         upper limit
    		 3.81

    Secondary: Change from Baseline in the EORTC Quality Of Life Questionnaire Oesophageal Module (QLQ-OES18) Subscale Scores in All Participants

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    End point title
    		 Change from Baseline in the EORTC Quality Of Life Questionnaire Oesophageal Module (QLQ-OES18) Subscale Scores in All Participants
    End point description
    The EORTC QLQ-OES18 is a disease-specific questionnaire developed and validated to address measurements specific to esophageal cancer and contains 18 items assessing symptoms of dysphagia, pain, reflux symptoms, eating restrictions, anxiety, dry mouth, taste, body image, and hair loss. For the purposes of this study, the Dysphagia subscale (3 items), Pain subscale (3 items), and Reflux subscale (2 items) were evaluated. All subscale items were scored using a four-point Likert scale with the following response choices: 1=not at all, 2=a little, 3=quite a bit, 4=very much. Raw scores for the subscales were standardized into a range of 0 to 100 by linear transformation, with higher symptom scores represent a higher ("worse") level of symptoms. Per protocol, change from baseline to Week 18 in the Dysphagia, Pain, and Reflux subscales was reported for all randomized participants who received at least one dose of study treatment and completed at least 1 EORTC QLQ-OES18 assessment.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 18
    End point values
    		 Pembrolizumab + SOC Placebo + SOC
    Number of subjects analysed
    366
    359
    Units: Score on a Scale
    least squares mean (confidence interval 95%)
        Dysphagia subscale
    -3.18 (-7.19 to 0.82)
    2.36 (-1.77 to 6.49)
        Pain subscale
    -4.78 (-7.01 to -2.56)
    -1.85 (-4.14 to 0.45)
        Reflux subscale
    -0.22 (-2.81 to 2.36)
    0.71 (-1.96 to 3.38)
    Statistical analysis title
    		 EORTC QLQ-OES18- Dysphagia + Pain + Reflux
    Statistical analysis description
    DYSPHAGIA: Change from baseline to Week 18 in EORTC QLQ-OES18 Dysphagia subscale was compared between treatment arms based on a cLDA model with EORTC QLQ-OES18 scores as the response variable with covariates for treatment by study visit interaction, and stratification factors including geographic region (Asia versus Rest of the World) and tumor histology (Adenocarcinoma versus Squamous Cell Carcinoma) and ECOG performance status (0 versus 1).
    Comparison groups
    Pembrolizumab + SOC v Placebo + SOC
    Number of subjects included in analysis
    725
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0436
    Method
    		 constrained Longitudinal Data Analysis
    Parameter type
    		 Difference in LS Means
    Point estimate
    -5.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.93
         upper limit
    		 -0.16
    Statistical analysis title
    		 EORTC QLQ-OES18- Dysphagia + Pain + Reflux
    Statistical analysis description
    REFLUX: Change from baseline to Week 18 in EORTC QLQ-OES18 Reflux subscale was compared between treatment arms based on a cLDA model with EORTC QLQ-OES18 scores as the response variable with covariates for treatment by study visit interaction, and stratification factors including geographic region (Asia versus Rest of the World) and tumor histology (Adenocarcinoma versus Squamous Cell Carcinoma) and ECOG performance status (0 versus 1).
    Comparison groups
    Pembrolizumab + SOC v Placebo + SOC
    Number of subjects included in analysis
    725
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.5932
    Method
    		 constrained Longitudinal Data Analysis
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.36
         upper limit
    		 2.49
    Statistical analysis title
    		 EORTC QLQ-OES18- Dysphagia + Pain + Reflux
    Statistical analysis description
    PAIN: Change from baseline to Week 18 in EORTC QLQ-OES18 Pain subscale was compared between treatment arms based on a cLDA model with EORTC QLQ-OES18 scores as the response variable with covariates for treatment by study visit interaction, and stratification factors including geographic region (Asia versus Rest of the World) and tumor histology (Adenocarcinoma versus Squamous Cell Carcinoma) and ECOG performance status (0 versus 1).
