Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register   allows you to search for protocol and results information on:
  • interventional clinical trials that were approved in the European Union (EU)/European Economic Area (EEA) under the Clinical Trials Directive 2001/20/EC
  • clinical trials conducted outside the EU/EEA that are linked to European paediatric-medicine development

    • EU/EEA interventional clinical trials approved under or transitioned to the Clinical Trial Regulation 536/2014 are publicly accessible through the
    Clinical Trials Information System (CTIS).

    The EU Clinical Trials Register currently displays   43870   clinical trials with a EudraCT protocol, of which   7289   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

    Phase 1 trials conducted solely on adults and that are not part of an agreed paediatric investigation plan (PIP) are not publicly available (see Frequently Asked Questions ).  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    A Phase III Randomized, Controlled Clinical Trial of Pembrolizumab with or without Platinum-Based Combination Chemotherapy versus Chemotherapy in Subjects with Advanced or Metastatic Urothelial Carcinoma

    Summary
    EudraCT number
    		 2015-005731-41
    Trial protocol
    		 DE   HU   IE   ES   GB   BE   NL  
    Global end of trial date
    15 Sep 2022

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

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    3475-361
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02853305
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 JAPIC-CTI: 163458, Merck Protocol Number: MK-3475-361, Merck: KEYNOTE-361
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme LLC
    Sponsor organisation address
    126 East Lincoln Avenue, P.O. Box 2000, Rahway, NJ, United States Minor Outlying Islands, 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
    15 Sep 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Apr 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Sep 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is to determine the efficacy and safety of pembrolizumab (pembro, MK-3475) with or without chemotherapy versus chemotherapy alone in participants with advanced or metastatic urothelial carcinoma (bladder cancer). The primary hypotheses are that pembrolizumab plus chemotherapy is superior to chemotherapy alone with respect to Progression-free Survival (PFS) and Overall Survival (OS) in all participants, and that pembrolizumab alone is superior to chemotherapy alone with respect to OS in all participants and in participants with programmed cell death ligand 1 (PD-L1) positive tumors (Combined Positive Score [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
    15 Sep 2016
    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: 19
    Country: Number of subjects enrolled
    Belgium: 22
    Country: Number of subjects enrolled
    Brazil: 19
    Country: Number of subjects enrolled
    Canada: 55
    Country: Number of subjects enrolled
    Chile: 19
    Country: Number of subjects enrolled
    France: 115
    Country: Number of subjects enrolled
    Germany: 40
    Country: Number of subjects enrolled
    Hungary: 62
    Country: Number of subjects enrolled
    Ireland: 13
    Country: Number of subjects enrolled
    Israel: 58
    Country: Number of subjects enrolled
    Japan: 104
    Country: Number of subjects enrolled
    Korea, Republic of: 19
    Country: Number of subjects enrolled
    Netherlands: 22
    Country: Number of subjects enrolled
    Russian Federation: 53
    Country: Number of subjects enrolled
    South Africa: 10
    Country: Number of subjects enrolled
    Spain: 107
    Country: Number of subjects enrolled
    Taiwan: 34
    Country: Number of subjects enrolled
    Thailand: 16
    Country: Number of subjects enrolled
    Turkey: 73
    Country: Number of subjects enrolled
    United Kingdom: 45
    Country: Number of subjects enrolled
    United States: 105
    Worldwide total number of subjects
    1010
    EEA total number of subjects
    381
    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)
    346
    From 65 to 84 years
    645
    85 years and over
    19

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Participants with advanced or metastatic urothelial carcinoma were recruited to examine the efficacy and safety of pembrolizumab plus chemotherapy (pembro combo) versus pembrolizumab alone (pembro) or chemotherapy alone (chemo).

    Pre-assignment
    Screening details
    		 1,010 participants were randomized 1:1:1 to receive pembrolizumab plus chemotherapy, pembrolizumab alone, and chemotherapy alone. Per protocol, response/progression or adverse events (AEs) that occurred during the second course were 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
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Pembrolizumab + ST Chemotherapy (Pembro Combo)
    Arm description
    		 Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for a maximum of 35 doses PLUS standard therapy (ST) chemotherapy with EITHER cisplatin 70 mg/m^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle + gemcitabine IV infusion 1,000 mg/m^2 on Day 1 and Day 8 of each 3-week cycle, OR carboplatin at an area under the curve 5 (AUC 5) (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle + gemcitabine 1,000 mg/m^2 IV on Day 1 and Day 8 of each 3-week cycle. Eligible participants who stopped 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
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered 200 mg IV on Day 1 of each 3-week cycle for a maximum of 35 doses

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered 1,000 mg/m^2 IV on Day 1 and Day 8 of each 3-week cycle.

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered at an area under the curve 5 (AUC 5) (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle 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
    Administered 70 mg/m^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle

    Arm title
    		 Pembrolizumab (Pembro)
    Arm description
    		 Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for a maximum of 35 doses. Eligible participants who stopped pembrolizumab with 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
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered 200 mg IV on Day 1 of each 3-week cycle for a maximum of 35 doses

    Arm title
    		 ST Chemotherapy (Chemo)
    Arm description
    		 Participants received ST chemotherapy with EITHER cisplatin 70 mg/m^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine IV infusion 1,000 mg/m^2 on Day 1 and Day 8 of each 3-week cycle OR carboplatin at AUC 5 (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine 1,000 mg/m^2 IV on Day 1 and Day 8 of each 3-week cycle.
    Arm type
    		 Active comparator

    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
    Administered 70 mg/m^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered 1,000 mg/m^2 IV on Day 1 and Day 8 of each 3-week cycle.

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered at an area under the curve 5 (AUC 5) (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle 3-week cycle

    Number of subjects in period 1
    		Pembrolizumab + ST Chemotherapy (Pembro Combo) Pembrolizumab (Pembro) ST Chemotherapy (Chemo)
    Started
    351
    307
    352
    Received First Course of Pembrolizumab
    349
    302
    342
    Received Second Course of Pembrolizumab
    14
    15
    0
    Completed
    0
    0
    0
    Not completed
    351
    307
    352
         Adverse event, serious fatal
    287
    249
    300
         Consent withdrawn by subject
    2
    8
    3
         Transferred to Extension Study
    46
    30
    25
         Did Not Continue on Extension Study
    16
    20
    24

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Pembrolizumab + ST Chemotherapy (Pembro Combo)
    Reporting group description
    		 Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for a maximum of 35 doses PLUS standard therapy (ST) chemotherapy with EITHER cisplatin 70 mg/m^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle + gemcitabine IV infusion 1,000 mg/m^2 on Day 1 and Day 8 of each 3-week cycle, OR carboplatin at an area under the curve 5 (AUC 5) (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle + gemcitabine 1,000 mg/m^2 IV on Day 1 and Day 8 of each 3-week cycle. Eligible participants who stopped 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 (Pembro)
    Reporting group description
    		 Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for a maximum of 35 doses. Eligible participants who stopped pembrolizumab with 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
    ST Chemotherapy (Chemo)
    Reporting group description
    		 Participants received ST chemotherapy with EITHER cisplatin 70 mg/m^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine IV infusion 1,000 mg/m^2 on Day 1 and Day 8 of each 3-week cycle OR carboplatin at AUC 5 (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine 1,000 mg/m^2 IV on Day 1 and Day 8 of each 3-week cycle.

    Reporting group values
    		 Pembrolizumab + ST Chemotherapy (Pembro Combo) Pembrolizumab (Pembro) ST Chemotherapy (Chemo) Total
    Number of subjects
    		 351 307 352 1010
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 118 109 119 346
        From 65-84 years
    		 228 189 228 645
        85 years and over
    		 5 9 5 19
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 68.3 ± 9.2 67.0 ± 10.1 68.0 ± 9.6 -
    Sex: Female, Male
    Units:
        Female
    		 79 79 90 248
        Male
    		 272 228 262 762
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 1 0 1
        Asian
    		 64 47 70 181
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0
        Black or African American
    		 1 3 4 8
        White
    		 243 212 235 690
        More than one race
    		 1 2 1 4
        Unknown or Not Reported
    		 42 42 42 126
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 26 25 32 83
        Not Hispanic or Latino
    		 269 231 261 761
        Unknown or Not Reported
    		 56 51 59 166
    PD-L1 CPS Status-IVRS
    The Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) Status indicates tumor PD-L1 positivity using both tumor cells and inflammatory cells that are positive for PD-L1 by immunohistochemistry (IHC). Higher percentages of PD-L1 CPS staining corresponded to higher positivity of PD-L1 on a tumor. The number of participants with CPS <10% and CPS ≥10% at baseline randomization by Interactive Voice Response System (IVRS) is presented
    Units: Subjects
        PD-L1 CPS<10
    		 192 148 193 533
        PD-L1 CPS≥10
    		 159 159 159 477
    Investigator Choice of Cisplatin or Carboplatin - IVRS
    The Investigator’s choice of chemotherapy drug (cisplatin or carboplatin) at baseline randomization by IVRS is presented.
    Units: Subjects
        Cisplatin
    		 160 138 160 458
        Carboplatin
    		 191 169 192 552

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Pembrolizumab + ST Chemotherapy (Pembro Combo)
    Reporting group description
    		 Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for a maximum of 35 doses PLUS standard therapy (ST) chemotherapy with EITHER cisplatin 70 mg/m^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle + gemcitabine IV infusion 1,000 mg/m^2 on Day 1 and Day 8 of each 3-week cycle, OR carboplatin at an area under the curve 5 (AUC 5) (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle + gemcitabine 1,000 mg/m^2 IV on Day 1 and Day 8 of each 3-week cycle. Eligible participants who stopped 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 (Pembro)
    Reporting group description
    		 Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for a maximum of 35 doses. Eligible participants who stopped pembrolizumab with 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
    ST Chemotherapy (Chemo)
    Reporting group description
    		 Participants received ST chemotherapy with EITHER cisplatin 70 mg/m^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine IV infusion 1,000 mg/m^2 on Day 1 and Day 8 of each 3-week cycle OR carboplatin at AUC 5 (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine 1,000 mg/m^2 IV on Day 1 and Day 8 of each 3-week cycle.

