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    Clinical Trial Results:
    A Randomized, Active-Controlled, Partially Blinded, Biomarker Select, Phase III Clinical Trial of Pembrolizumab as Monotherapy and in Combination with Cisplatin+5-Fluorouracil versus Placebo+Cisplatin+5-Fluorouracil as First-Line Treatment in Subjects with Advanced Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma

    Summary
    EudraCT number
    		 2015-000972-88
    Trial protocol
    		 LT   DE   LV   NL   ES   CZ   FR   AT   HU   BE   PL   IT  
    Global end of trial date
    06 Jun 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 May 2023
    First version publication date
    05 May 2023
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    3475-062
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02494583
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme LLC
    Sponsor organisation address
    126 East Lincoln Avenue, P.O. Box 2000, Rahway, NJ, United States, 07065
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme LLC, ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme LLC, ClinicalTrialsDisclosure@merck.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    06 Jun 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Mar 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Jun 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This was a study of pembrolizumab as first-line treatment for participants with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma. Participants whose tumors expressed programmed death-ligand 1 (PD-L1) were randomly assigned to one of the three treatment arms of the study: pembrolizumab as monotherapy [pembro mono], pembrolizumab plus standard of care (SOC) chemotherapy with cisplatin plus 5-fluorouracil (5-FU) or capecitabine [pembro combo], or placebo plus SOC chemotherapy with cisplatin plus 5-fluorouracil (5-FU) or capecitabine [SOC]. The primary hypotheses compared pembrolizumab plus SOC chemotherapy OR pembrolizumab monotherapy with SOC chemotherapy alone in terms of Progression-free Survival (PFS) and Overall Survival (OS) in participants with PD-L1 Combined Positive Score (CPS) ≥1 and participants with PD-L1 CPS ≥10.
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    31 Jul 2015
    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: 9
    Country: Number of subjects enrolled
    Australia: 19
    Country: Number of subjects enrolled
    Austria: 6
    Country: Number of subjects enrolled
    Belgium: 11
    Country: Number of subjects enrolled
    Brazil: 33
    Country: Number of subjects enrolled
    Chile: 44
    Country: Number of subjects enrolled
    Colombia: 11
    Country: Number of subjects enrolled
    Czechia: 19
    Country: Number of subjects enrolled
    Germany: 19
    Country: Number of subjects enrolled
    Guatemala: 22
    Country: Number of subjects enrolled
    Hong Kong: 7
    Country: Number of subjects enrolled
    Hungary: 28
    Country: Number of subjects enrolled
    Italy: 22
    Country: Number of subjects enrolled
    Japan: 103
    Country: Number of subjects enrolled
    Korea, Republic of: 50
    Country: Number of subjects enrolled
    Latvia: 23
    Country: Number of subjects enrolled
    Lithuania: 14
    Country: Number of subjects enrolled
    Mexico: 14
    Country: Number of subjects enrolled
    Netherlands: 7
    Country: Number of subjects enrolled
    New Zealand: 3
    Country: Number of subjects enrolled
    Poland: 44
    Country: Number of subjects enrolled
    Russian Federation: 64
    Country: Number of subjects enrolled
    South Africa: 21
    Country: Number of subjects enrolled
    Spain: 34
    Country: Number of subjects enrolled
    Switzerland: 15
    Country: Number of subjects enrolled
    Taiwan: 27
    Country: Number of subjects enrolled
    United Kingdom: 25
    Country: Number of subjects enrolled
    United States: 69
    Worldwide total number of subjects
    763
    EEA total number of subjects
    227
    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)
    445
    From 65 to 84 years
    315
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma who were programmed death-ligand 1 (PD-L1)-positive (Combined Positive Score [CPS]≥1) and human epidermal growth factor receptor 2 (HER2/neu)-negative were recruited to the study.

    Pre-assignment
    Screening details
    		 763 were randomized 1:1:1 to pembrolizumab monotherapy (pembro mono), pembrolizumab plus standard of care (SOC) chemotherapy (pembro combo), or placebo plus SOC. Per protocol, response/progression or adverse events (AEs) occurring during second course not counted towards efficacy outcome measures or safety outcome measures, respectively.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor
    Blinding implementation details
    For pembrolizumab (monotherapy); the participant, the trial site personnel, the Sponsor and/or designee were not blinded to this treatment arm since only one type of trial medication was administered on this arm.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Pembrolizumab Monotherapy (Pembro Mono)
    Arm description
    		 Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W). Eligible participants who stopped the initial course of pembrolizumab with Stable Disease (SD) or better but progressed after discontinuation may have been able to initiate a second course of pembrolizumab for up to 17 cycles (up to approximately 1 additional year) at the investigator's discretion.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    KEYTRUDA®, MK-3475
    Pharmaceutical forms
    Concentrate and solvent for concentrate for solution for infusion, Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    200 mg/kg IV, administered Q3W

    Arm title
    		 Pembrolizumab + SOC Chemotherapy (Pembro Combo)
    Arm description
    		 Participants received pembrolizumab 200 mg Q3W plus cisplatin 80 mg/m^2 Q3W plus 5-fluorouracil (5-FU) 800 mg/m^2/day IV infusion on Days 1-5 Q3W. Capecitabine 1000 mg/m^2 twice a day (BID) on Days 1-14 Q3W could be substituted for 5-FU per local guidelines. Eligible participants who stopped the initial course of pembrolizumab with Stable Disease (SD) or better but progressed after discontinuation may have been able to initiate a second course of pembrolizumab for up to 17 cycles (up to approximately 1 additional year) at the investigator's discretion.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    KEYTRUDA®, MK-3475
    Pharmaceutical forms
    Concentrate and solvent for concentrate for solution for infusion, Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    200 mg/kg IV, administered Q3W

    Investigational medicinal product name
    Capecitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Capecitabine 1000 mg/m^2 twice daily by oral tablet on Day 1-14 of each 3-week cycle.

    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
    5-FU 800 mg/m^2/day IV continuous from Day 1-5 of each 3-week cycle.

    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 IV on Day 1 of each week in 3-week cycles (6 cycle maximum per local country guidelines).

    Arm title
    		 Placebo + SOC Chemotherapy (SOC)
    Arm description
    		 Participants received placebo IV Q3W plus cisplatin 80 mg/m^2 Q3W plus 5-FU 800 mg/m^2/day IV infusion on Days 1-5 Q3W. Capecitabine 1000 mg/m^2 BID on Days 1-14 Q3W could be substituted for 5-FU per local guidelines.
    Arm type
    		 Experimental

    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
    Normal saline IV on Day 1 of each week in 3-week cycles for up to 35 cycles (approximately 2 years).

    Investigational medicinal product name
    Capecitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Capecitabine 1000 mg/m^2 twice daily by oral tablet on Day 1-14 of each 3-week cycle.

    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
    5-FU 800 mg/m^2/day IV continuous from Day 1-5 of each 3-week cycle.

    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 IV on Day 1 of each week in 3-week cycles (6 cycle maximum per local country guidelines).

    Number of subjects in period 1
    		Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + SOC Chemotherapy (Pembro Combo) Placebo + SOC Chemotherapy (SOC)
    Started
    256
    257
    250
    Received First Course of Pembrolizumab
    254
    250
    244
    Received Second Course of Pembrolizumab
    4
    5
    0
    Completed
    0
    0
    0
    Not completed
    256
    257
    250
         Consent withdrawn by subject
    7
    15
    15
         Screen Failure
    -
    1
    -
         Transferred to Extension Study
    15
    15
    6
         Death
    224
    214
    225
         Lost to follow-up
    1
    -
    -
         Did Not Continue on Extension Study
    8
    10
    4
         Protocol deviation
    1
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Pembrolizumab Monotherapy (Pembro Mono)
    Reporting group description
    		 Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W). Eligible participants who stopped the initial course of pembrolizumab with Stable Disease (SD) or better but progressed after discontinuation may have been able to initiate a second course of pembrolizumab for up to 17 cycles (up to approximately 1 additional year) at the investigator's discretion.

    Reporting group title
    Pembrolizumab + SOC Chemotherapy (Pembro Combo)
    Reporting group description
    		 Participants received pembrolizumab 200 mg Q3W plus cisplatin 80 mg/m^2 Q3W plus 5-fluorouracil (5-FU) 800 mg/m^2/day IV infusion on Days 1-5 Q3W. Capecitabine 1000 mg/m^2 twice a day (BID) on Days 1-14 Q3W could be substituted for 5-FU per local guidelines. Eligible participants who stopped the initial course of pembrolizumab with Stable Disease (SD) or better but progressed after discontinuation may have been able to initiate a second course of pembrolizumab for up to 17 cycles (up to approximately 1 additional year) at the investigator's discretion.