    Comparison groups
    Pembrolizumab + SOC v Placebo + SOC
    Number of subjects included in analysis
    725
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0487
    Method
    		 constrained Longitudinal Data Analysis
    Parameter type
    		 Difference in LS Means
    Point estimate
    -2.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.86
         upper limit
    		 -0.02

    Secondary: Change from Baseline in the EORTC QLQ-OES18 Subscale Scores in Participants With ESCC Whose Tumors are PD-L1 Biomarker-Positive (CPS ≥10)

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    End point title
    		 Change from Baseline in the EORTC QLQ-OES18 Subscale Scores in Participants With ESCC Whose Tumors are PD-L1 Biomarker-Positive (CPS ≥10)
    End point description
    EORTC QLQ-OES18 is a disease-specific questionnaire developed and validated to address measurements specific to esophageal cancer containing 18 items assessing symptoms of dysphagia, pain, reflux symptoms, eating restrictions, anxiety, dry mouth, taste, body image, and hair loss. For the purposes of this study, the Dysphagia subscale (3 items), Pain subscale (3 items), and Reflux subscale (2 items) were evaluated. All subscale items scored using a 4-point Likert scale with the following response choices: 1=not at all, 2=a little, 3=quite a bit, 4=very much. Raw scores for subscales were standardized into a range of 0-100 by linear transformation, with higher symptom scores representing a higher ("worse") level of symptoms. Change from baseline to Week 18 in the Dysphagia, Pain, and Reflux subscales reported for all randomized participants with ESCC and PD-L1 CPS≥10 in each treatment arm who received ≥1 dose of study treatment and completed at least 1 EORTC QLQ-OES18 assessment.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 18
    End point values
    		 Pembrolizumab + SOC Placebo + SOC
    Number of subjects analysed
    142
    135
    Units: Score on a Scale
    least squares mean (confidence interval 95%)
        Dysphagia subscale
    -5.11 (-11.51 to 1.30)
    3.57 (-3.22 to 10.36)
        Pain subscale
    -2.55 (-6.11 to 1.01)
    -0.42 (-4.20 to 3.36)
        Reflux subscale
    -0.16 (-4.43 to 4.11)
    4.94 (0.43 to 9.46)
    Statistical analysis title
    		 EORTC QLQ-OES18- Dysphagia + Pain + Reflux
    Statistical analysis description
    DYSPHAGIA: Change from baseline to Week 18 in EORTC QLQ-OES18 Dysphagia subscale was compared between treatment arms based on a cLDA model with EORTC QLQ-OES18 scores as the response variable with covariates for treatment by study visit interaction, and stratification factors including geographic region (Asia versus Rest of the World) and ECOG performance status (0 versus 1).
    Comparison groups
    Pembrolizumab + SOC v Placebo + SOC
    Number of subjects included in analysis
    277
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0564
    Method
    		 constrained Longitudinal Data Analysis
    Parameter type
    		 Difference in LS Means
    Point estimate
    -8.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -17.59
         upper limit
    		 0.24
    Statistical analysis title
    		 EORTC QLQ-OES18- Dysphagia + Pain + Reflux
    Statistical analysis description
    REFLUX: Change from baseline to Week 18 in EORTC QLQ-OES18 Reflux subscale was compared between treatment arms based on a cLDA model with EORTC QLQ-OES18 scores as the response variable with covariates for treatment by study visit interaction, and stratification factors including geographic region (Asia versus Rest of the World) and ECOG performance status (0 versus 1).
    Comparison groups
    Pembrolizumab + SOC v Placebo + SOC
    Number of subjects included in analysis
    277
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0816
    Method
    		 constrained Longitudinal Data Analysis
    Parameter type
    		 Difference in LS Means
    Point estimate
    -5.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.86
         upper limit
    		 0.65
    Statistical analysis title
    		 EORTC QLQ-OES18- Dysphagia + Pain + Reflux
    Statistical analysis description
    PAIN: Change from baseline to Week 18 in EORTC QLQ-OES18 Pain subscale was compared between treatment arms based on a cLDA model with EORTC QLQ-OES18 scores as the response variable with covariates for treatment by study visit interaction, and stratification factors including geographic region (Asia versus Rest of the World) and ECOG performance status (0 versus 1).
    Comparison groups
    Pembrolizumab + SOC v Placebo + SOC
    Number of subjects included in analysis
    277
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.3813
    Method
    		 constrained Longitudinal Data Analysis
    Parameter type
    		 Difference in LS Means
    Point estimate
    -2.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.93
         upper limit
    		 2.66

    Secondary: Change from Baseline in the EORTC QLQ-OES18 Subscale Scores in Participants Whose Tumors are PD-L1 Biomarker-Positive (CPS ≥10)

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    End point title
    		 Change from Baseline in the EORTC QLQ-OES18 Subscale Scores in Participants Whose Tumors are PD-L1 Biomarker-Positive (CPS ≥10)
    End point description
    EORTC QLQ-OES18 is a disease-specific questionnaire developed and validated to address measurements specific to esophageal cancer and contains 18 items assessing symptoms of dysphagia, pain, reflux symptoms, eating restrictions, anxiety, dry mouth, taste, body image, and hair loss. For the purposes of this study, the Dysphagia subscale (3 items), Pain subscale (3 items), and Reflux subscale (2 items) were evaluated. All subscale items were scored using a 4-point Likert scale with the following response choices: 1=not at all, 2=a little, 3=quite a bit, 4=very much. Raw scores for the subscales were standardized into a range of 0 to 100 by linear transformation, with higher symptom scores representing a higher ("worse") level of symptoms. Change from baseline to Week 18 in the Dysphagia, Pain, and Reflux subscales was reported for all randomized PD-L1 CPS≥10 participants in each treatment arm who received ≥1 dose of study treatment and completed ≥1 EORTC QLQ-OES18 assessment.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 18
    End point values
    		 Pembrolizumab + SOC Placebo + SOC
    Number of subjects analysed
    184
    187
    Units: Score on a Scale
    least squares mean (confidence interval 95%)
        Dysphagia subscale
    -7.18 (-12.76 to -1.60)
    1.02 (-4.66 to 6.70)
        Pain subscale
    -3.51 (-6.69 to -0.33)
    0.07 (-3.18 to 3.31)
        Reflux subscale
    -0.52 (-4.17 to 3.14)
    4.25 (0.52 to 7.97)
    Statistical analysis title
    		 EORTC QLQ-OES18- Dysphagia + Pain + Reflux
    Statistical analysis description
    DYSPHAGIA: Change from baseline to Week 18 in EORTC QLQ-OES18 Dysphagia subscale was compared between treatment arms based on a cLDA model with EORTC QLQ-OES18 scores as the response variable with covariates for treatment by study visit interaction, and stratification factors including geographic region (Asia versus Rest of the World) and tumor histology (Adenocarcinoma versus Squamous Cell Carcinoma).