    Primary: Pembro Combo vs Chemo: Progression-free Survival (PFS) Using Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR)

    		 Close Top of page
    End point title
    		 Pembro Combo vs Chemo: Progression-free Survival (PFS) Using Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR)
    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. The sponsor allowed a maximum of 10 target lesions in total and 5 per organ on this study. Per protocol, PFS in the pembro combo arm was compared to the chemo arm as a pre-specified primary analysis of the Intent-To-Treat (ITT) population (all randomized participants). PFS is reported here for all randomized participants in the pembro combo arm and chemo arm. Per protocol, PFS was compared separately between all participants of the pembro arm and chemo arm and is presented later in the record.
    End point type
    Primary
    End point timeframe
    Up to approximately 42 months
    End point values
    		 Pembrolizumab + ST Chemotherapy (Pembro Combo) Pembrolizumab (Pembro) ST Chemotherapy (Chemo)
    Number of subjects analysed
    351
    0 [1]
    352
    Units: Months
        median (confidence interval 95%)
    8.3 (7.5 to 8.5)
    ( to )
    7.1 (6.4 to 7.9)
    Notes
    [1] - PFS was compared separately between all participants of the pembro arm and chemo arm
    Statistical analysis title
    		 PFS: Pembro Combo vs Chemo
    Statistical analysis description
    PFS in all participants of the pembro combo arm was compared to PFS in all participants of the chemo arm to address the first primary hypothesis (superiority to chemo). The hazard ratio (HR) and its 95% confidence interval (CI) were estimated using a stratified Cox regression model with Efron's method of tie handling with treatment as a covariate stratified by investigator’s choice of chemotherapy (cisplatin or carboplatin) and PD-L1 status (CPS<10 vs. CPS≥10) at baseline.
    Comparison groups
    Pembrolizumab + ST Chemotherapy (Pembro Combo) v ST Chemotherapy (Chemo)
    Number of subjects included in analysis
    703
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0033
    Method
    		 Stratified Log-Rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.65
         upper limit
    		 0.93

    Primary: Pembro Combo vs Chemo: Overall Survival (OS)

    		 Close Top of page
    End point title
    		 Pembro Combo vs Chemo: Overall Survival (OS)
    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 chemo arm as a pre-specified primary analysis of the ITT population (all randomized participants). OS is reported here for all randomized participants in the pembro combo arm and chemo arm. Per protocol, OS was compared separately between all participants of the pembro arm and chemo arm and is presented later in the record.
    End point type
    Primary
    End point timeframe
    Up to approximately 42 months
    End point values
    		 Pembrolizumab + ST Chemotherapy (Pembro Combo) Pembrolizumab (Pembro) ST Chemotherapy (Chemo)
    Number of subjects analysed
    351
    0 [2]
    352
    Units: Months
        median (confidence interval 95%)
    17.0 (14.5 to 19.5)
    ( to )
    14.3 (12.3 to 16.7)
    Notes
    [2] - OS was compared separately between all participants of the pembro arm and chemo arm
    Statistical analysis title
    		 OS: Pembro Combo vs Chemo
    Statistical analysis description
    OS in all participants of the pembro combo arm was compared to OS in all participants of the chemo arm to address the second primary hypothesis (superiority to chemo). The HR and its 95% CI were estimated using a stratified Cox regression model with Efron's method of tie handling with treatment as a covariate stratified by investigator’s choice of chemotherapy (cisplatin or carboplatin) and PD-L1 status (CPS<10 vs. CPS≥10) at baseline.
    Comparison groups
    Pembrolizumab + ST Chemotherapy (Pembro Combo) v ST Chemotherapy (Chemo)
    Number of subjects included in analysis
    703
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0407
    Method
    		 Stratified Log-Rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.72
         upper limit
    		 1.02

    Primary: Pembro vs Chemo: OS in Participants With Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥10%

    		 Close Top of page
    End point title
    		 Pembro vs Chemo: OS in Participants With Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (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 CPS ≥10% subset of the pembro arm was compared to OS in the CPS ≥10% subset of the chemo arm for this endpoint as a pre-specified primary analysis of the ITT population. OS is reported here for all randomized participants in the pembro arm and chemo arm who were PD-L1 CPS ≥10%. Per protocol, OS in the CPS ≥10% subset of the pembro combo arm was not a pre-specified analysis of the ITT population and is not presented.
    End point type
    Primary
    End point timeframe
    Up to approximately 42 months
    End point values
    		 Pembrolizumab + ST Chemotherapy (Pembro Combo) Pembrolizumab (Pembro) ST Chemotherapy (Chemo)
    Number of subjects analysed
    0 [3]
    160
    158
    Units: Months
        median (confidence interval 95%)
    ( to )
    16.1 (13.6 to 19.9)
    15.2 (11.6 to 23.3)
    Notes
    [3] - OS in the CPS ≥10% subset of the pembro combo arm was not a pre-specified analysis of ITT population
    Statistical analysis title
    		 OS: Pembro vs Chemo, CPS ≥10%
    Statistical analysis description
    OS in CPS≥10 participants of the pembro arm was compared to OS in CPS≥10 participants of the chemo arm. The comparison was based on a Cox regression model with Efron's method of tie handling with treatment as a covariate stratified by investigator’s choice of chemotherapy (cisplatin or carboplatin) at baseline.
    Comparison groups
    Pembrolizumab (Pembro) v ST Chemotherapy (Chemo)
    Number of subjects included in analysis
    318
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.77
         upper limit
    		 1.32

    Primary: Pembro vs Chemo: OS

    		 Close Top of page
    End point title
    		 Pembro vs Chemo: OS
    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 arm was compared to the chemo arm as a pre-specified primary analysis of the ITT population (all randomized participants). OS is reported here for all randomized participants in the pembro arm and chemo arm. Per protocol, OS was compared separately between all participants of the pembro combo arm and chemo arm and is presented earlier in the record.
    End point type
    Primary
    End point timeframe
    Up to approximately 42 months
    End point values
    		 Pembrolizumab + ST Chemotherapy (Pembro Combo) Pembrolizumab (Pembro) ST Chemotherapy (Chemo)
    Number of subjects analysed
    0 [4]
    307
    352
    Units: Months
        median (confidence interval 95%)
    ( to )
    15.6 (12.1 to 17.9)
    14.3 (12.3 to 16.7)
    Notes
    [4] - OS was compared separately between all participants of the pembro combo arm and chemo arm
    Statistical analysis title
    		 OS: Pembro vs Chemo
    Statistical analysis description
    OS in all participants of the pembro arm was compared to OS in all participants of the chemo arm. The comparison was based on a Cox regression model with Efron's method of tie handling with treatment as a covariate stratified by investigator’s choice of chemotherapy (cisplatin or carboplatin) and PD-L1 status (CPS<10 vs. CPS≥10) at baseline.
    Comparison groups
    Pembrolizumab (Pembro) v ST Chemotherapy (Chemo)
    Number of subjects included in analysis
    659
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.77
         upper limit
    		 1.11

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

    		 Close Top of page
    End point title
    		 Number of Participants Who Experience an Adverse Event (AE)
    End point description
    An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a pre-existing condition that was temporally associated with the use of the Sponsor’s product was also an AE. The number of participants that experienced at least one AE was reported for each treatment arm. All randomized participants who received at least 1 dose of trial treatment were analyzed.
    End point type
    Secondary
    End point timeframe
    Up to approximately 55 months
    End point values
    		 Pembrolizumab + ST Chemotherapy (Pembro Combo) Pembrolizumab (Pembro) ST Chemotherapy (Chemo)
    Number of subjects analysed
    349
    302
    342
    Units: Participants
    348
    289
    341
    No statistical analyses for this end point

    Secondary: Number of Participants Who Discontinue Study Drug Due to an AE

    		 Close Top of page
    End point title
    		 Number of Participants Who Discontinue Study Drug Due to an AE
    End point description
    An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a pre-existing condition that was temporally associated with the use of the Sponsor’s product was also an AE. The number of participants that discontinued any study drug due to an AE was reported for each treatment arm. All randomized participants who received at least 1 dose of trial treatment were analyzed.
    End point type
    Secondary
    End point timeframe
    Up to approximately 52 months
    End point values
    		 Pembrolizumab + ST Chemotherapy (Pembro Combo) Pembrolizumab (Pembro) ST Chemotherapy (Chemo)
    Number of subjects analysed
    349
    302
    342
    Units: Participants
    108
    48
    62
    No statistical analyses for this end point