    Reporting group title
    Placebo + SOC Chemotherapy (SOC)
    Reporting group description
    		 Participants received placebo IV Q3W plus cisplatin 80 mg/m^2 Q3W plus 5-FU 800 mg/m^2/day IV infusion on Days 1-5 Q3W. Capecitabine 1000 mg/m^2 BID on Days 1-14 Q3W could be substituted for 5-FU per local guidelines.

    Reporting group values
    		 Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + SOC Chemotherapy (Pembro Combo) Placebo + SOC Chemotherapy (SOC) Total
    Number of subjects
    		 256 257 250 763
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 154 152 139 445
        From 65-84 years
    		 102 105 108 315
        85 years and over
    		 0 0 3 3
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 59.9 ( 11.6 ) 60.9 ( 11.6 ) 60.7 ( 12.7 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 76 62 71 209
        Male
    		 180 195 179 554
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 9 7 13 29
        Asian
    		 69 71 67 207
        Native Hawaiian or Other Pacific Islander
    		 1 0 1 2
        Black or African American
    		 4 4 5 13
        White
    		 164 167 154 485
        More than one race
    		 9 6 7 22
        Unknown or Not Reported
    		 0 2 3 5
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 45 54 46 145
        Not Hispanic or Latino
    		 206 196 197 599
        Unknown or Not Reported
    		 5 7 7 19
    Region of Enrollment
    Participants were stratified according to geographic region of enrolling site: Europe (including Israel)/North America/Australia, Asia (including East Asia [South Korea, Hong Kong, Taiwan], South East Asia [Malaysia], Thailand, Singapore, Japan), or Rest of the World (including South America).
    Units: Subjects
        Europe/North America/Australia
    		 148 148 147 443
        Asia
    		 62 64 61 187
        Rest of the World
    		 46 45 42 133
    Disease Status
    Participants were stratified according to gastric cancer disease status as either locally advanced unresectable or metastatic disease.
    Units: Subjects
        Locally advanced
    		 10 12 13 35
        Metastatic
    		 245 243 235 723
        Missing
    		 1 2 2 5
    Fluoropyrimidine Treatment
    Participants receiving SOC chemotherapy were stratified according to fluoropyrimidine treatment (5-FU or capecitabine).
    Units: Subjects
        5-FU
    		 97 98 95 290
        Capecitabine
    		 159 159 155 473

    End points

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    End points reporting groups
    Reporting group title
    Pembrolizumab Monotherapy (Pembro Mono)
    Reporting group description
    		 Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W). Eligible participants who stopped the initial course of pembrolizumab with Stable Disease (SD) or better but progressed after discontinuation may have been able to initiate a second course of pembrolizumab for up to 17 cycles (up to approximately 1 additional year) at the investigator's discretion.

    Reporting group title
    Pembrolizumab + SOC Chemotherapy (Pembro Combo)
    Reporting group description
    		 Participants received pembrolizumab 200 mg Q3W plus cisplatin 80 mg/m^2 Q3W plus 5-fluorouracil (5-FU) 800 mg/m^2/day IV infusion on Days 1-5 Q3W. Capecitabine 1000 mg/m^2 twice a day (BID) on Days 1-14 Q3W could be substituted for 5-FU per local guidelines. Eligible participants who stopped the initial course of pembrolizumab with Stable Disease (SD) or better but progressed after discontinuation may have been able to initiate a second course of pembrolizumab for up to 17 cycles (up to approximately 1 additional year) at the investigator's discretion.

    Reporting group title
    Placebo + SOC Chemotherapy (SOC)
    Reporting group description
    		 Participants received placebo IV Q3W plus cisplatin 80 mg/m^2 Q3W plus 5-FU 800 mg/m^2/day IV infusion on Days 1-5 Q3W. Capecitabine 1000 mg/m^2 BID on Days 1-14 Q3W could be substituted for 5-FU per local guidelines.

    Primary: Pembro Combo vs SOC: Progression Free Survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by Blinded Independent Central Review (BICR) in Participants With PD-L1 CPS ≥1 (All Participants)

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    End point title
    		 Pembro Combo vs SOC: Progression Free Survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by Blinded Independent Central Review (BICR) in Participants With PD-L1 CPS ≥1 (All Participants)
    End point description
    PFS was defined as the time from randomization to the first documented progressive disease (PD) per RECIST 1.1 based on BICR, 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. Per protocol, PFS in the pembro combo arm was compared to the SOC arm as a pre-specified primary analysis of the Intent-To-Treat (ITT) population. PFS is reported here for all participants in the pembro combo arm and SOC arm who were PD-L1 CPS ≥1 (all participants). Per protocol, PFS was compared separately between CPS ≥1 participants of the pembro mono arm and SOC arm and is presented later in the record. All CPS ≥1 participants in the ITT population randomized to the pembro combo arm and SOC arm were analyzed.
    End point type
    Primary
    End point timeframe
    Up to approximately 36 months
    End point values
    		 Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + SOC Chemotherapy (Pembro Combo) Placebo + SOC Chemotherapy (SOC)
    Number of subjects analysed
    0 [1]
    257
    250
    Units: Months
        median (confidence interval 95%)
    ( to )
    6.9 (5.7 to 7.3)
    6.4 (5.7 to 7.0)
    Notes
    [1] - The pembro mono arm was compared to the SOC arm separately and not included in this analysis.
    Statistical analysis title
    		 PFS: Pembro Combo vs SOC, CPS ≥1
    Statistical analysis description
    PFS in CPS ≥1 participants of the pembro combo arm was compared to PFS in CPS ≥1 participants of the SOC arm to address the first primary hypothesis (superiority to SOC). The comparison was based on a Cox regression model with Efron’s method of tie handling with treatment as a covariate with stratification according to geographic region, disease status, and fluoropyrimidine treatment.
    Comparison groups
    Pembrolizumab + SOC Chemotherapy (Pembro Combo) v Placebo + SOC Chemotherapy (SOC)
    Number of subjects included in analysis
    507
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.03918 [2]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 1.02
    Notes
    [2] - One-sided p-value based on log-rank test with stratification.

    Primary: Pembro Combo vs SOC: Overall Survival (OS) in Participants With PD-L1 CPS ≥1 (All Participants)

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    End point title
    		 Pembro Combo vs SOC: Overall Survival (OS) in Participants With PD-L1 CPS ≥1 (All Participants)
    End point description
    OS 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 in the pembro combo arm was compared to the SOC arm as a pre-specified primary analysis of the ITT population. OS is reported here for all participants in the pembro combo arm and SOC arm who were PD-L1 CPS ≥1 (all participants). Per protocol, OS was compared separately between CPS ≥1 participants of the pembro mono arm and SOC arm and is presented later in the record. All CPS ≥1 participants in the ITT population randomized to the pembro combo arm and SOC arm were analyzed.
    End point type
    Primary
    End point timeframe
    Up to approximately 42 months
    End point values
    		 Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + SOC Chemotherapy (Pembro Combo) Placebo + SOC Chemotherapy (SOC)
    Number of subjects analysed
    0 [3]
    257
    250
    Units: Months
        median (confidence interval 95%)
    ( to )
    12.5 (10.8 to 13.9)
    11.1 (9.2 to 12.8)
    Notes
    [3] - The pembro mono arm was compared to the SOC arm separately and not included in this analysis.
    Statistical analysis title
    		 OS: Pembro Combo vs SOC, CPS ≥1
    Statistical analysis description
    OS in CPS ≥1 participants of the pembro combo arm was compared to OS in CPS ≥1 participants of the SOC arm to address the second primary hypothesis (superiority to SOC). The comparison was based on a Cox regression model with Efron’s method of tie handling with treatment as a covariate with stratification according to geographic region, disease status, and Fluoropyrimidine treatment.
    Comparison groups
    Pembrolizumab + SOC Chemotherapy (Pembro Combo) v Placebo + SOC Chemotherapy (SOC)
    Number of subjects included in analysis
    507
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.04611 [4]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 1.03
    Notes
    [4] - One-sided p-value based on log-rank test with stratification.