    Comparison groups
    Pembrolizumab + SOC v Placebo + SOC
    Number of subjects included in analysis
    371
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0317
    Method
    		 constrained Longitudinal Data Analysis
    Parameter type
    		 Difference in LS Means
    Point estimate
    -8.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -15.67
         upper limit
    		 -0.73
    Statistical analysis title
    		 EORTC QLQ-OES18- Dysphagia + Pain + Reflux
    Statistical analysis description
    REFLUX: Change from baseline to Week 18 in EORTC QLQ-OES18 Reflux subscale was compared between treatment arms based on a cLDA model with EORTC QLQ-OES18 scores as the response variable with covariates for treatment by study visit interaction, and stratification factors including geographic region (Asia versus Rest of the World) and tumor histology (Adenocarcinoma versus Squamous Cell Carcinoma).
    Comparison groups
    Pembrolizumab + SOC v Placebo + SOC
    Number of subjects included in analysis
    371
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0555
    Method
    		 constrained Longitudinal Data Analysis
    Parameter type
    		 Difference in LS Means
    Point estimate
    -4.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.64
         upper limit
    		 0.11
    Statistical analysis title
    		 EORTC QLQ-OES18- Dysphagia + Pain + Reflux
    Statistical analysis description
    PAIN: Change from baseline to Week 18 in EORTC QLQ-OES18 Pain subscale was compared between treatment arms based on a cLDA model with EORTC QLQ-OES18 scores as the response variable with covariates for treatment by study visit interaction, and stratification factors including geographic region (Asia versus Rest of the World) and tumor histology (Adenocarcinoma versus Squamous Cell Carcinoma).
    Comparison groups
    Pembrolizumab + SOC v Placebo + SOC
    Number of subjects included in analysis
    371
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0945
    Method
    		 constrained Longitudinal Data Analysis
    Parameter type
    		 Difference in LS Means
    Point estimate
    -3.57
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.77
         upper limit
    		 0.62

    Secondary: Change from Baseline in the EORTC QLQ-OES18 Subscale Scores in Participants With ESCC

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    End point title
    		 Change from Baseline in the EORTC QLQ-OES18 Subscale Scores in Participants With ESCC
    End point description
    EORTC QLQ-OES18 is a disease-specific questionnaire developed and validated to address measurements specific to esophageal cancer and contains 18 items assessing symptoms of dysphagia, pain, reflux symptoms, eating restrictions, anxiety, dry mouth, taste, body image, and hair loss. For the purposes of this study, the Dysphagia subscale (3 items), Pain subscale (3 items), and Reflux subscale (2 items) were evaluated. All subscale items were scored using a four-point Likert scale with the following response choices: 1=not at all, 2=a little, 3=quite a bit, 4=very much. Raw scores for the subscales were standardized into a range of 0 to 100 by linear transformation, with higher symptom scores representing a higher ("worse") level of symptoms. Change from baseline to Week 18 in the Dysphagia, Pain, and Reflux subscales was reported for all randomized participants with ESCC in each treatment arm who received ≥1 dose of study treatment and completed ≥1 EORTC QLQ-OES18 assessment.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 18
    End point values
    		 Pembrolizumab + SOC Placebo + SOC
    Number of subjects analysed
    270
    261
    Units: Score on a Scale
    least squares mean (confidence interval 95%)
        Dysphagia subscale
    -1.18 (-5.82 to 3.47)
    3.32 (-1.50 to 8.13)
        Pain subscale
    -4.03 (-6.64 to -1.43)
    -2.33 (-5.02 to 0.37)
        Reflux subscale
    -0.40 (-3.39 to 2.59)
    1.09 (-2.01 to 4.19)
    Statistical analysis title
    		 EORTC QLQ-OES18- Dysphagia + Pain + Reflux
    Statistical analysis description
    DYSPHAGIA: Change from baseline to Week 18 in EORTC QLQ-OES18 Dysphagia subscale was compared between treatment arms based on a cLDA model with EORTC QLQ-OES18 scores as the response variable with covariates for treatment by study visit interaction, and stratification factors including geographic region (Asia versus Rest of the World) and ECOG performance status (0 versus 1).