    Secondary: Pembro vs Chemo: PFS Using RECIST 1.1 as Assessed by BICR

    		 Close Top of page
    End point title
    		 Pembro vs Chemo: PFS Using RECIST 1.1 as Assessed by BICR
    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. The sponsor allowed a maximum of 10 target lesions in total and 5 per organ on this study. Per protocol, PFS in the pembro arm was compared to the chemo arm as a pre-specified analysis of the ITT population (all randomized participants). PFS is reported here for all randomized participants in the pembro arm and chemo arm. Per protocol, PFS was compared separately between all participants of the pembro combo arm and chemo arm and is presented earlier in the record.
    End point type
    Secondary
    End point timeframe
    Up to approximately 42 months
    End point values
    		 Pembrolizumab + ST Chemotherapy (Pembro Combo) Pembrolizumab (Pembro) ST Chemotherapy (Chemo)
    Number of subjects analysed
    0 [5]
    307
    352
    Units: Months
        median (confidence interval 95%)
    ( to )
    3.9 (2.3 to 5.1)
    7.1 (6.4 to 7.9)
    Notes
    [5] - PFS was compared separately between all participants of the pembro combo arm and chemo arm
    Statistical analysis title
    		 PFS: Pembro vs Chemo
    Statistical analysis description
    PFS in all participants of the pembro arm was compared to PFS in all participants of the chemo arm. The comparison was based on a Cox regression model with Efron's method of tie handling with treatment as a covariate stratified by investigator’s choice of chemotherapy (cisplatin or carboplatin) and PD-L1 status (CPS<10 vs. CPS≥10) at baseline.
    Comparison groups
    Pembrolizumab (Pembro) v ST Chemotherapy (Chemo)
    Number of subjects included in analysis
    659
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.09
         upper limit
    		 1.58

    Secondary: Pembro Combo vs Chemo: Duration of Response (DOR) Using RECIST 1.1 as Assessed by BICR

    		 Close Top of page
    End point title
    		 Pembro Combo vs Chemo: Duration of Response (DOR) Using RECIST 1.1 as Assessed by BICR
    End point description
    For participants who demonstrated a confirmed CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1 based upon BICR, 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. DOR is reported here for all randomized participants in the pembro combo arm and chemo arm who demonstrated a confirmed CR or PR. Per protocol, DOR was assessed separately in responders of the pembro arm and chemo arm and is presented later in the record.
    End point type
    Secondary
    End point timeframe
    Up to approximately 42 months
    End point values
    		 Pembrolizumab + ST Chemotherapy (Pembro Combo) Pembrolizumab (Pembro) ST Chemotherapy (Chemo)
    Number of subjects analysed
    192
    0 [6]
    158
    Units: Months
        median (confidence interval 95%)
    8.5 (8.2 to 11.4)
    ( to )
    6.2 (5.8 to 6.6)
    Notes
    [6] - DOR was assessed separately in responders of the pembro arm and chemo arm
    No statistical analyses for this end point

    Secondary: Pembro Combo vs Chemo: Objective Response Rate (ORR) Using RECIST 1.1 as Assessed by BICR

    		 Close Top of page
    End point title
    		 Pembro Combo vs Chemo: Objective Response Rate (ORR) Using RECIST 1.1 as Assessed by BICR
    End point description
    ORR was defined as the percentage of participants in the analysis population who had a Complete Response (CR: disappearance of all target lesions) or a Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions) per RECIST 1.1. based upon BICR. The sponsor allowed a maximum of 10 target lesions in total and 5 per organ on this study. Per protocol, ORR in the pembro combo arm was compared to the chemo 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 randomized participants in the pembro combo arm and chemo arm. Per protocol, ORR was compared separately between participants of the pembro arm and chemo arm and is presented later in the record.
    End point type
    Secondary
    End point timeframe
    Up to approximately 42 months
    End point values
    		 Pembrolizumab + ST Chemotherapy (Pembro Combo) Pembrolizumab (Pembro) ST Chemotherapy (Chemo)
    Number of subjects analysed
    351
    0 [7]
    352
    Units: Percentage of Participants
        number (confidence interval 95%)
    54.7 (49.3 to 60.0)
    ( to )
    44.9 (39.6 to 50.2)
    Notes
    [7] - ORR was compared separately between participants of the pembro arm and chemo arm
    Statistical analysis title
    		 ORR: Pembro Combo vs Chemo
    Statistical analysis description
    ORR in participants of the pembro combo arm was compared to ORR in participants of the chemo arm. The comparison was based on the Miettinen & Nurminen method stratified by investigator’s choice of chemotherapy (cisplatin or carboplatin) and PD-L1 status (CPS<10 vs. CPS≥10) at baseline.
    Comparison groups
    Pembrolizumab + ST Chemotherapy (Pembro Combo) v ST Chemotherapy (Chemo)
    Number of subjects included in analysis
    703
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Difference in Percentage
    Point estimate
    9.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.4
         upper limit
    		 17.1

    Secondary: Pembro Combo vs Chemo: Disease Control Rate (DCR) Using RECIST 1.1 as Assessed by BICR

    		 Close Top of page
    End point title
    		 Pembro Combo vs Chemo: Disease Control Rate (DCR) Using RECIST 1.1 as Assessed by BICR
    End point description
    DCR was defined as the percentage of participants who had a confirmed CR (disappearance of all target lesions), PR (at least a 30% decrease in the sum of diameters of target lesions), or Stable Disease (SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD [at least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered PD]). Per protocol, DCR in the pembro combo arm was compared to the chemo arm as a pre-specified secondary analysis of the ITT population. The percentage of participants who experienced a confirmed CR, PR, or SD according to RECIST 1.1 as assessed by BICR was reported as the DCR for all randomized participants in the pembro combo arm and chemo arm. Per protocol, DCR was compared separately between participants of the pembro arm and chemo arm and is presented later in the record.
    End point type
    Secondary
    End point timeframe
    Up to approximately 42 months
    End point values
    		 Pembrolizumab + ST Chemotherapy (Pembro Combo) Pembrolizumab (Pembro) ST Chemotherapy (Chemo)
    Number of subjects analysed
    351
    0 [8]
    352
    Units: Percentage of Participants
        number (confidence interval 95%)
    80.3 (75.8 to 84.4)
    ( to )
    75.9 (71.0 to 80.2)
    Notes
    [8] - DCR was compared separately between participants of the pembro arm and chemo arm
    Statistical analysis title
    		 DCR: Pembro Combo vs Chemo
    Statistical analysis description
    DCR in participants of the pembro combo arm was compared to DCR in participants of the chemo arm based on the Miettinen & Nurminen method stratified by investigator’s choice of chemotherapy (cisplatin or carboplatin) and PD-L1 status (CPS<10 vs. CPS≥10) at baseline.
    Comparison groups
    Pembrolizumab + ST Chemotherapy (Pembro Combo) v ST Chemotherapy (Chemo)
    Number of subjects included in analysis
    703
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Difference in Percentage
    Point estimate
    4.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.6
         upper limit
    		 10.6

    Secondary: Pembro vs Chemo: ORR Using RECIST 1.1 as Assessed by BICR

    		 Close Top of page
    End point title
    		 Pembro vs Chemo: ORR Using RECIST 1.1 as Assessed by BICR
    End point description
    ORR was defined as the percentage of participants in the analysis population who had a CR (disappearance of all target lesions) or a PR (≥30% decrease in the sum of diameters of target lesions) per RECIST 1.1. based upon BICR. The sponsor allowed a maximum of 10 target lesions in total and 5 per organ on this study. Per protocol, ORR in the pembro arm was compared to the chemo 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 randomized participants in the pembro arm and chemo arm. Per protocol, ORR was compared separately between participants of the pembro combo arm and chemo arm and is presented earlier in the record.
    End point type
    Secondary
    End point timeframe
    Up to approximately 42 months
    End point values
    		 Pembrolizumab + ST Chemotherapy (Pembro Combo) Pembrolizumab (Pembro) ST Chemotherapy (Chemo)
    Number of subjects analysed
    0 [9]
    307
    352
    Units: Percentage of Participants
        number (confidence interval 95%)
    ( to )
    30.3 (25.2 to 35.8)
    44.9 (39.6 to 50.2)
    Notes
    [9] - ORR was compared separately between participants of the pembro combo arm and chemo arm
    Statistical analysis title
    		 ORR: Pembro vs Chemo
    Statistical analysis description
    ORR in participants of the pembro arm was compared to ORR in participants of the chemo arm. The comparison was based on the Miettinen & Nurminen method stratified by investigator’s choice of chemotherapy (cisplatin or carboplatin) and PD-L1 status (CPS<10 vs. CPS≥10) at baseline.
    Comparison groups
    Pembrolizumab (Pembro) v ST Chemotherapy (Chemo)
    Number of subjects included in analysis
    659
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Difference in Percentage
    Point estimate
    -14.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -22
         upper limit
    		 -7.4