    Primary: Pembro Combo vs SOC: OS in Participants With PD-L1 CPS ≥10

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    End point title
    		 Pembro Combo vs SOC: OS in Participants With PD-L1 CPS ≥10
    End point description
    OS 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 in the pembro combo arm was compared to the SOC arm as a pre-specified primary analysis of the ITT population. OS is reported here for all participants in the pembro combo arm and SOC arm who were PD-L1 CPS ≥10. Per protocol, OS was compared separately between CPS ≥10 participants of the pembro mono arm and SOC arm and is presented later in the record. All CPS ≥10 participants in the ITT population randomized to the pembro combo arm and SOC arm were analyzed.
    End point type
    Primary
    End point timeframe
    Up to approximately 42 months
    End point values
    		 Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + SOC Chemotherapy (Pembro Combo) Placebo + SOC Chemotherapy (SOC)
    Number of subjects analysed
    0 [5]
    99
    90
    Units: Months
        median (confidence interval 95%)
    ( to )
    12.3 (9.5 to 14.8)
    10.8 (8.5 to 13.8)
    Notes
    [5] - The pembro mono arm was compared to the SOC arm separately and not included in this analysis.
    Statistical analysis title
    		 OS: Pembro Combo vs SOC, CPS ≥10
    Statistical analysis description
    OS in CPS ≥10 participants of the pembro combo arm was compared to OS in CPS ≥10 participants of the SOC arm to address the third primary hypothesis (superiority to SOC). The comparison was based on a Cox regression model with Efron’s method of tie handling with treatment as a covariate with stratification according to geographic region, disease status, and Fluoropyrimidine treatment.
    Comparison groups
    Pembrolizumab + SOC Chemotherapy (Pembro Combo) v Placebo + SOC Chemotherapy (SOC)
    Number of subjects included in analysis
    189
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.15804 [6]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.62
         upper limit
    		 1.17
    Notes
    [6] - One-sided p-value based on log-rank test with stratification.

    Primary: Pembro Mono vs SOC: OS in Participants With PD-L1 CPS ≥1 (All Participants)

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    End point title
    		 Pembro Mono vs SOC: OS in Participants With PD-L1 CPS ≥1 (All Participants)
    End point description
    OS 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 in the pembro mono arm was compared to the SOC arm as a pre-specified primary analysis of the ITT population. OS is reported here for all participants in the pembro mono arm and SOC arm who were PD-L1 CPS ≥1 (all participants). Per protocol, OS was compared separately between CPS ≥1 participants of the pembro combo arm and SOC arm and is presented earlier in the record. All CPS ≥1 participants in the ITT population randomized to the pembro mono arm and SOC arm were analyzed.
    End point type
    Primary
    End point timeframe
    Up to approximately 42 months
    End point values
    		 Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + SOC Chemotherapy (Pembro Combo) Placebo + SOC Chemotherapy (SOC)
    Number of subjects analysed
    256
    0 [7]
    250
    Units: Months
        median (confidence interval 95%)
    10.6 (7.7 to 13.8)
    ( to )
    11.1 (9.2 to 12.8)
    Notes
    [7] - The pembro combo arm was compared to the SOC arm separately and not included in this analysis.
    Statistical analysis title
    		 OS non-inferiority: Pembro Mono vs SOC, CPS ≥1
    Statistical analysis description
    OS in CPS ≥1 participants of the pembro mono arm was compared to OS in CPS ≥1 participants of the SOC arm to address the fourth primary hypothesis (non-inferiority to SOC). The comparison was based on a Cox regression model with Efron’s method of tie handling with treatment as a covariate with stratification according to geographic region, disease status, and Fluoropyrimidine treatment.
    Comparison groups
    Pembrolizumab Monotherapy (Pembro Mono) v Placebo + SOC Chemotherapy (SOC)
    Number of subjects included in analysis
    506
    Analysis specification
    Pre-specified
    Analysis type
    		 [8]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.91
    Confidence interval
         level
    		 99.2%
         sides
    2-sided
         lower limit
    		 0.69
         upper limit
    		 1.18
    Notes
    [8] - Pre-specified non-inferiority margin: if the upper bound of the confidence interval (based on the alpha level allocated to the analysis) for the hazard ratio ([HR], pembro mono arm vs SOC) is < 1.2, the pembro mono arm could be considered as non-inferior to the SOC arm in terms of OS.
    Statistical analysis title
    		 OS superiority: Pembro Mono vs SOC, CPS ≥1
    Statistical analysis description
    OS in CPS ≥1 participants of the pembro mono arm was compared to OS in CPS ≥1 participants of the SOC arm to address the fifth primary hypothesis (superiority to SOC). The comparison was based on a Cox regression model with Efron’s method of tie handling with treatment as a covariate with stratification according to geographic region, disease status, and Fluoropyrimidine treatment.
    Comparison groups
    Pembrolizumab Monotherapy (Pembro Mono) v Placebo + SOC Chemotherapy (SOC)
    Number of subjects included in analysis
    506
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.16205 [9]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.74
         upper limit
    		 1.1
    Notes
    [9] - One-sided p-value based on log-rank test with stratification.

    Primary: Pembro Mono vs SOC: OS in Participants With PD-L1 CPS ≥10

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    End point title
    		 Pembro Mono vs SOC: OS in Participants With PD-L1 CPS ≥10
    End point description
    OS 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 in the pembro mono arm was compared to the SOC arm as a pre-specified primary analysis of the ITT population. OS is reported here for all participants in the pembro mono arm and SOC arm who were PD-L1 CPS ≥10. Per protocol, OS was compared separately between CPS ≥10 participants of the pembro combo arm and SOC arm and is presented earlier in the record. All CPS ≥10 participants in the ITT population randomized to the pembro mono arm and SOC arm were analyzed.
    End point type
    Primary
    End point timeframe
    Up to approximately 42 months
    End point values
    		 Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + SOC Chemotherapy (Pembro Combo) Placebo + SOC Chemotherapy (SOC)
    Number of subjects analysed
    92
    0 [10]
    90
    Units: Months
        median (confidence interval 95%)
    17.4 (9.1 to 23.1)
    ( to )
    10.8 (8.5 to 13.8)
    Notes
    [10] - The pembro combo arm was compared to the SOC arm separately and not included in this analysis.
    Statistical analysis title
    		 OS: Pembro Mono vs SOC, CPS ≥10
    Statistical analysis description
    OS in CPS ≥10 participants of the pembro mono arm was compared to OS in CPS ≥10 participants of the SOC arm to address the sixth primary hypothesis (superiority to SOC). The comparison was based on a Cox regression model with Efron’s method of tie handling with treatment as a covariate with stratification according to geographic region, disease status, and Fluoropyrimidine treatment.
    Comparison groups
    Pembrolizumab Monotherapy (Pembro Mono) v Placebo + SOC Chemotherapy (SOC)
    Number of subjects included in analysis
    182
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.01491 [11]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.69
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.49
         upper limit
    		 0.97
    Notes
    [11] - One-sided p-value based on log-rank test with stratification.

    Secondary: Pembro Combo vs SOC: Objective Response Rate (ORR) per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥1 (All Participants)

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    End point title
    		 Pembro Combo vs SOC: Objective Response Rate (ORR) per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥1 (All Participants)
    End point description
    ORR was defined as the percentage of participants in the analysis population who have a Complete Response (CR: disappearance of all target lesions) or a Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions) per RECIST 1.1. based upon BICR. Per protocol, ORR in the pembro combo arm was compared to the SOC arm as a pre-specified secondary analysis of the ITT population. The percentage of participants who experienced CR or PR is reported here as the ORR for all participants in the pembro combo arm and SOC arm who were PD-L1 CPS ≥1 (all participants). Per protocol, ORR was compared separately between CPS ≥1 participants of the pembro mono arm and SOC arm and is presented later in the record. All CPS ≥1 participants in the ITT population randomized to the pembro combo arm and SOC arm were analyzed.
    End point type
    Secondary
    End point timeframe
    Up to approximately 42 months
    End point values
    		 Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + SOC Chemotherapy (Pembro Combo) Placebo + SOC Chemotherapy (SOC)
    Number of subjects analysed
    0 [12]
    257
    250
    Units: Percentage of Participants
        number (confidence interval 95%)
    ( to )
    48.6 (42.4 to 54.9)
    37.2 (31.2 to 43.5)
    Notes
    [12] - The pembro mono arm was compared to the SOC arm separately and not included in this analysis.
    Statistical analysis title
    		 ORR: Pembro Combo vs SOC, CPS ≥1
    Statistical analysis description
    ORR in CPS ≥1 participants of the pembro combo arm was compared to ORR in CPS ≥1 participants of the SOC arm based on Miettinen & Nurminen method stratified by geographic region, disease status, and Fluoropyrimidine treatment.
    Comparison groups
    Pembrolizumab + SOC Chemotherapy (Pembro Combo) v Placebo + SOC Chemotherapy (SOC)
    Number of subjects included in analysis
    507
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.00447 [13]
    Method
    		 Miettinen & Nurminen method
    Parameter type
    		 Difference in ORR Percentage
    Point estimate
    11.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.9
         upper limit
    		 20
    Notes
    [13] - No formal hypothesis testing performed; nominal p-value provided for treatment comparison.