    Comparison groups
    Pembrolizumab + SOC v Placebo + SOC
    Number of subjects included in analysis
    531
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1632
    Method
    		 constrained Longitudinal Data Analysis
    Parameter type
    		 Difference in LS Means
    Point estimate
    -4.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.81
         upper limit
    		 1.83
    Statistical analysis title
    		 EORTC QLQ-OES18- Dysphagia + Pain + Reflux
    Statistical analysis description
    REFLUX: Change from baseline to Week 18 in EORTC QLQ-OES18 Reflux subscale was compared between treatment arms based on a cLDA model with EORTC QLQ-OES18 scores as the response variable with covariates for treatment by study visit interaction, and stratification factors including geographic region (Asia versus Rest of the World) and ECOG performance status (0 versus 1).
    Comparison groups
    Pembrolizumab + SOC v Placebo + SOC
    Number of subjects included in analysis
    531
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.4598
    Method
    		 constrained Longitudinal Data Analysis
    Parameter type
    		 Difference in LS Means
    Point estimate
    -1.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.47
         upper limit
    		 2.48
    Statistical analysis title
    		 EORTC QLQ-OES18- Dysphagia + Pain + Reflux
    Statistical analysis description
    PAIN: Change from baseline to Week 18 in EORTC QLQ-OES18 Pain subscale was compared between treatment arms based on a cLDA model with EORTC QLQ-OES18 scores as the response variable with covariates for treatment by study visit interaction, and stratification factors including geographic region (Asia versus Rest of the World) and ECOG performance status (0 versus 1).
    Comparison groups
    Pembrolizumab + SOC v Placebo + SOC
    Number of subjects included in analysis
    531
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.3259
    Method
    		 constrained Longitudinal Data Analysis
    Parameter type
    		 Difference in LS Means
    Point estimate
    -1.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.12
         upper limit
    		 1.71

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to approximately 70 months
    Adverse event reporting additional description
    Serious and Non serious AE tables include all treated participants. Per protocol, disease progression of cancer on study was not considered an AE unless considered related to study drug. Thus, MedDRA preferred terms "Neoplasm progression", "Malignant neoplasm progression" and "Disease progression" not related to study drug were excluded as AEs.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    Placebo + SOC
    Reporting group description
    		 Participants received placebo to pembrolizumab (saline) IV Q3W along with SOC chemotherapy with cisplatin 80 mg/m^2 IV Q3W and 5-FU 800 mg/m^2/day continuous IV infusion on Days 1 to 5 (120 hours) Q3W. All treatments were administered on an outpatient basis beginning on Day 1 of each 3-week dosing cycle.

    Reporting group title
    Pembrolizumab + SOC
    Reporting group description
    		 Participants received pembrolizumab 200 mg IV Q3W plus SOC chemotherapy with cisplatin 80 mg/m^2 IV Q3W and 5-FU 800 mg/m^2/day continuous IV infusion on Days 1 to 5 (120 hours) Q3W. All treatments were administered on an outpatient basis beginning on Day 1 of each 3-week dosing cycle.

    Serious adverse events
    		 Placebo + SOC Pembrolizumab + SOC
    Total subjects affected by serious adverse events
         subjects affected / exposed
    204 / 370 (55.14%)
    207 / 370 (55.95%)
         number of deaths (all causes)
    363
    331
         number of deaths resulting from adverse events
    38
    29
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder cancer recurrent
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cancer pain
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal submucosal tumour
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasm swelling
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour associated fever
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    2 / 370 (0.54%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Venous thrombosis
         subjects affected / exposed
    1 / 370 (0.27%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic thrombosis
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vena cava thrombosis
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subclavian vein thrombosis
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jugular vein thrombosis
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 370 (0.00%)
    2 / 370 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dry gangrene
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    3 / 370 (0.81%)
    2 / 370 (0.54%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Hospitalisation
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 370 (0.27%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    1 / 1
    Asthenia
         subjects affected / exposed
    1 / 370 (0.27%)
    2 / 370 (0.54%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest discomfort
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    7 / 370 (1.89%)
    2 / 370 (0.54%)
         occurrences causally related to treatment / all
    1 / 7
    0 / 2
         deaths causally related to treatment / all
    1 / 7
    0 / 2
    Fatigue
         subjects affected / exposed
    6 / 370 (1.62%)
    3 / 370 (0.81%)
         occurrences causally related to treatment / all
    5 / 6
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 370 (0.27%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    4 / 370 (1.08%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    4 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 370 (0.27%)
    5 / 370 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Strangulated hernia
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden cardiac death
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Systemic inflammatory response syndrome
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular device occlusion
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumatosis
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 370 (0.27%)
    2 / 370 (0.54%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 370 (0.27%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis chronic
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspiration
         subjects affected / exposed
    2 / 370 (0.54%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 370 (0.27%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Emphysema
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 370 (0.27%)
    2 / 370 (0.54%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    2 / 370 (0.54%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    7 / 370 (1.89%)
    7 / 370 (1.89%)
         occurrences causally related to treatment / all
    1 / 7
    2 / 7
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Pneumothorax
         subjects affected / exposed
    1 / 370 (0.27%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 370 (0.00%)
    12 / 370 (3.24%)
         occurrences causally related to treatment / all
    0 / 0
    13 / 13
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Pleuritic pain
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 370 (0.27%)
    3 / 370 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagobronchial fistula
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Interstitial lung disease
         subjects affected / exposed
    1 / 370 (0.27%)
    2 / 370 (0.54%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    1 / 1
    1 / 1
    Tracheal stenosis
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    3 / 370 (0.81%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Personality change
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device occlusion
         subjects affected / exposed
    1 / 370 (0.27%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device failure
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device dislocation
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    2 / 370 (0.54%)
    3 / 370 (0.81%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 370 (0.54%)
    2 / 370 (0.54%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 370 (0.54%)
    3 / 370 (0.81%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    6 / 370 (1.62%)
    4 / 370 (1.08%)
         occurrences causally related to treatment / all
    6 / 7
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    4 / 370 (1.08%)
    2 / 370 (0.54%)
         occurrences causally related to treatment / all
    4 / 4
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    10 / 370 (2.70%)
    5 / 370 (1.35%)
         occurrences causally related to treatment / all
    10 / 13
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product administration error
         subjects affected / exposed
    0 / 370 (0.00%)
    2 / 370 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alcohol poisoning
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Accidental overdose
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal anastomotic stenosis
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal stoma complication
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrostomy tube site complication
         subjects affected / exposed
    2 / 370 (0.54%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural complication
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anastomotic fistula
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheal obstruction
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheal haemorrhage
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Tracheo-oesophageal fistula
         subjects affected / exposed
    1 / 370 (0.27%)
    3 / 370 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Pericardial effusion
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    1 / 370 (0.27%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 370 (0.00%)
    2 / 370 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Angina unstable
         subjects affected / exposed
    0 / 370 (0.00%)
    2 / 370 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriospasm coronary
         subjects affected / exposed
    1 / 370 (0.27%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    2 / 370 (0.54%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Cardiac failure
         subjects affected / exposed
    2 / 370 (0.54%)
    2 / 370 (0.54%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Coronary artery stenosis
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Depressed level of consciousness
         subjects affected / exposed
    1 / 370 (0.27%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 370 (0.27%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 370 (0.27%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    1 / 370 (0.27%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 370 (0.27%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    3 / 370 (0.81%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    3 / 370 (0.81%)
    2 / 370 (0.54%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cognitive disorder
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vocal cord paralysis
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    10 / 370 (2.70%)
    3 / 370 (0.81%)
         occurrences causally related to treatment / all
    6 / 10
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 370 (0.27%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune thrombocytopenia
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    13 / 370 (3.51%)
    9 / 370 (2.43%)
         occurrences causally related to treatment / all
    12 / 13
    9 / 9
         deaths causally related to treatment / all
    1 / 1
    1 / 1
    Neutropenia
         subjects affected / exposed
    3 / 370 (0.81%)
    5 / 370 (1.35%)
         occurrences causally related to treatment / all
    3 / 3
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    3 / 370 (0.81%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    5 / 370 (1.35%)
    7 / 370 (1.89%)
         occurrences causally related to treatment / all
    2 / 5
    5 / 7
         deaths causally related to treatment / all
    0 / 1
    1 / 1
    Abdominal distension
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Autoimmune colitis
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 370 (0.27%)
    4 / 370 (1.08%)
         occurrences causally related to treatment / all
    1 / 1
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diaphragmatic hernia
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulum intestinal haemorrhagic
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenitis
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    13 / 370 (3.51%)