    Secondary: PFS Using RECIST 1.1 as Assessed by BICR at 6 Months

    		 Close Top of page
    End point title
    		 PFS Using RECIST 1.1 as Assessed by BICR at 6 Months
    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. The sponsor allowed a maximum of 10 target lesions in total and 5 per organ on this study. Per protocol, PFS was compared between arms as a pre-specified secondary analysis of the ITT population (all randomized participants). PFS is reported here for all randomized participants at 6 months based on the product-limit (Kaplan-Meier) method for censored data.
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    		 Pembrolizumab + ST Chemotherapy (Pembro Combo) Pembrolizumab (Pembro) ST Chemotherapy (Chemo)
    Number of subjects analysed
    351
    307
    352
    Units: Percentage of Participants
        number (confidence interval 95%)
    73.7 (68.6 to 78.0)
    43.6 (37.9 to 49.1)
    70.3 (64.8 to 75.0)
    No statistical analyses for this end point

    Secondary: Pembro vs Chemo: DCR Using RECIST 1.1 as Assessed by BICR

    		 Close Top of page
    End point title
    		 Pembro vs Chemo: DCR Using RECIST 1.1 as Assessed by BICR
    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. The sponsor allowed a maximum of 10 target lesions in total and 5 per organ on this study. Per protocol, PFS was compared between arms as a pre-specified secondary analysis of the ITT population (all randomized participants). PFS is reported here for all randomized participants at 6 months based on the product-limit (Kaplan-Meier) method for censored data.
    End point type
    Secondary
    End point timeframe
    Up to approximately 42 months
    End point values
    		 Pembrolizumab + ST Chemotherapy (Pembro Combo) Pembrolizumab (Pembro) ST Chemotherapy (Chemo)
    Number of subjects analysed
    0 [10]
    307
    352
    Units: Percentage of Participants
        number (confidence interval 95%)
    ( to )
    47.2 (41.5 to 53.0)
    75.9 (71.0 to 80.2)
    Notes
    [10] - DCR was compared separately between participants of the pembro combo arm and chemo arm
    Statistical analysis title
    		 DCR: Pembro vs Chemo
    Statistical analysis description
    DCR in participants of the pembro arm was compared to DCR in participants of the chemo arm based on the Miettinen & Nurminen method stratified by investigator’s choice of chemotherapy (cisplatin or carboplatin) and PD-L1 status (CPS<10 vs. CPS≥10) at baseline.
    Comparison groups
    Pembrolizumab (Pembro) v ST Chemotherapy (Chemo)
    Number of subjects included in analysis
    659
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Difference in Percentage
    Point estimate
    -28.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -35.9
         upper limit
    		 -21.6

    Secondary: Pembro vs Chemo: DOR Using RECIST 1.1 as Assessed by BICR

    		 Close Top of page
    End point title
    		 Pembro vs Chemo: DOR Using RECIST 1.1 as Assessed by BICR
    End point description
    For participants with confirmed CR (disappearance of all target lesions) or PR (≥30% decrease in sum of diameters of target lesions) per RECIST 1.1 based upon BICR, DOR was defined as 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 date of last tumor assessment. Per RECIST 1.1, PD 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. Appearance of 1 or more new lesions also considered PD. DOR reported for all randomized participants in pembro arm and chemo arm who had CR or PR. Values of 9999 indicate undefined DOR upper 95% confidence limit (DOR rate not low enough at time of cut-off date). Per protocol, DOR was assessed separately in responders of the pembro combo arm and chemo arm and is presented earlier in the record.
    End point type
    Secondary
    End point timeframe
    Up to approximately 42 months
    End point values
    		 Pembrolizumab + ST Chemotherapy (Pembro Combo) Pembrolizumab (Pembro) ST Chemotherapy (Chemo)
    Number of subjects analysed
    0 [11]
    93
    158
    Units: Months
        median (confidence interval 95%)
    ( to )
    28.2 (13.5 to 9999)
    6.2 (5.8 to 6.6)
    Notes
    [11] - DOR was assessed separately in responders of the pembro combo arm and chemo arm
    No statistical analyses for this end point

    Secondary: Pembro Combo vs Chemo: 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

    		 Close Top of page
    End point title
    		 Pembro Combo vs Chemo: 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. Per protocol, change from baseline to Week 18 in the GHS/QoL combined score was compared between all treated participants of the pembro combo arm and the chemo arm with ≥1 EORTC-QLQ-C30 assessment completed. Per protocol, change from baseline (CFB) to Week 18 in the GHS/QoL combined score was compared separately between all participants of the pembro arm and chemo arm and is presented later in the record.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 18
    End point values
    		 Pembrolizumab + ST Chemotherapy (Pembro Combo) Pembrolizumab (Pembro) ST Chemotherapy (Chemo)
    Number of subjects analysed
    336
    0 [12]
    337
    Units: Score on a Scale
        least squares mean (confidence interval 95%)
    2.54 (-0.08 to 5.16)
    ( to )
    -0.14 (-2.91 to 2.63)
    Notes
    [12] - CFB to Week 18 in GHS/QoL combined score compared separately between the pembro arm and chemo arm
    Statistical analysis title
    		 EORTC QLQ-C30 GHS/QoL: Pembro Combo vs Chemo
    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 chemo arm. Comparison based on constrained longitudinal data analysis (cLDA) model with GHS/QoL score as response variable, and with treatment by study visit interactions and stratification factors (investigator’s choice of chemotherapy [cisplatin or carboplatin] and PD-L1 status [CPS<10 vs. CPS≥10]) at baseline as covariates.
    Comparison groups
    Pembrolizumab + ST Chemotherapy (Pembro Combo) v ST Chemotherapy (Chemo)
    Number of subjects included in analysis
    673
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Difference in LS Means
    Point estimate
    2.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.76
         upper limit
    		 6.12

    Secondary: PFS Using RECIST 1.1 as Assessed by BICR at 18 Months

    		 Close Top of page
    End point title
    		 PFS Using RECIST 1.1 as Assessed by BICR at 18 Months
    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. The sponsor allowed a maximum of 10 target lesions in total and 5 per organ on this study. Per protocol, PFS was compared between arms as a pre-specified secondary analysis of the ITT population (all randomized participants). PFS is reported here for all randomized participants at 18 months based on the product-limit (Kaplan-Meier) method for censored data.
    End point type
    Secondary
    End point timeframe
    18 months
    End point values
    		 Pembrolizumab + ST Chemotherapy (Pembro Combo) Pembrolizumab (Pembro) ST Chemotherapy (Chemo)
    Number of subjects analysed
    351
    307
    352
    Units: Percentage of Participants
        number (confidence interval 95%)
    23.0 (18.4 to 27.8)
    19.1 (14.7 to 24.0)
    13.5 (9.3 to 18.4)
    No statistical analyses for this end point

    Secondary: PFS Using RECIST 1.1 as Assessed by BICR at 12 Months

    		 Close Top of page
    End point title
    		 PFS Using RECIST 1.1 as Assessed by BICR at 12 Months
    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. The sponsor allowed a maximum of 10 target lesions in total and 5 per organ on this study. Per protocol, PFS was compared between arms as a pre-specified secondary analysis of the ITT population (all randomized participants). PFS is reported here for all randomized participants at 12 months based on the product-limit (Kaplan-Meier) method for censored data.
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Pembrolizumab + ST Chemotherapy (Pembro Combo) Pembrolizumab (Pembro) ST Chemotherapy (Chemo)
    Number of subjects analysed
    351
    307
    352
    Units: Percentage of Participants
        number (confidence interval 95%)
    33.7 (28.6 to 38.9)
    26.6 (21.6 to 31.9)
    20.9 (16.0 to 26.1)
    No statistical analyses for this end point

    Secondary: Pembro Combo vs Chemo: Time to Deterioration (TTD) in the EORTC-QLQ-C30 GHS/QoL (Items 29 and 30) Combined Score

    		 Close Top of page
    End point title
    		 Pembro Combo vs Chemo: Time to Deterioration (TTD) in the EORTC-QLQ-C30 GHS/QoL (Items 29 and 30) Combined Score
    End point description
    EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the QoL 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). Raw scores were standardized by linear transformation so that scores ranged from 0 to 100, with a higher score indicating a better overall outcome. TTD in GHS/QoL was defined as the time from first dose date to the first onset of a ≥10 point decrease from baseline in GHS/QoL combined score without confirmation. Per protocol, TTD in GHS/QoL combined score was compared between all treated participants of the pembro combo arm and chemo arm with ≥1 EORTC-QLQ-C30 assessment at baseline. TTD in GHS/QoL combined score was compared separately between the pembro arm and chemo arm and is presented later in the record.
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 25 months
    End point values
    		 Pembrolizumab + ST Chemotherapy (Pembro Combo) Pembrolizumab (Pembro) ST Chemotherapy (Chemo)
    Number of subjects analysed
    314
    0 [13]
    311
    Units: Months
        median (confidence interval 95%)
    8.0 (5.9 to 10.3)
    ( to )
    4.5 (2.8 to 8.2)
    Notes
    [13] - TTD in GHS/QoL combined score was compared separately between the pembro arm and chemo arm
    Statistical analysis title
    		 EORTC QLQ-C30 GHS/QoL TTD: Pembro Combo vs Chemo
    Statistical analysis description
    TTD in GHS/QoL combined score was compared between all participants of the pembro combo arm and the chemo arm. Comparison based on Cox regression model with Efron's method of tie handling with treatment as a covariate stratified by investigator’s choice of chemotherapy (cisplatin or carboplatin) and PD-L1 status (CPS<10 vs. CPS≥10) at baseline.
    Comparison groups
    Pembrolizumab + ST Chemotherapy (Pembro Combo) v ST Chemotherapy (Chemo)
    Number of subjects included in analysis
    625
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.62
         upper limit
    		 1