    Secondary: Pembro Mono vs SOC: DOR per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥1 (All Participants)

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    End point title
    		 Pembro Mono vs SOC: DOR per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥1 (All Participants)
    End point description
    DOR was defined as the time from first documented evidence of confirmed CR or PR until PD or death, 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. All CPS ≥1 participants in the ITT population randomized to the pembro mono arm and SOC arm and who demonstrated a confirmed CR or PR were analyzed. Values of 9999 indicate that the median DOR and DOR range lower and upper limits were not reached (no progressive disease by time of last disease assessment). Per protocol, DOR was compared separately between CPS ≥1 responders of the pembro combo arm and SOC arm and is presented earlier in the record.
    End point type
    Secondary
    End point timeframe
    Up to approximately 42 months
    End point values
    		 Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + SOC Chemotherapy (Pembro Combo) Placebo + SOC Chemotherapy (SOC)
    Number of subjects analysed
    38
    0 [14]
    93
    Units: Months
        median (full range (min-max))
    9999 (9999 to 9999)
    ( to )
    9999 (9999 to 9999)
    Notes
    [14] - The pembro combo arm was compared to the SOC arm separately and not included in this analysis.
    No statistical analyses for this end point

    Secondary: Pembro Combo vs SOC: Duration of Response (DOR) per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥1 (All Participants)

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    End point title
    		 Pembro Combo vs SOC: Duration of Response (DOR) per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥1 (All Participants)
    End point description
    DOR was defined as the time from first documented evidence of confirmed CR or PR until PD or death, 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. All CPS ≥1 participants in the ITT population randomized to the pembro combo arm and SOC arm and who demonstrated a confirmed CR or PR were analyzed. Values of 9999 indicate that the median DOR and DOR range lower and upper limits were not reached (no progressive disease by time of last disease assessment). Per protocol, DOR was compared separately between CPS ≥1 responders of the pembro mono arm and SOC arm and is presented later in the record.
    End point type
    Secondary
    End point timeframe
    Up to approximately 42 months
    End point values
    		 Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + SOC Chemotherapy (Pembro Combo) Placebo + SOC Chemotherapy (SOC)
    Number of subjects analysed
    0 [15]
    125
    93
    Units: Months
        median (full range (min-max))
    ( to )
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    Notes
    [15] - The pembro mono arm was compared to the SOC arm separately and not included in this analysis.
    No statistical analyses for this end point

    Secondary: Pembro Mono vs SOC: ORR per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥1 (All Participants)

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    End point title
    		 Pembro Mono vs SOC: ORR per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥1 (All Participants)
    End point description
    ORR was defined as the percentage of participants in the analysis population who have a CR (disappearance of all target lesions) or PR (≥30% decrease in the sum of diameters of target lesions) per RECIST 1.1. based upon BICR. Per protocol, ORR in the pembro mono arm was compared to the SOC arm as a pre-specified secondary analysis of the ITT population. The percentage of participants who experienced CR or PR is reported here as the ORR for all participants in the pembro mono arm and SOC arm who were PD-L1 CPS ≥1 (all participants). Per protocol, ORR was compared separately between CPS ≥1 participants of the pembro combo arm and SOC arm and is presented earlier in the record. All CPS ≥1 participants in the ITT population randomized to the pembro mono arm and SOC arm were analyzed.
    End point type
    Secondary
    End point timeframe
    Up to approximately 42 months
    End point values
    		 Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + SOC Chemotherapy (Pembro Combo) Placebo + SOC Chemotherapy (SOC)
    Number of subjects analysed
    256
    0 [16]
    250
    Units: Percentage of Participants
        number (confidence interval 95%)
    14.8 (10.7 to 19.8)
    ( to )
    37.2 (31.2 to 43.5)
    Notes
    [16] - The pembro combo arm was compared to the SOC arm separately and not included in this analysis.
    Statistical analysis title
    		 ORR: Pembro Mono vs SOC, CPS ≥1
    Statistical analysis description
    ORR in CPS ≥1 participants of the pembro mono arm was compared to ORR in CPS ≥1 participants of the SOC arm based on Miettinen & Nurminen method stratified by geographic region, disease status, and Fluoropyrimidine treatment.
    Comparison groups
    Pembrolizumab Monotherapy (Pembro Mono) v Placebo + SOC Chemotherapy (SOC)
    Number of subjects included in analysis
    506
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 > 0.99999 [17]
    Method
    		 Miettinen & Nurminen method
    Parameter type
    		 Difference in ORR Percentage
    Point estimate
    -22.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -29.6
         upper limit
    		 -14.9
    Notes
    [17] - No formal hypothesis testing performed; nominal p-value provided for treatment comparison.

    Secondary: Pembro Mono vs SOC: PFS per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥1 (All Participants)

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    End point title
    		 Pembro Mono vs SOC: PFS per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥1 (All Participants)
    End point description
    PFS was defined as the time from randomization to the first documented PD per RECIST 1.1 based on BICR, 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. Per protocol, PFS in the pembro mono arm was compared to the SOC arm as a pre-specified secondary analysis of the ITT population. PFS is reported here for all participants in the pembro mono arm and SOC arm who were PD-L1 CPS ≥1 (all participants). Per protocol, PFS was compared separately between CPS ≥1 participants of the pembro combo arm and SOC arm and is presented earlier in the record. All CPS ≥1 participants in the ITT population randomized to the pembro mono arm and SOC arm were analyzed.
    End point type
    Secondary
    End point timeframe
    Up to approximately 42 months
    End point values
    		 Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + SOC Chemotherapy (Pembro Combo) Placebo + SOC Chemotherapy (SOC)
    Number of subjects analysed
    256
    0 [18]
    250
    Units: Months
        median (confidence interval 95%)
    2.0 (1.5 to 2.8)
    ( to )
    6.4 (5.7 to 7.1)
    Notes
    [18] - The pembro combo arm was compared to the SOC arm separately and not included in this analysis.
    Statistical analysis title
    		 ORR: Pembro Mono vs SOC, CPS ≥1
    Statistical analysis description
    PFS in CPS ≥1 participants of the pembro mono arm was compared to PFS in CPS ≥1 participants of the SOC arm based on a Cox regression model with Efron’s method of tie handling with treatment as a covariate with stratification according to geographic region, disease status, and fluoropyrimidine treatment.
    Comparison groups
    Pembrolizumab Monotherapy (Pembro Mono) v Placebo + SOC Chemotherapy (SOC)
    Number of subjects included in analysis
    506
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 1 [19]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.36
         upper limit
    		 1.98
    Notes
    [19] - No formal hypothesis testing performed; nominal p-value provided for treatment comparison.

    Secondary: Pembro Mono vs SOC: Change from Baseline to Week 18 in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status/Quality of Life (Items 29 and 30) Combined Score

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    End point title
    		 Pembro Mono vs SOC: Change from Baseline to Week 18 in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status/Quality of Life (Items 29 and 30) Combined Score
    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. Participants in the pembro mono arm and SOC arm who received ≥1 dose of study drug and who had EORTC-QLQ-C30 assessments available at baseline or post-baseline up to Week 18 were analyzed. Per protocol, change from baseline to Week 18 in the GHS/QoL combined score was compared separately between all participants of the pembro combo arm and SOC arm and is presented later in the record.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 18
    End point values
    		 Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + SOC Chemotherapy (Pembro Combo) Placebo + SOC Chemotherapy (SOC)
    Number of subjects analysed
    251
    0 [20]
    243
    Units: Score on a Scale
        least squares mean (confidence interval 95%)
    -1.91 (-5.81 to 1.98)
    ( to )
    -1.75 (-5.17 to 1.66)
    Notes
    [20] - The pembro combo arm was compared to the SOC arm separately and not included in this analysis.
    Statistical analysis title
    		 EORTC-QLQ-C30 GHS/QoL: Pembro Mono vs SOC
    Statistical analysis description
    Change from baseline to Week 18 in EORTC-QLQ-C30 GHS/QoL combined score was compared between all participants of the pembro mono arm and the SOC arm. Comparison based on constrained longitudinal data analysis (cLDA) model with GHS/QoL score as response variable and treatment by visit interaction and stratification factors (geographic region, disease status, and fluoropyrimidine treatment) as covariates.
    Comparison groups
    Pembrolizumab Monotherapy (Pembro Mono) v Placebo + SOC Chemotherapy (SOC)
    Number of subjects included in analysis
    494
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.948 [21]
    Method
    		 cLDA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.01
         upper limit
    		 4.69
    Notes
    [21] - No formal hypothesis testing performed; nominal p-value provided for treatment comparison.