    17 / 370 (4.59%)
         occurrences causally related to treatment / all
    2 / 13
    2 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    1 / 370 (0.27%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocutaneous fistula
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Faecaloma
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric fistula
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    1 / 370 (0.27%)
    3 / 370 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    4 / 370 (1.08%)
    4 / 370 (1.08%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastrointestinal obstruction
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    3 / 370 (0.81%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    2 / 370 (0.54%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal perforation
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    7 / 370 (1.89%)
    5 / 370 (1.35%)
         occurrences causally related to treatment / all
    7 / 7
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal obstruction
         subjects affected / exposed
    3 / 370 (0.81%)
    5 / 370 (1.35%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal stenosis
         subjects affected / exposed
    4 / 370 (1.08%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumatosis intestinalis
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    5 / 370 (1.35%)
    4 / 370 (1.08%)
         occurrences causally related to treatment / all
    5 / 5
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    6 / 370 (1.62%)
    4 / 370 (1.08%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 4
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Vomiting
         subjects affected / exposed
    6 / 370 (1.62%)
    9 / 370 (2.43%)
         occurrences causally related to treatment / all
    7 / 7
    10 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal fistula
         subjects affected / exposed
    0 / 370 (0.00%)
    2 / 370 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hepatobiliary disorders
    Liver disorder
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Autoimmune hepatitis
         subjects affected / exposed
    0 / 370 (0.00%)
    2 / 370 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bile duct stone
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary obstruction
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis chronic
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Granulomatous liver disease
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Hepatic function abnormal
         subjects affected / exposed
    0 / 370 (0.00%)
    2 / 370 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    1 / 370 (0.27%)
    2 / 370 (0.54%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous emphysema
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cold sweat
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    6 / 370 (1.62%)
    11 / 370 (2.97%)
         occurrences causally related to treatment / all
    5 / 6
    8 / 12
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Chronic kidney disease
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prerenal failure
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proteinuria
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    3 / 370 (0.81%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal injury
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal tubular necrosis
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tubulointerstitial nephritis
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureteric obstruction
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Graves' disease
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperthyroidism
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypophysitis
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypopituitarism
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inappropriate antidiuretic hormone secretion
         subjects affected / exposed
    1 / 370 (0.27%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Polymyalgia rheumatica
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoporotic fracture
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 370 (0.27%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle twitching
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Giardiasis
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal wall infection
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute sinusitis
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    1 / 370 (0.27%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    2 / 370 (0.54%)
    2 / 370 (0.54%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 370 (0.00%)
    2 / 370 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 370 (0.27%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cytomegalovirus infection
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 370 (0.00%)
    3 / 370 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Extradural abscess
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal bacterial infection
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal infection
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 370 (0.27%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral discitis
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine infection
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral candidiasis
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    32 / 370 (8.65%)
    38 / 370 (10.27%)
         occurrences causally related to treatment / all
    3 / 36
    13 / 40
         deaths causally related to treatment / all
    0 / 10
    1 / 6
    Pneumonia aspiration
         subjects affected / exposed
    7 / 370 (1.89%)
    11 / 370 (2.97%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 11
         deaths causally related to treatment / all
    0 / 2
    0 / 3
    Pneumonia influenzal
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psoas abscess
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    0 / 370 (0.00%)
    3 / 370 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Pulmonary tuberculosis
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 370 (0.27%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Salmonellosis
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    5 / 370 (1.35%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    3 / 5
    0 / 2
         deaths causally related to treatment / all