    Secondary: Pembro vs Chemo: Change from Baseline To Week 18 in the EORTC QLQ-C30 GHS/QoL Combined Score

    		 Close Top of page
    End point title
    		 Pembro vs Chemo: Change from Baseline To Week 18 in the EORTC QLQ-C30 GHS/QoL 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. Per protocol, change from baseline to Week 18 in the GHS/QoL combined score was compared between all treated participants of the pembro arm and the chemo arm with ≥1 EORTC-QLQ-C30 assessment completed. Per protocol, change from baseline (CFB) to Week 18 in the GHS/QoL combined score was compared separately between all participants of the pembro combo arm and chemo arm and is presented earlier in the record.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 18
    End point values
    		 Pembrolizumab + ST Chemotherapy (Pembro Combo) Pembrolizumab (Pembro) ST Chemotherapy (Chemo)
    Number of subjects analysed
    0 [14]
    301
    337
    Units: Score on a Scale
        least squares mean (confidence interval 95%)
    ( to )
    -1.89 (-5.04 to 1.26)
    -0.95 (-3.95 to 2.06)
    Notes
    [14] - CFB to Week 18 in GHS/QoL combined score compared separately between pembro combo arm and chemo arm
    Statistical analysis title
    		 EORTC QLQ-C30 GHS/QoL: Pembro vs Chemo
    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 arm and the chemo arm. Comparison based on cLDA model with GHS/QoL score as response variable, and with treatment by study visit interactions and stratification factors (investigator’s choice of chemotherapy [cisplatin or carboplatin] and PD-L1 status [CPS<10 vs. CPS≥10]) at baseline as covariates.
    Comparison groups
    Pembrolizumab (Pembro) v ST Chemotherapy (Chemo)
    Number of subjects included in analysis
    638
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.06
         upper limit
    		 3.18

    Secondary: Pembro vs Chemo: TTD in the EORTC-QLQ-C30 GHS/QoL (Items 29 and 30) Combined Score

    		 Close Top of page
    End point title
    		 Pembro vs Chemo: TTD in the EORTC-QLQ-C30 GHS/QoL (Items 29 and 30) Combined Score
    End point description
    EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the QoL 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). Raw scores were standardized by linear transformation so that scores ranged from 0 to 100, with a higher score indicating a better overall outcome. TTD in GHS/QoL was defined as the time from first dose date to the first onset of a ≥10 point decrease from baseline in GHS/QoL combined score without confirmation. Per protocol, TTD in GHS/QoL combined score was compared between all treated participants of the pembro arm and chemo arm with ≥1 EORTC-QLQ-C30 assessment at baseline. TTD in GHS/QoL combined score was compared separately between the pembro combo arm and chemo arm and is presented earlier in the record.
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 25 months
    End point values
    		 Pembrolizumab + ST Chemotherapy (Pembro Combo) Pembrolizumab (Pembro) ST Chemotherapy (Chemo)
    Number of subjects analysed
    0 [15]
    275
    311
    Units: Months
        median (confidence interval 95%)
    ( to )
    3.6 (2.1 to 5.2)
    4.5 (2.8 to 8.2)
    Notes
    [15] - TTD in GHS/QoL combined score was compared separately between the pembro combo arm and chemo arm
    Statistical analysis title
    		 EORTC QLQ-C30 GHS/QoL TTD: Pembro vs Chemo
    Statistical analysis description
    TTD in GHS/QoL combined score was compared between all participants of the pembro arm and the chemo arm. Comparison based on Cox regression model with Efron's method of tie handling with treatment as a covariate stratified by investigator’s choice of chemotherapy (cisplatin or carboplatin) and PD-L1 status (CPS<10 vs. CPS≥10) at baseline.
    Comparison groups
    Pembrolizumab (Pembro) v ST Chemotherapy (Chemo)
    Number of subjects included in analysis
    586
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.93
         upper limit
    		 1.49

    Adverse events

    		 Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    Up to approximately 70 months
    Adverse event reporting additional description
    All-Cause Mortality reported for all randomized participants. Serious and Other AEs include all treated participants according to treatment received. Per protocol, MedDRA preferred terms "Neoplasm progression", "Malignant neoplasm progression" and "Disease progression" unrelated to drug 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 + ST Chemotherapy (Pembro Combo) First Course
    Reporting group description
    		 Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle (Q3W) for a maximum of 35 doses PLUS ST chemotherapy with EITHER cisplatin 70 mg/m^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine IV infusion 1,000 mg/m^2 on Day 1 and Day 8 of each 3-week cycle, OR carboplatin at an area under the curve 5 (AUC 5) (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine 1,000 mg/m^2 IV on Day 1 and Day 8 of each 3-week cycle.

    Reporting group title
    Pembrolizumab (Pembro) First Course
    Reporting group description
    		 Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W) for a maximum of 35 doses.

    Reporting group title
    Pembrolizumab (Pembro) 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 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 + ST Chemotherapy (Pembro Combo) 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 ST 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
    ST Chemotherapy (Chemo) First Course
    Reporting group description
    		 Participants received ST chemotherapy with EITHER cisplatin 70 mg/m^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine IV infusion 1,000 mg/m^2 on Day 1 and Day 8 of each 3-week cycle OR carboplatin at AUC 5 (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle plus gemcitabine 1,000 mg/m^2 IV on Day 1 and Day 8 of each 3-week cycle.