    Secondary: Pembro Combo vs SOC: Change from Baseline to Week 18 in the EORTC QLQ-C30 Global Health Status/Quality of Life (Items 29 and 30) Combined Score

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    End point title
    		 Pembro Combo vs SOC: Change from Baseline to Week 18 in the EORTC QLQ-C30 Global Health Status/Quality of Life (Items 29 and 30) Combined Score
    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 GHS question "How would you rate your overall health during the past week?" (Item 29) and the 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. Participants in the pembro combo arm and SOC arm who received ≥1 dose of study drug and who had EORTC-QLQ-C30 assessments available at baseline or post-baseline up to Week 18 were analyzed. Per protocol, change from baseline to Week 18 in the GHS/QoL combined score was compared separately between all participants of the pembro mono arm and SOC arm and is presented earlier in the record.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 18
    End point values
    		 Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + SOC Chemotherapy (Pembro Combo) Placebo + SOC Chemotherapy (SOC)
    Number of subjects analysed
    0 [22]
    245
    243
    Units: Score on a Scale
        least squares mean (confidence interval 95%)
    ( to )
    -0.09 (-3.36 to 3.19)
    -2.07 (-5.43 to 1.29)
    Notes
    [22] - The pembro mono arm was compared to the SOC arm separately and not included in this analysis.
    Statistical analysis title
    		 EORTC-QLQ-C30 GHS/QoL: Pembro Combo vs SOC
    Statistical analysis description
    Change from baseline to Week 18 in EORTC-QLQ-C30 GHS/QoL combined score was compared between all participants of the pembro combo arm and the SOC arm. Comparison based on cLDA model with GHS/QoL score as response variable and treatment by visit interaction and stratification factors (geographic region, disease status, and fluoropyrimidine treatment) as covariates.
    Comparison groups
    Pembrolizumab + SOC Chemotherapy (Pembro Combo) v Placebo + SOC Chemotherapy (SOC)
    Number of subjects included in analysis
    488
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.368 [23]
    Method
    		 cLDA
    Parameter type
    		 Difference in LS Means
    Point estimate
    1.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.34
         upper limit
    		 6.31
    Notes
    [23] - No formal hypothesis testing performed; nominal p-value provided for treatment comparison.

    Secondary: Pembro Mono vs. SOC: Change from Baseline to Week 18 in EORTC QLQ-Module for Gastric Cancer (STO22) Pain Symptom Subscale Score

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    End point title
    		 Pembro Mono vs. SOC: Change from Baseline to Week 18 in EORTC QLQ-Module for Gastric Cancer (STO22) Pain Symptom Subscale Score
    End point description
    EORTC-QLQ-STO22 is a 22-item questionnaire developed to assess QoL of gastric cancer participants. It consists of 5 multi-item subscales that assess dysphagia (3 items), dietary restriction (4 items), pain (4 items), upper gastro-esophageal symptoms (3 items), and emotional problems (3 items), and questions on dry mouth, taste, body image, and hair loss. Participant responses to the Pain symptom subscale (Items 34-37) were scored on a 4-point scale (1=Not at all to 4=Very much). Raw scores were standardized by linear transformation so that scores ranged from 0 to 100, with a higher score indicating more problems. Participants in the pembro mono arm and SOC arm who received ≥1 dose of study drug and who had EORTC-QLQ-STO22 assessments available at baseline or post-baseline up to Week 18 were analyzed. Per protocol, change from baseline to Week 18 in the EORTC-QLQ-STO22 Pain score was compared separately between the pembro combo arm and SOC arm and is presented later in the record.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 18
    End point values
    		 Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + SOC Chemotherapy (Pembro Combo) Placebo + SOC Chemotherapy (SOC)
    Number of subjects analysed
    251
    0 [24]
    243
    Units: Score on a Scale
        least squares mean (confidence interval 95%)
    -1.14 (-4.67 to 2.39)
    ( to )
    -3.49 (-6.60 to -0.38)
    Notes
    [24] - The pembro combo arm was compared to the SOC arm separately and not included in this analysis.
    Statistical analysis title
    		 EORTC-QLQ-STO22: Pembro Mono vs SOC
    Statistical analysis description
    Change from baseline to Week 18 in EORTC-QLQ-STO22 Pain symptom subscale score was compared between all participants of the pembro mono arm and the SOC arm. Comparison based on cLDA model with GHS/QoL score as response variable and treatment by visit interaction and stratification factors (geographic region, disease status, and fluoropyrimidine treatment) as covariates.
    Comparison groups
    Pembrolizumab Monotherapy (Pembro Mono) v Placebo + SOC Chemotherapy (SOC)
    Number of subjects included in analysis
    494
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.308 [25]
    Method
    		 cLDA
    Parameter type
    		 Difference in LS Means
    Point estimate
    2.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.18
         upper limit
    		 6.89
    Notes
    [25] - No formal hypothesis testing performed; nominal p-value provided for treatment comparison.

    Secondary: Pembro Combo vs. SOC: Change from Baseline to Week 18 in EORTC QLQ-STO22 Pain Symptom Subscale Score

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    End point title
    		 Pembro Combo vs. SOC: Change from Baseline to Week 18 in EORTC QLQ-STO22 Pain Symptom Subscale Score
    End point description
    EORTC-QLQ-STO22 is a 22-item questionnaire developed to assess QoL of gastric cancer participants. It consists of 5 multi-item subscales that assess dysphagia (3 items), dietary restriction (4 items), pain (4 items), upper gastro-esophageal symptoms (3 items), and emotional problems (3 items), and questions on dry mouth, taste, body image, and hair loss. Participant responses to the Pain symptom subscale (Items 34-37) were scored on a 4-point scale (1=Not at all to 4=Very much). Raw scores were standardized by linear transformation so that scores ranged from 0 to 100, with a higher score indicating more problems. Participants in the pembro combo arm and SOC arm who received ≥1 dose of study drug and who had EORTC-QLQ-STO22 assessments available at baseline or post-baseline up to Week 18 were analyzed. Per protocol, change from baseline to Week 18 in the EORTC-QLQ-STO22 Pain score was compared separately between the pembro mono arm and SOC arm and is presented earlier in the record.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 18
    End point values
    		 Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + SOC Chemotherapy (Pembro Combo) Placebo + SOC Chemotherapy (SOC)
    Number of subjects analysed
    0 [26]
    245
    243
    Units: Score on a Scale
        least squares mean (confidence interval 95%)
    ( to )
    -10.12 (-13.08 to -7.17)
    -3.56 (-6.61 to -0.51)
    Notes
    [26] - The pembro mono arm was compared to the SOC arm separately and not included in this analysis.
    Statistical analysis title
    		 EORTC-QLQ-STO22: Pembro Combo vs SOC
    Statistical analysis description
    Change from baseline to Week 18 in EORTC-QLQ-STO22 Pain symptom subscale score was compared between all participants of the pembro combo arm and the SOC arm. Comparison based on cLDA model with GHS/QoL score as response variable and treatment by visit interaction and stratification factors (geographic region, disease status, and fluoropyrimidine treatment) as covariates.
    Comparison groups
    Pembrolizumab + SOC Chemotherapy (Pembro Combo) v Placebo + SOC Chemotherapy (SOC)
    Number of subjects included in analysis
    488
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.001 [27]
    Method
    		 cLDA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -6.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.55
         upper limit
    		 -2.58
    Notes
    [27] - No formal hypothesis testing performed; nominal p-value provided for treatment comparison.