    1 / 3
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stoma site infection
         subjects affected / exposed
    1 / 370 (0.27%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral myositis
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular device infection
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic candida
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 370 (0.27%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 370 (0.27%)
    2 / 370 (0.54%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    2 / 370 (0.54%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperammonaemia
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    8 / 370 (2.16%)
    6 / 370 (1.62%)
         occurrences causally related to treatment / all
    4 / 9
    4 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    6 / 370 (1.62%)
    6 / 370 (1.62%)
         occurrences causally related to treatment / all
    4 / 6
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cachexia
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hypocalcaemia
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 370 (0.27%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    6 / 370 (1.62%)
    7 / 370 (1.89%)
         occurrences causally related to treatment / all
    3 / 6
    5 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    2 / 370 (0.54%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    6 / 370 (1.62%)
    7 / 370 (1.89%)
         occurrences causally related to treatment / all
    2 / 6
    8 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypophagia
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypovolaemia
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    1 / 370 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    3 / 370 (0.81%)
    2 / 370 (0.54%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypochloraemia
         subjects affected / exposed
    0 / 370 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo + SOC Pembrolizumab + SOC
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    364 / 370 (98.38%)
    367 / 370 (99.19%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    29 / 370 (7.84%)
    23 / 370 (6.22%)
         occurrences all number
    35
    24
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    122 / 370 (32.97%)
    147 / 370 (39.73%)
         occurrences all number
    182
    231
    Asthenia
         subjects affected / exposed
    44 / 370 (11.89%)
    58 / 370 (15.68%)
         occurrences all number
    71
    103
    Chest pain
         subjects affected / exposed
    20 / 370 (5.41%)
    28 / 370 (7.57%)
         occurrences all number
    21
    39
    Pyrexia
         subjects affected / exposed
    44 / 370 (11.89%)
    53 / 370 (14.32%)
         occurrences all number
    60
    72
    Oedema peripheral
         subjects affected / exposed
    29 / 370 (7.84%)
    16 / 370 (4.32%)
         occurrences all number
    34
    20
    Oedema
         subjects affected / exposed
    20 / 370 (5.41%)
    22 / 370 (5.95%)
         occurrences all number
    50
    59
    Mucosal inflammation
         subjects affected / exposed
    65 / 370 (17.57%)
    59 / 370 (15.95%)
         occurrences all number
    116
    114
    Malaise
         subjects affected / exposed
    42 / 370 (11.35%)
    45 / 370 (12.16%)
         occurrences all number
    63
    75
    Respiratory, thoracic and mediastinal disorders
    Productive cough
         subjects affected / exposed
    24 / 370 (6.49%)
    22 / 370 (5.95%)
         occurrences all number
    24
    27
    Oropharyngeal pain
         subjects affected / exposed
    12 / 370 (3.24%)
    19 / 370 (5.14%)
         occurrences all number
    12
    21
    Hiccups
         subjects affected / exposed
    53 / 370 (14.32%)
    56 / 370 (15.14%)
         occurrences all number
    102
    112
    Dyspnoea
         subjects affected / exposed
    29 / 370 (7.84%)
    34 / 370 (9.19%)
         occurrences all number
    29
    39
    Cough
         subjects affected / exposed
    56 / 370 (15.14%)
    59 / 370 (15.95%)
         occurrences all number
    64
    71
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    44 / 370 (11.89%)
    49 / 370 (13.24%)
         occurrences all number
    56
    59
    Investigations
    Lymphocyte count decreased
         subjects affected / exposed
    21 / 370 (5.68%)
    24 / 370 (6.49%)
         occurrences all number
    47
    52
    Blood creatinine increased
         subjects affected / exposed
    77 / 370 (20.81%)
    78 / 370 (21.08%)
         occurrences all number
    115
    130
    Aspartate aminotransferase increased
         subjects affected / exposed
    27 / 370 (7.30%)
    25 / 370 (6.76%)
         occurrences all number
    33
    43
    Alanine aminotransferase increased
         subjects affected / exposed
    26 / 370 (7.03%)
    24 / 370 (6.49%)
         occurrences all number
    32
    43
    Neutrophil count decreased
         subjects affected / exposed
    107 / 370 (28.92%)
    138 / 370 (37.30%)
         occurrences all number
    235
    279
    White blood cell count decreased
         subjects affected / exposed
    67 / 370 (18.11%)
    96 / 370 (25.95%)
         occurrences all number
    154
    215
    Weight decreased
         subjects affected / exposed
    89 / 370 (24.05%)
    87 / 370 (23.51%)
         occurrences all number
    110
    97
    Platelet count decreased
         subjects affected / exposed
    57 / 370 (15.41%)
    59 / 370 (15.95%)
         occurrences all number
    96
    100
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    30 / 370 (8.11%)
    36 / 370 (9.73%)
         occurrences all number
    38
    42
    Dysgeusia
         subjects affected / exposed
    32 / 370 (8.65%)
    39 / 370 (10.54%)
         occurrences all number
    35
    46
    Headache
         subjects affected / exposed
    25 / 370 (6.76%)
    30 / 370 (8.11%)
         occurrences all number
    30
    56
    Peripheral sensory neuropathy
         subjects affected / exposed
    30 / 370 (8.11%)
    36 / 370 (9.73%)
         occurrences all number
    32
    36
    Neuropathy peripheral
         subjects affected / exposed
    37 / 370 (10.00%)
    37 / 370 (10.00%)
         occurrences all number
    43
    41
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    37 / 370 (10.00%)
    28 / 370 (7.57%)
         occurrences all number