    Serious adverse events
    		 Pembrolizumab + ST Chemotherapy (Pembro Combo) First Course Pembrolizumab (Pembro) First Course Pembrolizumab (Pembro) Second Course Pembrolizumab + ST Chemotherapy (Pembro Combo) Second Course ST Chemotherapy (Chemo) First Course
    Total subjects affected by serious adverse events
         subjects affected / exposed
    189 / 349 (54.15%)
    145 / 302 (48.01%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    138 / 342 (40.35%)
         number of deaths (all causes)
    283
    244
    8
    4
    300
         number of deaths resulting from adverse events
    2
    2
    0
    0
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    0 / 349 (0.00%)
    2 / 302 (0.66%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Adenocarcinoma of colon
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Cancer pain
         subjects affected / exposed
    3 / 349 (0.86%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    0 / 349 (0.00%)
    2 / 302 (0.66%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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 pain
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Lymphangiosis carcinomatosa
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 342 (0.29%)
         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
    Embolism
         subjects affected / exposed
    0 / 349 (0.00%)
    2 / 302 (0.66%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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 / 1
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    4 / 349 (1.15%)
    3 / 302 (0.99%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    3 / 342 (0.88%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 3
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arterial haemorrhage
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Orthostatic hypotension
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Lymphoedema
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Iliac artery occlusion
         subjects affected / exposed
    1 / 349 (0.29%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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 / 1
    0 / 0
    0 / 0
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Pelvic venous thrombosis
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Peripheral ischaemia
         subjects affected / exposed
    0 / 349 (0.00%)
    2 / 302 (0.66%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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 pain
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    General disorders and administration site conditions
    Malaise
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Asthenia
         subjects affected / exposed
    2 / 349 (0.57%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    6 / 349 (1.72%)
    3 / 302 (0.99%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 6
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 349 (0.29%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    2 / 342 (0.58%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza like illness
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    General physical health deterioration
         subjects affected / exposed
    3 / 349 (0.86%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 342 (0.29%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypothermia
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Inflammation
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Gait disturbance
         subjects affected / exposed
    0 / 349 (0.00%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 342 (0.29%)
         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
    Medical device site laceration
         subjects affected / exposed
    0 / 349 (0.00%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 342 (0.29%)
         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
    Mucosal inflammation
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 349 (0.00%)
    2 / 302 (0.66%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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 / 2
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    6 / 349 (1.72%)
    3 / 302 (0.99%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    4 / 342 (1.17%)
         occurrences causally related to treatment / all
    3 / 7
    3 / 3
    0 / 0
    0 / 0
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Oedema peripheral
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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 system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 349 (0.00%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 342 (0.29%)
         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
    Drug hypersensitivity
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Sarcoidosis
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Reproductive system and breast disorders
    Female genital tract fistula
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Pelvic pain
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 342 (0.29%)
         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
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Aspiration
         subjects affected / exposed
    0 / 349 (0.00%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 342 (0.29%)
         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
    Interstitial lung disease
         subjects affected / exposed
    3 / 349 (0.86%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pharyngeal stenosis
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Pleural effusion
         subjects affected / exposed
    1 / 349 (0.29%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Haemoptysis
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Pneumothorax
         subjects affected / exposed
    1 / 349 (0.29%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Pneumonitis
         subjects affected / exposed
    1 / 349 (0.29%)
    4 / 302 (1.32%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 342 (0.29%)
         occurrences causally related to treatment / all
    1 / 1
    4 / 4
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Dyspnoea
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 349 (0.29%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    2 / 349 (0.57%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    2 / 342 (0.58%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Pulmonary oedema
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Pulmonary haemorrhage
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Pulmonary embolism
         subjects affected / exposed
    6 / 349 (1.72%)
    3 / 302 (0.99%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    4 / 342 (1.17%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 3
    0 / 0
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Productive cough
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Psychiatric disorders
    Completed suicide
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Confusional state
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Delirium
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Mental status changes
         subjects affected / exposed
    1 / 349 (0.29%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    2 / 342 (0.58%)
         occurrences causally related to treatment / all
    0 / 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
    Product issues
    Device occlusion
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Investigations
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Blood creatinine increased
         subjects affected / exposed
    2 / 349 (0.57%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood potassium increased
         subjects affected / exposed
    0 / 349 (0.00%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 342 (0.29%)
         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
    Haemoglobin decreased
         subjects affected / exposed
    0 / 349 (0.00%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 342 (0.29%)
         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
    Anticoagulation drug level above therapeutic
         subjects affected / exposed
    0 / 349 (0.00%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 342 (0.29%)
         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
    International normalised ratio increased
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Liver function test increased
         subjects affected / exposed
    0 / 349 (0.00%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 342 (0.29%)
         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
    Neutrophil count decreased
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    7 / 342 (2.05%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    11 / 349 (3.15%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    15 / 342 (4.39%)
         occurrences causally related to treatment / all
    12 / 13
    0 / 1
    0 / 0
    0 / 0
    22 / 24
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    2 / 342 (0.58%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Abdominal wound dehiscence
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Femur fracture
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 349 (0.29%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Joint dislocation
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Joint injury
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Lower limb fracture
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Hip fracture
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Overdose
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Post procedural complication
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Post procedural discharge
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Skull fracture
         subjects affected / exposed
    0 / 349 (0.00%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 342 (0.29%)
         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
    Post procedural haematoma
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Procedural pneumothorax
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Rib fracture
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Post procedural fever
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 342 (0.29%)
         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
    Urethral injury
         subjects affected / exposed
    0 / 349 (0.00%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 342 (0.29%)
         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
    Urostomy complication
         subjects affected / exposed
    0 / 349 (0.00%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 342 (0.29%)
         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 / 0
    Congenital, familial and genetic disorders
    Dolichocolon
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Odontogenic cyst
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Acute myocardial infarction
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Angina pectoris
         subjects affected / exposed
    0 / 349 (0.00%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 342 (0.29%)
         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
    Aortic valve stenosis
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Arrhythmia
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Atrial fibrillation
         subjects affected / exposed
    4 / 349 (1.15%)
    2 / 302 (0.66%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    2 / 342 (0.58%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Cardiac failure
         subjects affected / exposed
    0 / 349 (0.00%)
    5 / 302 (1.66%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 5
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 3
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 349 (0.00%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 342 (0.29%)
         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 failure chronic
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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 arrest
         subjects affected / exposed
    3 / 349 (0.86%)
    2 / 302 (0.66%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 342 (0.29%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 2
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    1 / 3
    0 / 2
    0 / 0
    0 / 0
    0 / 1
    Cardio-respiratory arrest
         subjects affected / exposed
    2 / 349 (0.57%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Coronary artery disease
         subjects affected / exposed
    0 / 349 (0.00%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 342 (0.29%)
         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
    Myocarditis
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Left ventricular failure
         subjects affected / exposed
    0 / 349 (0.00%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 342 (0.29%)
         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
    Myocardial infarction
         subjects affected / exposed
    2 / 349 (0.57%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    2 / 342 (0.58%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Myocardial ischaemia
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Left ventricular dysfunction
         subjects affected / exposed
    0 / 349 (0.00%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 342 (0.29%)
         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
    Nervous system disorders
    Cerebral infarction
         subjects affected / exposed
    0 / 349 (0.00%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 342 (0.29%)
         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
    Cerebral venous thrombosis
         subjects affected / exposed
    0 / 349 (0.00%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 342 (0.29%)
         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
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Cerebrovascular accident
         subjects affected / exposed
    2 / 349 (0.57%)
    2 / 302 (0.66%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    2 / 342 (0.58%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dementia
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Encephalitis autoimmune
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Myoclonus
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Hepatic encephalopathy
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Ischaemic stroke
         subjects affected / exposed
    2 / 349 (0.57%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 342 (0.29%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Polyneuropathy
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Seizure
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Spinal cord compression
         subjects affected / exposed
    0 / 349 (0.00%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 342 (0.29%)
         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
    Subarachnoid haemorrhage
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Transient ischaemic attack
         subjects affected / exposed
    0 / 349 (0.00%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 342 (0.29%)
         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
    Uraemic encephalopathy
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Syncope
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    9 / 349 (2.58%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    11 / 342 (3.22%)
         occurrences causally related to treatment / all
    8 / 9
    0 / 0
    0 / 0
    0 / 0
    11 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Anaemia
         subjects affected / exposed
    15 / 349 (4.30%)
    6 / 302 (1.99%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    19 / 342 (5.56%)
         occurrences causally related to treatment / all
    11 / 15
    0 / 8
    0 / 0
    0 / 0
    15 / 19
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematotoxicity
         subjects affected / exposed
    0 / 349 (0.00%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 342 (0.29%)
         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
    Thrombotic thrombocytopenic purpura
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    12 / 349 (3.44%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    10 / 342 (2.92%)
         occurrences causally related to treatment / all
    13 / 15
    0 / 0
    0 / 0
    0 / 0
    11 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    10 / 349 (2.87%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    2 / 342 (0.58%)