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

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    End point title
    		 Number of Participants Experiencing 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 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 adverse event. The number of participants who experienced an AE was reported for each arm according to the treatment received. All randomized participants who received at least 1 dose of trial treatment were analyzed.
    End point type
    Secondary
    End point timeframe
    Up to approximately 33 months
    End point values
    		 Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + SOC Chemotherapy (Pembro Combo) Placebo + SOC Chemotherapy (SOC)
    Number of subjects analysed
    254
    250
    244
    Units: Participants
    242
    244
    240
    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 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 adverse event. The number of participants who discontinued study treatment due to an AE was reported for each arm according to the treatment received. All randomized participants who received at least 1 dose of trial treatment were analyzed.
    End point type
    Secondary
    End point timeframe
    Up to approximately 30 months
    End point values
    		 Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + SOC Chemotherapy (Pembro Combo) Placebo + SOC Chemotherapy (SOC)
    Number of subjects analysed
    254
    250
    244
    Units: Participants
    29
    85
    58
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to approximately 78 months
    Adverse event reporting additional description
    All-Cause Mortality reported for all randomized participants. Serious AEs and Other AEs were reported for all randomized participants who received at least 1 dose of study treatment. Per protocol, MedDRA preferred terms "Neoplasm progression", "Malignant neoplasm progression" and "Disease progression" not related to study drug are excluded as AEs.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Pembrolizumab Monotherapy (Pembro Mono) First Course
    Reporting group description
    		 Participants received pembrolizumab 200 mg IV Q3W.

    Reporting group title
    Pembrolizumab + SOC Chemotherapy (Pembro Combo)-First Course
    Reporting group description
    		 Participants received pembrolizumab 200 mg Q3W plus cisplatin 80 mg/m^2 Q3W plus 5-FU 800 mg/m^2/day IV infusion on Days 1-5 Q3W. Capecitabine 1000 mg/m^2 twice a day (BID) on Days 1-14 Q3W could be substituted for 5-FU per local guidelines.

    Reporting group title
    Pembrolizumab + SOC Chemotherapy-Second Course
    Reporting group description
    		 Eligible participants who stopped the initial course of pembrolizumab (200 mg IV Q3W for up to 35 treatments [approximately 2 years]) administered in combination with SOC chemotherapy, and experienced Stable Disease (SD) or better but progressed after discontinuation initiated a second course of pembrolizumab at the investigator's discretion for up to 17 cycles (up to approximately 1 additional year).

    Reporting group title
    Pembrolizumab Monotherapy Second Course
    Reporting group description
    		 Eligible participants who stopped the initial course of pembrolizumab (200 mg IV Q3W for up to 35 treatments [approximately 2 years]) with Stable Disease (SD) or better but progressed after discontinuation initiated a second course of pembrolizumab at the investigator's discretion for up to 17 cycles (up to approximately 1 additional year).

    Reporting group title
    Placebo + SOC Chemotherapy (SOC)-First Course
    Reporting group description
    		 Participants received placebo IV Q3W plus cisplatin 80 mg/m^2 Q3W plus 5-FU 800 mg/m^2/day IV infusion on Days 1-5 Q3W. Capecitabine 1000 mg/m^2 BID on Days 1-14 Q3W could be substituted for 5-FU per local guidelines.