    57
    54
    Neutropenia
         subjects affected / exposed
    90 / 370 (24.32%)
    95 / 370 (25.68%)
         occurrences all number
    179
    190
    Leukopenia
         subjects affected / exposed
    29 / 370 (7.84%)
    25 / 370 (6.76%)
         occurrences all number
    72
    56
    Anaemia
         subjects affected / exposed
    199 / 370 (53.78%)
    185 / 370 (50.00%)
         occurrences all number
    295
    288
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    27 / 370 (7.30%)
    36 / 370 (9.73%)
         occurrences all number
    30
    38
    Gastrointestinal disorders
    Dysphagia
         subjects affected / exposed
    53 / 370 (14.32%)
    46 / 370 (12.43%)
         occurrences all number
    66
    56
    Constipation
         subjects affected / exposed
    149 / 370 (40.27%)
    147 / 370 (39.73%)
         occurrences all number
    210
    238
    Abdominal pain upper
         subjects affected / exposed
    27 / 370 (7.30%)
    20 / 370 (5.41%)
         occurrences all number
    41
    21
    Abdominal pain
         subjects affected / exposed
    18 / 370 (4.86%)
    28 / 370 (7.57%)
         occurrences all number
    21
    33
    Nausea
         subjects affected / exposed
    231 / 370 (62.43%)
    245 / 370 (66.22%)
         occurrences all number
    507
    523
    Stomatitis
         subjects affected / exposed
    93 / 370 (25.14%)
    97 / 370 (26.22%)
         occurrences all number
    146
    160
    Vomiting
         subjects affected / exposed
    114 / 370 (30.81%)
    121 / 370 (32.70%)
         occurrences all number
    200
    226
    Diarrhoea
         subjects affected / exposed
    120 / 370 (32.43%)
    129 / 370 (34.86%)
         occurrences all number
    190
    226
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    26 / 370 (7.03%)
    44 / 370 (11.89%)
         occurrences all number
    33
    56
    Pruritus
         subjects affected / exposed
    12 / 370 (3.24%)
    31 / 370 (8.38%)
         occurrences all number
    13
    33
    Dry skin
         subjects affected / exposed
    10 / 370 (2.70%)
    20 / 370 (5.41%)
         occurrences all number
    10
    21
    Alopecia
         subjects affected / exposed
    39 / 370 (10.54%)
    55 / 370 (14.86%)
         occurrences all number
    40
    55
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    24 / 370 (6.49%)
    40 / 370 (10.81%)
         occurrences all number
    27
    46
    Hyperthyroidism
         subjects affected / exposed
    3 / 370 (0.81%)
    19 / 370 (5.14%)
         occurrences all number
    4
    19
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    30 / 370 (8.11%)
    27 / 370 (7.30%)
         occurrences all number
    35
    34
    Arthralgia
         subjects affected / exposed
    24 / 370 (6.49%)
    30 / 370 (8.11%)
         occurrences all number
    26
    38
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    23 / 370 (6.22%)
    12 / 370 (3.24%)
         occurrences all number
    26
    15
    Upper respiratory tract infection
         subjects affected / exposed
    18 / 370 (4.86%)
    19 / 370 (5.14%)
         occurrences all number
    19
    19
    Pneumonia
         subjects affected / exposed
    22 / 370 (5.95%)
    20 / 370 (5.41%)
         occurrences all number
    23
    21
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    72 / 370 (19.46%)
    63 / 370 (17.03%)
         occurrences all number
    108
    95
    Hypomagnesaemia
         subjects affected / exposed
    23 / 370 (6.22%)
    34 / 370 (9.19%)
         occurrences all number
    29
    43
    Hypokalaemia
         subjects affected / exposed
    68 / 370 (18.38%)
    64 / 370 (17.30%)
         occurrences all number
    109
    107
    Hypocalcaemia
         subjects affected / exposed
    19 / 370 (5.14%)
    27 / 370 (7.30%)
         occurrences all number
    25
    34
    Hypoalbuminaemia
         subjects affected / exposed
    49 / 370 (13.24%)
    34 / 370 (9.19%)
         occurrences all number
    69
    43
    Hyperkalaemia
         subjects affected / exposed
    29 / 370 (7.84%)
    26 / 370 (7.03%)
         occurrences all number
    42
    47
    Hyperglycaemia
         subjects affected / exposed
    19 / 370 (5.14%)
    18 / 370 (4.86%)
         occurrences all number
    29
    25
    Dehydration
         subjects affected / exposed
    25 / 370 (6.76%)
    27 / 370 (7.30%)
         occurrences all number
    25
    32
    Decreased appetite
         subjects affected / exposed
    138 / 370 (37.30%)
    162 / 370 (43.78%)
         occurrences all number
    239
    283
    Hypophosphataemia
         subjects affected / exposed
    22 / 370 (5.95%)
    20 / 370 (5.41%)
         occurrences all number
    25
    27

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Jan 2018
    The major change of Amendment 2 (AM 2) was a change in the primary biomarker from GEP to PD-L1; clarification of the 5-FU dosing; an update to the Statistical Analysis Plan; and a reduction in PK/ADA sampling.
    21 Dec 2018
    The major change of AM 5 was to extend the enrollment period beyond the Global Cohort to achieve the required sample size of the China Cohort to investigate efficacy and safety in Chinese participants.
    10 Feb 2020
    Major changes of AM 8 included addition of 3 primary objectives and corresponding hypotheses (OS in ESCC participants, OS in ESCC participants with PD-L1 CPS ≥10, and PFS in ESCC participants), update of secondary objectives (ORR and DOR endpoints in the ESCC and ESCC PD-L1 CPS ≥10 populations) and exploratory objectives (PFS per immune related RECIST in the ESCC and ESCC PD-L1 CPS ≥10 populations), merging of the Global Cohort and the China Extension Study Cohort into the Global Study group, and inclusion of assessment of DOR, QoL (C30) and QoL (OES18) in all prespecified populations.
    14 Jul 2020
    Major changes of AM 9 included a change in the primary PFS endpoint from BICR-assessed to investigator-assessed, and elimination of one of the two planned efficacy interim analyses.
    01 Jul 2021
    The major change of AM 10 was to update the dose modification and toxicity management guidelines for immune-related AEs.
    28 Nov 2022
    The major change of AM 11 was to update the name of the Sponsor from “Merck Sharp & Dohme Corp.” to “Merck Sharp & Dohme LLC”.

    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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