         occurrences causally related to treatment / all
    9 / 10
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    2 / 349 (0.57%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Neutropenia
         subjects affected / exposed
    2 / 349 (0.57%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    3 / 342 (0.88%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Diplopia
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Epiretinal membrane
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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 disorders
    Autoimmune colitis
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Abdominal pain
         subjects affected / exposed
    3 / 349 (0.86%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 342 (0.29%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal fistula
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Ascites
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Colitis
         subjects affected / exposed
    2 / 349 (0.57%)
    2 / 302 (0.66%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 342 (0.29%)
         occurrences causally related to treatment / all
    2 / 2
    4 / 4
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis ischaemic
         subjects affected / exposed
    0 / 349 (0.00%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 342 (0.29%)
         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
    1 / 1
    Constipation
         subjects affected / exposed
    2 / 349 (0.57%)
    3 / 302 (0.99%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 342 (0.29%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 3
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    3 / 349 (0.86%)
    5 / 302 (1.66%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    4 / 342 (1.17%)
         occurrences causally related to treatment / all
    2 / 4
    2 / 5
    0 / 0
    0 / 0
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    2 / 349 (0.57%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Enterocolonic fistula
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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 fistula
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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 haemorrhage
         subjects affected / exposed
    1 / 349 (0.29%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Enterocolitis haemorrhagic
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Ileus
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Inguinal hernia
         subjects affected / exposed
    0 / 349 (0.00%)
    2 / 302 (0.66%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Melaena
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Large intestinal obstruction
         subjects affected / exposed
    2 / 349 (0.57%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
    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
    1 / 349 (0.29%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Intestinal obstruction
         subjects affected / exposed
    2 / 349 (0.57%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 342 (0.29%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 349 (0.29%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    4 / 342 (1.17%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    0 / 0
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    2 / 349 (0.57%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal ulcer
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Vomiting
         subjects affected / exposed
    3 / 349 (0.86%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    3 / 342 (0.88%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 0
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 349 (0.29%)
    3 / 302 (0.99%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 342 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    0 / 349 (0.00%)
    2 / 302 (0.66%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Short-bowel syndrome
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Hepatobiliary disorders
    Autoimmune hepatitis
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Acute hepatic failure
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Cholecystitis
         subjects affected / exposed
    0 / 349 (0.00%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 342 (0.29%)
         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
    Cholecystitis acute
         subjects affected / exposed
    0 / 349 (0.00%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 342 (0.29%)
         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
    Cirrhosis alcoholic
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Liver injury
         subjects affected / exposed
    2 / 349 (0.57%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    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
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Hepatotoxicity
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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 / 349 (0.29%)
    2 / 302 (0.66%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Angioedema
         subjects affected / exposed
    0 / 349 (0.00%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 342 (0.29%)
         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
    Dermatitis
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Dermatitis acneiform
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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 ulcer
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Toxic skin eruption
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Purpura
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Pruritus
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Drug eruption
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    17 / 349 (4.87%)
    13 / 302 (4.30%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    9 / 342 (2.63%)
         occurrences causally related to treatment / all
    10 / 21
    3 / 15
    0 / 0
    0 / 0
    5 / 9
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Autoimmune nephritis
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Bladder perforation
         subjects affected / exposed
    1 / 349 (0.29%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Bladder tamponade
         subjects affected / exposed
    0 / 349 (0.00%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 342 (0.29%)
         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
    Chronic kidney disease
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Tubulointerstitial nephritis
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Nephropathy
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Renal failure
         subjects affected / exposed
    2 / 349 (0.57%)
    2 / 302 (0.66%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    5 / 342 (1.46%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
    0 / 0
    0 / 0
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prerenal failure
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Pollakiuria
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Renal impairment
         subjects affected / exposed
    2 / 349 (0.57%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    3 / 349 (0.86%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 342 (0.29%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    9 / 349 (2.58%)
    14 / 302 (4.64%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    3 / 342 (0.88%)
         occurrences causally related to treatment / all
    4 / 10
    1 / 20
    0 / 0
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysuria
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Urinary tract obstruction
         subjects affected / exposed
    1 / 349 (0.29%)
    4 / 302 (1.32%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 349 (0.29%)
    5 / 302 (1.66%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 342 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urethral fistula
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Ureteric obstruction
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Endocrine disorders
    Adrenocortical insufficiency acute
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Hypercalcaemia of malignancy
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Hypophysitis
         subjects affected / exposed
    2 / 349 (0.57%)
    2 / 302 (0.66%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypopituitarism
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Adrenocorticotropic hormone deficiency
         subjects affected / exposed
    2 / 349 (0.57%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Thyroiditis
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Musculoskeletal and connective tissue disorders
    Gouty arthritis
         subjects affected / exposed
    0 / 349 (0.00%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 342 (0.29%)
         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
    Back pain
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Chondrocalcinosis
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Chondrocalcinosis pyrophosphate
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Arthralgia
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 342 (0.29%)
         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
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 349 (0.00%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 342 (0.29%)
         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
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Osteoporosis
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Pain in extremity
         subjects affected / exposed
    2 / 349 (0.57%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Polyarthritis
         subjects affected / exposed
    0 / 349 (0.00%)
    2 / 302 (0.66%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal stenosis
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Pathological fracture
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Infections and infestations
    Abdominal abscess
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Bacteraemia
         subjects affected / exposed
    2 / 349 (0.57%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    2 / 342 (0.58%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal sepsis
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Acute hepatitis B
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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 perforated
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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 infection
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Bacterial diarrhoea
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Bronchitis
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    COVID-19 pneumonia
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Catheter site infection
         subjects affected / exposed
    0 / 349 (0.00%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 342 (0.29%)
         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
    Cellulitis
         subjects affected / exposed
    3 / 349 (0.86%)
    4 / 302 (1.32%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    3 / 342 (0.88%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
    0 / 0
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Cystitis
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Dengue fever
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Endocarditis
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Diverticulitis
         subjects affected / exposed
    0 / 349 (0.00%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 342 (0.29%)
         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
    Device related sepsis
         subjects affected / exposed
    2 / 349 (0.57%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 349 (0.29%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Gastroenteritis
         subjects affected / exposed
    1 / 349 (0.29%)
    2 / 302 (0.66%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 342 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Escherichia sepsis
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Enterobacter bacteraemia
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Infection
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Oral candidiasis
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Neutropenic sepsis
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Lung abscess
         subjects affected / exposed
    0 / 349 (0.00%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 342 (0.29%)
         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
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Intervertebral discitis
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Influenza
         subjects affected / exposed
    3 / 349 (0.86%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Pelvic abscess
         subjects affected / exposed
    2 / 349 (0.57%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Parotid abscess
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Osteomyelitis
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Peritonitis
         subjects affected / exposed
    1 / 349 (0.29%)
    2 / 302 (0.66%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Pneumonia aspiration
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Periodontitis
         subjects affected / exposed
    0 / 349 (0.00%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 342 (0.29%)
         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
    Pseudomembranous colitis
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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 bacterial
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Pneumonia
         subjects affected / exposed
    8 / 349 (2.29%)
    6 / 302 (1.99%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    6 / 342 (1.75%)
         occurrences causally related to treatment / all
    1 / 8
    0 / 7
    0 / 0
    0 / 0
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
    0 / 0
    0 / 1
    Pyonephrosis
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Pyelonephritis acute
         subjects affected / exposed
    4 / 349 (1.15%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (0.00%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    5 / 349 (1.43%)
    6 / 302 (1.99%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    3 / 342 (0.88%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 6
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Sepsis
         subjects affected / exposed
    3 / 349 (0.86%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    4 / 342 (1.17%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 0
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Rash pustular
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Respiratory tract infection
         subjects affected / exposed
    1 / 349 (0.29%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Scrotal infection
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Septic arthritis staphylococcal
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Septic shock
         subjects affected / exposed
    3 / 349 (0.86%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 342 (0.29%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Skin bacterial infection
         subjects affected / exposed
    0 / 349 (0.00%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 342 (0.29%)
         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
    Skin infection
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Stoma site infection
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Urinary tract infection
         subjects affected / exposed
    31 / 349 (8.88%)
    19 / 302 (6.29%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    22 / 342 (6.43%)
         occurrences causally related to treatment / all
    9 / 65
    2 / 22
    0 / 0
    0 / 0
    7 / 28
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection bacterial
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Urosepsis
         subjects affected / exposed
    13 / 349 (3.72%)
    7 / 302 (2.32%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    7 / 342 (2.05%)
         occurrences causally related to treatment / all
    2 / 15
    0 / 7
    0 / 0
    0 / 0
    2 / 7
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    0 / 0
    0 / 1
    Viral infection
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Wound infection