    Serious adverse events
    		 Pembrolizumab Monotherapy (Pembro Mono) First Course Pembrolizumab + SOC Chemotherapy (Pembro Combo)-First Course Pembrolizumab + SOC Chemotherapy-Second Course Pembrolizumab Monotherapy Second Course Placebo + SOC Chemotherapy (SOC)-First Course
    Total subjects affected by serious adverse events
         subjects affected / exposed
    93 / 254 (36.61%)
    122 / 250 (48.80%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    117 / 244 (47.95%)
         number of deaths (all causes)
    229
    232
    1
    2
    240
         number of deaths resulting from adverse events
    3
    5
    0
    0
    3
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Uterine cancer
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oncologic complication
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal cancer
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    0 / 254 (0.00%)
    2 / 250 (0.80%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    1 / 254 (0.39%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 254 (0.39%)
    2 / 250 (0.80%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    3 / 244 (1.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 254 (0.39%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Superficial vein thrombosis
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 254 (0.00%)
    3 / 250 (1.20%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    2 / 244 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    2 / 254 (0.79%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    1 / 1
    Mucosal inflammation
         subjects affected / exposed
    0 / 254 (0.00%)
    2 / 250 (0.80%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    3 / 244 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    0 / 0
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 254 (0.39%)
    3 / 250 (1.20%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    6 / 254 (2.36%)
    3 / 250 (1.20%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 3
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 6
    0 / 3
    0 / 0
    0 / 0
    0 / 1
    Pain
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 254 (0.79%)
    5 / 250 (2.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    5 / 244 (2.05%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 5
    0 / 0
    0 / 0
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral swelling
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 254 (0.79%)
    8 / 250 (3.20%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    13 / 244 (5.33%)
         occurrences causally related to treatment / all
    1 / 2
    6 / 9
    0 / 0
    0 / 0
    9 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Pleural effusion
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    3 / 254 (1.18%)
    2 / 250 (0.80%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    3 / 3
    2 / 2
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Pneumothorax
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Respiratory failure
         subjects affected / exposed
    2 / 254 (0.79%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Completed suicide
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    2 / 244 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    Depression
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood calcium decreased
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood magnesium decreased
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Creatinine renal clearance decreased
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Lower limb fracture
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anastomotic stenosis
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural haemorrhage
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Extrasystoles
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 254 (0.39%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral thrombosis
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral venous sinus thrombosis
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness postural
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Embolic stroke
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 254 (0.39%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 254 (0.00%)
    2 / 250 (0.80%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    3 / 244 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    0 / 254 (0.00%)
    9 / 250 (3.60%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    7 / 244 (2.87%)
         occurrences causally related to treatment / all
    0 / 0
    8 / 9
    0 / 0
    0 / 0
    7 / 8
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    3 / 254 (1.18%)
    12 / 250 (4.80%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    10 / 244 (4.10%)
         occurrences causally related to treatment / all
    0 / 3
    11 / 14
    0 / 0
    0 / 0
    12 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 254 (0.00%)
    3 / 250 (1.20%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypochromic anaemia
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 254 (0.00%)
    2 / 250 (0.80%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    3 / 244 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo positional
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    1 / 254 (0.39%)
    6 / 250 (2.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    6 / 6
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 254 (0.39%)
    4 / 250 (1.60%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    2 / 244 (0.82%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain lower
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal distension
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 254 (0.39%)
    3 / 250 (1.20%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    2 / 244 (0.82%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal obstruction
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 254 (0.79%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    3 / 244 (1.23%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Gastric perforation
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    5 / 254 (1.97%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    2 / 254 (0.79%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    2 / 254 (0.79%)
    3 / 250 (1.20%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    5 / 244 (2.05%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 0
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 254 (0.39%)
    7 / 250 (2.80%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    9 / 244 (3.69%)
         occurrences causally related to treatment / all
    1 / 1
    6 / 7
    0 / 0
    0 / 0
    9 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    3 / 254 (1.18%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 254 (0.39%)
    2 / 250 (0.80%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 254 (0.00%)
    5 / 250 (2.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    5 / 244 (2.05%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 7
    0 / 0
    0 / 0
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophageal obstruction
         subjects affected / exposed
    0 / 254 (0.00%)
    2 / 250 (0.80%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Obstruction gastric
         subjects affected / exposed
    2 / 254 (0.79%)
    2 / 250 (0.80%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    3 / 244 (1.23%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Incarcerated hiatus hernia
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Intestinal perforation
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mechanical ileus
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 254 (1.18%)
    6 / 250 (2.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    12 / 244 (4.92%)
         occurrences causally related to treatment / all
    0 / 3
    3 / 7
    0 / 0
    0 / 0
    11 / 15
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    3 / 254 (1.18%)
    2 / 250 (0.80%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    2 / 244 (0.82%)
         occurrences causally related to treatment / all
    0 / 3
    2 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Stomatitis
         subjects affected / exposed
    0 / 254 (0.00%)
    2 / 250 (0.80%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    3 / 244 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    2 / 244 (0.82%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Salivary hypersecretion
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritoneocutaneous fistula
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Biliary obstruction
         subjects affected / exposed
    0 / 254 (0.00%)
    2 / 250 (0.80%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Autoimmune hepatitis
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholangitis acute
         subjects affected / exposed
    1 / 254 (0.39%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic cirrhosis
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune-mediated hepatitis
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertransaminasaemia
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Liver disorder
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Diabetic foot
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stevens-Johnson syndrome
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    4 / 254 (1.57%)
    8 / 250 (3.20%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    8 / 244 (3.28%)
         occurrences causally related to treatment / all
    0 / 4
    5 / 8
    0 / 0
    0 / 0
    5 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Autoimmune nephritis
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tubulointerstitial nephritis
         subjects affected / exposed
    2 / 254 (0.79%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prerenal failure
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 254 (0.39%)
    3 / 250 (1.20%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    2 / 244 (0.82%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 3
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal injury
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephritis
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Addison's disease
         subjects affected / exposed
    1 / 254 (0.39%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Adrenal insufficiency
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypothyroidism
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypophysitis
         subjects affected / exposed
    1 / 254 (0.39%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 254 (0.39%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    2 / 244 (0.82%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Compartment syndrome
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myositis
         subjects affected / exposed
    2 / 254 (0.79%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis perforated
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Amoebiasis
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal sepsis
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Biliary tract infection
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Candida sepsis
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis infectious
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    2 / 254 (0.79%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection bacterial
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningitis tuberculous
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophageal candidiasis
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oral candidiasis
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pharyngitis bacterial
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    5 / 254 (1.97%)
    7 / 250 (2.80%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    8 / 244 (3.28%)
         occurrences causally related to treatment / all
    0 / 5
    3 / 7
    0 / 0
    0 / 0
    1 / 10
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 3
    Pneumonia aspiration
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia klebsiella
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate infection
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    1 / 254 (0.39%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 254 (0.39%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    3 / 244 (1.23%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Sepsis
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    4 / 244 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 254 (0.00%)
    2 / 250 (0.80%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular device infection
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 254 (0.00%)
    2 / 250 (0.80%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    5 / 244 (2.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    2 / 254 (0.79%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    3 / 254 (1.18%)
    2 / 250 (0.80%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    5 / 244 (2.05%)
         occurrences causally related to treatment / all
    3 / 3
    2 / 2
    0 / 0
    0 / 0
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    0 / 254 (0.00%)
    2 / 250 (0.80%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 254 (0.39%)
    7 / 250 (2.80%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    7 / 244 (2.87%)
         occurrences causally related to treatment / all
    0 / 1
    6 / 8
    0 / 0
    0 / 0
    6 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 254 (0.39%)
    2 / 250 (0.80%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    3 / 244 (1.23%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
    0 / 0
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    0 / 254 (0.00%)
    3 / 250 (1.20%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    2 / 244 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    5 / 254 (1.97%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    2 / 244 (0.82%)
         occurrences causally related to treatment / all
    2 / 5
    1 / 1
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Refeeding syndrome
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Type 1 diabetes mellitus
         subjects affected / exposed
    1 / 254 (0.39%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 250 (0.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    2 / 244 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 244 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Pembrolizumab Monotherapy (Pembro Mono) First Course Pembrolizumab + SOC Chemotherapy (Pembro Combo)-First Course Pembrolizumab + SOC Chemotherapy-Second Course Pembrolizumab Monotherapy Second Course Placebo + SOC Chemotherapy (SOC)-First Course
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    216 / 254 (85.04%)
    239 / 250 (95.60%)
    5 / 5 (100.00%)
    3 / 4 (75.00%)
    234 / 244 (95.90%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    11 / 254 (4.33%)
    10 / 250 (4.00%)
    1 / 5 (20.00%)
    1 / 4 (25.00%)
    12 / 244 (4.92%)
         occurrences all number
    12
    13
    1
    2
    17
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    4 / 254 (1.57%)
    14 / 250 (5.60%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    7 / 244 (2.87%)
         occurrences all number
    6
    16
    0
    0
    7
    Fatigue
         subjects affected / exposed
    49 / 254 (19.29%)
    105 / 250 (42.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    75 / 244 (30.74%)
         occurrences all number
    63
    156
    0
    0
    112
    Mucosal inflammation
         subjects affected / exposed
    3 / 254 (1.18%)
    41 / 250 (16.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    34 / 244 (13.93%)
         occurrences all number
    5
    57
    0
    0
    62
    Oedema peripheral
         subjects affected / exposed
    13 / 254 (5.12%)
    16 / 250 (6.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    19 / 244 (7.79%)
         occurrences all number
    14
    16
    0
    0
    22
    Pyrexia
         subjects affected / exposed
    25 / 254 (9.84%)
    32 / 250 (12.80%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    25 / 244 (10.25%)
         occurrences all number
    33
    38
    0
    0
    26
    Asthenia
         subjects affected / exposed
    30 / 254 (11.81%)
    41 / 250 (16.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    47 / 244 (19.26%)
         occurrences all number
    33
    53
    0
    0
    81
    Respiratory, thoracic and mediastinal disorders
    Hiccups
         subjects affected / exposed
    1 / 254 (0.39%)
    16 / 250 (6.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    12 / 244 (4.92%)
         occurrences all number
    1
    20
    0
    0
    21
    Epistaxis
         subjects affected / exposed
    0 / 254 (0.00%)
    5 / 250 (2.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    10 / 244 (4.10%)
         occurrences all number
    0
    5
    1
    0
    12
    Dyspnoea
         subjects affected / exposed
    11 / 254 (4.33%)
    19 / 250 (7.60%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    9 / 244 (3.69%)
         occurrences all number
    16
    23
    0
    0
    11
    Dysphonia
         subjects affected / exposed
    3 / 254 (1.18%)
    1 / 250 (0.40%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    2 / 244 (0.82%)
         occurrences all number
    3
    1
    1
    0
    2
    Cough
         subjects affected / exposed
    19 / 254 (7.48%)
    24 / 250 (9.60%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    23 / 244 (9.43%)
         occurrences all number
    23
    26
    0
    0
    26
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    21 / 254 (8.27%)
    18 / 250 (7.20%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    22 / 244 (9.02%)
         occurrences all number
    21
    19
    1
    0
    24
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    8 / 254 (3.15%)
    30 / 250 (12.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    34 / 244 (13.93%)
         occurrences all number
    8
    52
    0
    0
    59
    Alanine aminotransferase increased
         subjects affected / exposed
    13 / 254 (5.12%)
    7 / 250 (2.80%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    9 / 244 (3.69%)
         occurrences all number
    16
    8
    0
    0
    9
    Aspartate aminotransferase increased
         subjects affected / exposed
    18 / 254 (7.09%)
    9 / 250 (3.60%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    11 / 244 (4.51%)
         occurrences all number
    22
    10
    0
    0
    12
    White blood cell count decreased
         subjects affected / exposed
    4 / 254 (1.57%)
    30 / 250 (12.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    25 / 244 (10.25%)
         occurrences all number
    6
    71
    0
    0
    52
    Weight decreased
         subjects affected / exposed
    28 / 254 (11.02%)
    54 / 250 (21.60%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    33 / 244 (13.52%)
         occurrences all number
    28
    63
    0
    0
    33
    Platelet count decreased
         subjects affected / exposed
    3 / 254 (1.18%)
    23 / 250 (9.20%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    17 / 244 (6.97%)
         occurrences all number
    3
    38
    0
    0
    21
    Neutrophil count decreased
         subjects affected / exposed
    4 / 254 (1.57%)
    59 / 250 (23.60%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    40 / 244 (16.39%)
         occurrences all number
    15
    120
    0
    0
    79
    Blood uric acid increased
         subjects affected / exposed
    2 / 254 (0.79%)
    0 / 250 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    1 / 244 (0.41%)
         occurrences all number
    2
    0
    0
    1
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    14 / 254 (5.51%)
    20 / 250 (8.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    15 / 244 (6.15%)
         occurrences all number
    18
    21
    0
    0
    22
    Headache
         subjects affected / exposed
    16 / 254 (6.30%)
    24 / 250 (9.60%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    16 / 244 (6.56%)
         occurrences all number
    18
    26
    0
    0
    22
    Neuropathy peripheral
         subjects affected / exposed
    0 / 254 (0.00%)
    31 / 250 (12.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    16 / 244 (6.56%)
         occurrences all number
    0
    36
    0
    0
    17
    Peripheral sensory neuropathy
         subjects affected / exposed
    3 / 254 (1.18%)
    34 / 250 (13.60%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    16 / 244 (6.56%)
         occurrences all number
    3
    37
    0
    0
    18
    Dysgeusia
         subjects affected / exposed
    4 / 254 (1.57%)
    16 / 250 (6.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    20 / 244 (8.20%)
         occurrences all number
    4
    18
    0
    0
    21
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    61 / 254 (24.02%)
    112 / 250 (44.80%)
    0 / 5 (0.00%)
    3 / 4 (75.00%)
    108 / 244 (44.26%)
         occurrences all number
    73
    150
    0
    3
    144
    Leukopenia
         subjects affected / exposed
    0 / 254 (0.00%)
    21 / 250 (8.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    26 / 244 (10.66%)
         occurrences all number
    0
    52
    0
    0
    51
    Neutropenia
         subjects affected / exposed
    1 / 254 (0.39%)
    95 / 250 (38.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    102 / 244 (41.80%)
         occurrences all number
    2
    201
    0
    0
    222
    Thrombocytopenia
         subjects affected / exposed
    2 / 254 (0.79%)
    27 / 250 (10.80%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    26 / 244 (10.66%)
         occurrences all number
    5
    38
    0
    0
    33
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    0 / 254 (0.00%)
    22 / 250 (8.80%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    20 / 244 (8.20%)
         occurrences all number
    0
    24
    0
    0
    20
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    13 / 254 (5.12%)
    9 / 250 (3.60%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    10 / 244 (4.10%)
         occurrences all number
    21
    11
    0
    0
    10
    Abdominal discomfort
         subjects affected / exposed
    2 / 254 (0.79%)
    6 / 250 (2.40%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    2 / 244 (0.82%)
         occurrences all number
    2
    7
    0
    1
    2
    Abdominal pain
         subjects affected / exposed
    46 / 254 (18.11%)
    41 / 250 (16.40%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    41 / 244 (16.80%)
         occurrences all number
    56
    49
    1
    0
    54
    Abdominal pain upper
         subjects affected / exposed
    23 / 254 (9.06%)
    24 / 250 (9.60%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    23 / 244 (9.43%)
         occurrences all number
    26
    27
    0
    0
    25
    Ascites
         subjects affected / exposed
    6 / 254 (2.36%)
    8 / 250 (3.20%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    14 / 244 (5.74%)
         occurrences all number
    7
    8
    0
    0
    15
    Constipation
         subjects affected / exposed
    36 / 254 (14.17%)
    71 / 250 (28.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    68 / 244 (27.87%)
         occurrences all number
    43
    108
    0
    0
    83
    Diarrhoea
         subjects affected / exposed
    35 / 254 (13.78%)
    83 / 250 (33.20%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    71 / 244 (29.10%)
         occurrences all number
    60
    153
    0
    0
    106
    Dyspepsia
         subjects affected / exposed
    16 / 254 (6.30%)
    13 / 250 (5.20%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    11 / 244 (4.51%)
         occurrences all number
    18
    18
    0
    0
    13
    Dysphagia
         subjects affected / exposed
    11 / 254 (4.33%)
    15 / 250 (6.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    16 / 244 (6.56%)
         occurrences all number
    11
    17
    0
    0
    20
    Gastrooesophageal reflux disease
         subjects affected / exposed
    8 / 254 (3.15%)
    6 / 250 (2.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    13 / 244 (5.33%)
         occurrences all number
    8
    7
    0
    0
    14
    Nausea
         subjects affected / exposed
    49 / 254 (19.29%)
    162 / 250 (64.80%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    129 / 244 (52.87%)
         occurrences all number
    59
    295
    0
    0
    236
    Stomatitis
         subjects affected / exposed
    5 / 254 (1.97%)
    33 / 250 (13.20%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    35 / 244 (14.34%)
         occurrences all number
    6
    49
    0
    0
    39
    Vomiting
         subjects affected / exposed
    49 / 254 (19.29%)
    84 / 250 (33.60%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    79 / 244 (32.38%)
         occurrences all number
    64
    148
    0
    0
    142
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    20 / 254 (7.87%)
    31 / 250 (12.40%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    15 / 244 (6.15%)
         occurrences all number
    23
    41
    1
    0
    18
    Pruritus
         subjects affected / exposed
    22 / 254 (8.66%)
    21 / 250 (8.40%)
    1 / 5 (20.00%)
    1 / 4 (25.00%)
    8 / 244 (3.28%)
         occurrences all number
    27
    25
    1
    1
    11
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    0 / 254 (0.00%)
    60 / 250 (24.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    46 / 244 (18.85%)
         occurrences all number
    0
    69
    0
    0
    57
    Dry skin
         subjects affected / exposed
    6 / 254 (2.36%)
    15 / 250 (6.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    15 / 244 (6.15%)
         occurrences all number
    6
    16
    0
    0
    15
    Alopecia
         subjects affected / exposed
    2 / 254 (0.79%)
    19 / 250 (7.60%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    11 / 244 (4.51%)
         occurrences all number
    2
    19
    0
    0
    11
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 254 (0.00%)
    3 / 250 (1.20%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    2 / 244 (0.82%)
         occurrences all number
    0
    3
    0
    1
    2
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    21 / 254 (8.27%)
    28 / 250 (11.20%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    10 / 244 (4.10%)
         occurrences all number
    21
    29
    0
    0
    11
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    19 / 254 (7.48%)
    22 / 250 (8.80%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    7 / 244 (2.87%)
         occurrences all number
    20
    25
    0
    0
    7
    Back pain
         subjects affected / exposed
    30 / 254 (11.81%)
    13 / 250 (5.20%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    14 / 244 (5.74%)
         occurrences all number
    32
    14
    0
    0
    15
    Pain in extremity
         subjects affected / exposed
    4 / 254 (1.57%)
    17 / 250 (6.80%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    8 / 244 (3.28%)
         occurrences all number
    4
    23
    0
    0
    9
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    8 / 254 (3.15%)
    13 / 250 (5.20%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    2 / 244 (0.82%)
         occurrences all number
    8
    13
    0
    0
    2
    Metabolism and nutrition disorders
    Hypomagnesaemia
         subjects affected / exposed
    3 / 254 (1.18%)
    34 / 250 (13.60%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    32 / 244 (13.11%)
         occurrences all number
    11
    43
    0
    0
    48
    Hyponatraemia
         subjects affected / exposed
    15 / 254 (5.91%)
    12 / 250 (4.80%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    20 / 244 (8.20%)
         occurrences all number
    16
    21
    0
    0
    26
    Hypophosphataemia
         subjects affected / exposed
    2 / 254 (0.79%)
    15 / 250 (6.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    9 / 244 (3.69%)
         occurrences all number
    2
    21
    0
    0
    16
    Hypokalaemia
         subjects affected / exposed
    11 / 254 (4.33%)
    35 / 250 (14.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    42 / 244 (17.21%)
         occurrences all number
    16
    49
    0
    0
    61
    Hypocalcaemia
         subjects affected / exposed
    9 / 254 (3.54%)
    14 / 250 (5.60%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    14 / 244 (5.74%)
         occurrences all number
    10
    20
    0
    0
    16
    Hypoalbuminaemia
         subjects affected / exposed
    18 / 254 (7.09%)
    17 / 250 (6.80%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    23 / 244 (9.43%)
         occurrences all number
    21
    21
    0
    0
    28
    Dehydration
         subjects affected / exposed
    7 / 254 (2.76%)
    11 / 250 (4.40%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    16 / 244 (6.56%)
         occurrences all number
    7
    14
    0
    0
    19
    Decreased appetite
         subjects affected / exposed
    48 / 254 (18.90%)
    94 / 250 (37.60%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    90 / 244 (36.89%)
         occurrences all number
    53
    135
    0
    0
    127

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Jul 2016
    Major changes of Amendment (AM) 3 include clarification of Inclusion and Exclusion Criteria and revision of Withdrawal/Discontinuation Criteria.
    06 Oct 2016
    Major changes of AM 5 include revision of Inclusion and Exclusion Criteria.
    08 Mar 2017
    Major changes of AM 6 include removing primary PFS hypothesis comparing pembrolizumab monotherapy to SOC, and adding primary OS hypothesis evaluating non-inferiority of pembrolizuman monotherapy. Secondary ORR hypothesis comparing pembrolizumab plus SOC vs. SOC was added.
    15 Jan 2018
    Major changes of AM 8 included revising dose modification language and adding survival status follow-up to the study.
    11 May 2018
    Major changes of AM 10 included the addition of 2 primary hypotheses for OS: pembrolizumab plus SOC vs. SOC, and pembrolizumab monotherapy vs. SOC in participants with CPS≥10.
    22 Jan 2019
    Major changes of AM 12 included revision of Prohibited Concomitant Medication language and safety follow-up language.
    02 Aug 2021
    Major changes of AM 14 included the revision of sections of the protocol including the Trial Summary and Study Diagram to include study extension language, and updating the Dose Modification and Toxicity Management Guidelines for immune response AEs per Food and Drug Administration request.

    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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