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    2 / 349 (0.57%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acidosis
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Decreased appetite
         subjects affected / exposed
    0 / 349 (0.00%)
    2 / 302 (0.66%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Dehydration
         subjects affected / exposed
    3 / 349 (0.86%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    5 / 342 (1.46%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 1
    0 / 0
    0 / 0
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    1 / 349 (0.29%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Failure to thrive
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Fluid retention
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Hypokalaemia
         subjects affected / exposed
    2 / 349 (0.57%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    3 / 349 (0.86%)
    3 / 302 (0.99%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 342 (0.29%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 3
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Hyperkalaemia
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 342 (0.29%)
         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
    Fulminant type 1 diabetes mellitus
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Hyponatraemia
         subjects affected / exposed
    5 / 349 (1.43%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 342 (0.29%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    0 / 349 (0.00%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Type 1 diabetes mellitus
         subjects affected / exposed
    1 / 349 (0.29%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    0 / 342 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Pembrolizumab + ST Chemotherapy (Pembro Combo) First Course Pembrolizumab (Pembro) First Course Pembrolizumab (Pembro) Second Course Pembrolizumab + ST Chemotherapy (Pembro Combo) Second Course ST Chemotherapy (Chemo) First Course
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    345 / 349 (98.85%)
    275 / 302 (91.06%)
    1 / 15 (6.67%)
    0 / 14 (0.00%)
    337 / 342 (98.54%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    23 / 349 (6.59%)
    13 / 302 (4.30%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    10 / 342 (2.92%)
         occurrences all number
    26
    17
    0
    0
    10
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    84 / 349 (24.07%)
    42 / 302 (13.91%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    84 / 342 (24.56%)
         occurrences all number
    138
    50
    0
    0
    120
    Fatigue
         subjects affected / exposed
    147 / 349 (42.12%)
    78 / 302 (25.83%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    122 / 342 (35.67%)
         occurrences all number
    199
    94
    0
    0
    150
    Malaise
         subjects affected / exposed
    12 / 349 (3.44%)
    3 / 302 (0.99%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    20 / 342 (5.85%)
         occurrences all number
    13
    3
    0
    0
    23
    Mucosal inflammation
         subjects affected / exposed
    20 / 349 (5.73%)
    4 / 302 (1.32%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    9 / 342 (2.63%)
         occurrences all number
    23
    4
    0
    0
    15
    Oedema peripheral
         subjects affected / exposed
    47 / 349 (13.47%)
    27 / 302 (8.94%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    44 / 342 (12.87%)
         occurrences all number
    55
    34
    0
    0
    48
    Pyrexia
         subjects affected / exposed
    77 / 349 (22.06%)
    43 / 302 (14.24%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    41 / 342 (11.99%)
         occurrences all number
    112
    58
    0
    0
    62
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    55 / 349 (15.76%)
    30 / 302 (9.93%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    28 / 342 (8.19%)
         occurrences all number
    65
    34
    0
    0
    30
    Dyspnoea
         subjects affected / exposed
    55 / 349 (15.76%)
    34 / 302 (11.26%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    36 / 342 (10.53%)
         occurrences all number
    62
    40
    0
    0
    40
    Epistaxis
         subjects affected / exposed
    22 / 349 (6.30%)
    3 / 302 (0.99%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    23 / 342 (6.73%)
         occurrences all number
    25
    3
    0
    0
    31
    Hiccups
         subjects affected / exposed
    21 / 349 (6.02%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    14 / 342 (4.09%)
         occurrences all number
    29
    1
    0
    0
    22
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    35 / 349 (10.03%)
    19 / 302 (6.29%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    16 / 342 (4.68%)
         occurrences all number
    40
    19
    0
    0
    18
    Investigations
    Blood alkaline phosphatase increased
         subjects affected / exposed
    23 / 349 (6.59%)
    17 / 302 (5.63%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    11 / 342 (3.22%)
         occurrences all number
    31
    19
    0
    0
    21
    Alanine aminotransferase increased
         subjects affected / exposed
    54 / 349 (15.47%)
    20 / 302 (6.62%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    21 / 342 (6.14%)
         occurrences all number
    106
    22
    0
    0
    35
    Aspartate aminotransferase increased
         subjects affected / exposed
    52 / 349 (14.90%)
    21 / 302 (6.95%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    20 / 342 (5.85%)
         occurrences all number
    93
    33
    0
    0
    23
    Neutrophil count decreased
         subjects affected / exposed
    77 / 349 (22.06%)
    2 / 302 (0.66%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    69 / 342 (20.18%)
         occurrences all number
    174
    3
    0
    0
    152
    Blood creatinine increased
         subjects affected / exposed
    68 / 349 (19.48%)
    38 / 302 (12.58%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    39 / 342 (11.40%)
         occurrences all number
    105
    39
    0
    0
    51
    Platelet count decreased
         subjects affected / exposed
    78 / 349 (22.35%)
    5 / 302 (1.66%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    79 / 342 (23.10%)
         occurrences all number
    159
    5
    0
    0
    169
    White blood cell count decreased
         subjects affected / exposed
    55 / 349 (15.76%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    51 / 342 (14.91%)
         occurrences all number
    136
    1
    0
    0
    109
    Weight decreased
         subjects affected / exposed
    38 / 349 (10.89%)
    38 / 302 (12.58%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    22 / 342 (6.43%)
         occurrences all number
    43
    39
    0
    0
    23
    Nervous system disorders
    Neuropathy peripheral
         subjects affected / exposed
    24 / 349 (6.88%)
    2 / 302 (0.66%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    20 / 342 (5.85%)
         occurrences all number
    32
    2
    0
    0
    23
    Dizziness
         subjects affected / exposed
    45 / 349 (12.89%)
    19 / 302 (6.29%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    36 / 342 (10.53%)
         occurrences all number
    54
    23
    0
    0
    41
    Dysgeusia
         subjects affected / exposed
    25 / 349 (7.16%)
    8 / 302 (2.65%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    28 / 342 (8.19%)
         occurrences all number
    28
    8
    0
    0
    30
    Headache
         subjects affected / exposed
    42 / 349 (12.03%)
    17 / 302 (5.63%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    27 / 342 (7.89%)
         occurrences all number
    52
    23
    0
    0
    33
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    86 / 349 (24.64%)
    2 / 302 (0.66%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    89 / 342 (26.02%)
         occurrences all number
    175
    2
    0
    0
    180
    Neutropenia
         subjects affected / exposed
    126 / 349 (36.10%)
    2 / 302 (0.66%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    129 / 342 (37.72%)
         occurrences all number
    274
    2
    0
    0
    281
    Anaemia
         subjects affected / exposed
    227 / 349 (65.04%)
    75 / 302 (24.83%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    210 / 342 (61.40%)
         occurrences all number
    334
    103
    0
    0
    303
    Leukopenia
         subjects affected / exposed
    31 / 349 (8.88%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    25 / 342 (7.31%)
         occurrences all number
    60
    0
    0
    0
    55
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    102 / 349 (29.23%)
    58 / 302 (19.21%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    73 / 342 (21.35%)
         occurrences all number
    136
    81
    0
    0
    91
    Dyspepsia
         subjects affected / exposed
    14 / 349 (4.01%)
    6 / 302 (1.99%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    22 / 342 (6.43%)
         occurrences all number
    16
    6
    0
    0
    27
    Gastrooesophageal reflux disease
         subjects affected / exposed
    19 / 349 (5.44%)
    1 / 302 (0.33%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    6 / 342 (1.75%)
         occurrences all number
    20
    1
    0
    0
    7
    Nausea
         subjects affected / exposed
    180 / 349 (51.58%)
    43 / 302 (14.24%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    154 / 342 (45.03%)
         occurrences all number
    279
    53
    0
    0
    247
    Constipation
         subjects affected / exposed
    124 / 349 (35.53%)
    56 / 302 (18.54%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    107 / 342 (31.29%)
         occurrences all number
    155
    70
    0
    0
    140
    Abdominal pain upper
         subjects affected / exposed
    12 / 349 (3.44%)
    9 / 302 (2.98%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    26 / 342 (7.60%)
         occurrences all number
    15
    11
    0
    0
    26
    Abdominal pain
         subjects affected / exposed
    41 / 349 (11.75%)
    29 / 302 (9.60%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    29 / 342 (8.48%)
         occurrences all number
    51
    35
    0
    0
    31
    Stomatitis
         subjects affected / exposed
    22 / 349 (6.30%)
    13 / 302 (4.30%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    18 / 342 (5.26%)
         occurrences all number
    28
    14
    0
    0
    20
    Vomiting
         subjects affected / exposed
    91 / 349 (26.07%)
    33 / 302 (10.93%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    72 / 342 (21.05%)
         occurrences all number
    142
    43
    0
    0
    108
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    82 / 349 (23.50%)
    40 / 302 (13.25%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    24 / 342 (7.02%)
         occurrences all number
    108
    57
    0
    0
    33
    Alopecia
         subjects affected / exposed
    26 / 349 (7.45%)
    0 / 302 (0.00%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    28 / 342 (8.19%)
         occurrences all number
    26
    0
    0
    0
    29
    Dry skin
         subjects affected / exposed
    12 / 349 (3.44%)
    18 / 302 (5.96%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    7 / 342 (2.05%)
         occurrences all number
    13
    19
    0
    0
    7
    Pruritus
         subjects affected / exposed
    80 / 349 (22.92%)
    66 / 302 (21.85%)
    1 / 15 (6.67%)
    0 / 14 (0.00%)
    17 / 342 (4.97%)
         occurrences all number
    109
    89
    1
    0
    21
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    19 / 349 (5.44%)
    9 / 302 (2.98%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    7 / 342 (2.05%)
         occurrences all number
    22
    10
    0
    0
    10
    Haematuria
         subjects affected / exposed
    53 / 349 (15.19%)
    31 / 302 (10.26%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    18 / 342 (5.26%)
         occurrences all number
    66
    33
    0
    0
    19
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    34 / 349 (9.74%)
    30 / 302 (9.93%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    1 / 342 (0.29%)
         occurrences all number
    43
    33
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    45 / 349 (12.89%)
    35 / 302 (11.59%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    24 / 342 (7.02%)
         occurrences all number
    70
    41
    0
    0
    25
    Back pain
         subjects affected / exposed
    50 / 349 (14.33%)
    37 / 302 (12.25%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    19 / 342 (5.56%)
         occurrences all number
    67
    43
    0
    0
    22
    Pain in extremity
         subjects affected / exposed
    32 / 349 (9.17%)
    24 / 302 (7.95%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    14 / 342 (4.09%)
         occurrences all number
    36
    27
    0
    0
    17
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    19 / 349 (5.44%)
    14 / 302 (4.64%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    16 / 342 (4.68%)
         occurrences all number
    27
    20
    0
    0
    16
    Upper respiratory tract infection
         subjects affected / exposed
    26 / 349 (7.45%)
    10 / 302 (3.31%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    10 / 342 (2.92%)
         occurrences all number
    31
    14
    0
    0
    10
    Urinary tract infection
         subjects affected / exposed
    70 / 349 (20.06%)
    62 / 302 (20.53%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    48 / 342 (14.04%)
         occurrences all number
    109
    93
    0
    0
    55
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    31 / 349 (8.88%)
    25 / 302 (8.28%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    16 / 342 (4.68%)
         occurrences all number
    47
    36
    0
    0
    23
    Hypomagnesaemia
         subjects affected / exposed
    39 / 349 (11.17%)
    9 / 302 (2.98%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    24 / 342 (7.02%)
         occurrences all number
    53
    10
    0
    0
    26
    Hypokalaemia
         subjects affected / exposed
    33 / 349 (9.46%)
    19 / 302 (6.29%)
    1 / 15 (6.67%)
    0 / 14 (0.00%)
    11 / 342 (3.22%)
         occurrences all number
    61
    28
    1
    0
    12
    Hypoalbuminaemia
         subjects affected / exposed
    19 / 349 (5.44%)
    19 / 302 (6.29%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    7 / 342 (2.05%)
         occurrences all number
    28
    22
    0
    0
    8
    Hyperkalaemia
         subjects affected / exposed
    34 / 349 (9.74%)
    24 / 302 (7.95%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    17 / 342 (4.97%)
         occurrences all number
    60
    36
    0
    0
    22
    Hyperglycaemia
         subjects affected / exposed
    23 / 349 (6.59%)
    14 / 302 (4.64%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    7 / 342 (2.05%)
         occurrences all number
    54
    16
    0
    0
    14
    Decreased appetite
         subjects affected / exposed
    121 / 349 (34.67%)
    72 / 302 (23.84%)
    0 / 15 (0.00%)
    0 / 14 (0.00%)
    95 / 342 (27.78%)
         occurrences all number
    147
    79
    0
    0
    122

    More information

    		 Close Top of page

    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Nov 2017
    Major changes of Amendment (AM) 2 included revision and simplification of the Statistical Analysis Plan.
    16 Mar 2018
    Major changes of AM 4 included a recommendation from the external Data Monitoring Committee to stop accrual to the pembrolizumab monotherapy arm for participants whose tumors are PD-L1 CPS<10%.
    23 Oct 2019
    Major changes of AM 6 included a revision the Statistical Analysis Plan in order to account for a potential delayed treatment effect, which was observed with immunotherapy study data external to this study.
    15 May 2020
    Major changes of AM 8 included the removal of the requirement for the final analysis of approximately 532 PFS events in the combo and chemo arms in all participants, due to a significant drop off in the accrual of PFS events.
    30 Jun 2021
    Major changes of AM 10 included updating the dose modification and toxicity management guidelines for immune-related adverse events (irAEs).

    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
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

    European Medicines Agency © 1995-Wed May 01 01:20:42 CEST 2024 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    EMA HMA