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    Clinical Trial Results:
    A Randomized, Double-Blind, Phase III Study of Pembrolizumab (MK-3475) plus Chemotherapy vs Placebo plus Chemotherapy for Previously Untreated Locally Recurrent Inoperable or Metastatic Triple Negative Breast Cancer

    Summary
    EudraCT number
    		 2016-001432-35
    Trial protocol
    		 DE   DK   IE   ES   CZ   HU   BE   NL   PL   FR  
    Global end of trial date
    30 Oct 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Nov 2024
    First version publication date
    14 Nov 2024
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    MK-3475-355
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02819518
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 MSD: KEYNOTE-355
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme LLC.
    Sponsor organisation address
    126 East Lincoln Avenue, P.O. Box 2000, Rahway, NJ, United States, 07065
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme LLC, ClinicalTrialsDisclosure@msd.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme LLC., ClinicalTrialsDisclosure@msd.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    30 Oct 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Jun 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Oct 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The study will consist of two parts. In Part 1, the safety of pembrolizumab (MK-3475) in combination with one of three different chemotherapies will be assessed in the treatment of locally recurrent inoperable or metastatic triple negative breast cancer (TNBC), which has not been previously treated with chemotherapy. In Part 2, the safety and efficacy of pembrolizumab plus background chemotherapy will be assessed compared to the safety and efficacy of placebo plus background chemotherapy in the treatment of locally recurrent inoperable or metastatic TNBC, which has not been previously treated with chemotherapy. The primary objective of Part 1 is to evaluate the safety and tolerability of the 3 pembrolizumab and chemotherapy combinations. The primary objectives of Part 2 are to compare the progression-free survival (PFS) and the overall survival (OS) of pembrolizumab and chemotherapy to placebo and chemotherapy.
    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
    27 Jul 2016
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 80 Months
    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
    Australia: 20
    Country: Number of subjects enrolled
    Belgium: 14
    Country: Number of subjects enrolled
    Brazil: 57
    Country: Number of subjects enrolled
    Canada: 34
    Country: Number of subjects enrolled
    Chile: 27
    Country: Number of subjects enrolled
    Colombia: 21
    Country: Number of subjects enrolled
    Czechia: 13
    Country: Number of subjects enrolled
    Denmark: 12
    Country: Number of subjects enrolled
    France: 29
    Country: Number of subjects enrolled
    Germany: 32
    Country: Number of subjects enrolled
    Hong Kong: 7
    Country: Number of subjects enrolled
    Hungary: 27
    Country: Number of subjects enrolled
    Ireland: 10
    Country: Number of subjects enrolled
    Italy: 4
    Country: Number of subjects enrolled
    Japan: 91
    Country: Number of subjects enrolled
    Korea, Republic of: 32
    Country: Number of subjects enrolled
    Malaysia: 24
    Country: Number of subjects enrolled
    Mexico: 27
    Country: Number of subjects enrolled
    Netherlands: 3
    Country: Number of subjects enrolled
    New Zealand: 3
    Country: Number of subjects enrolled
    Poland: 56
    Country: Number of subjects enrolled
    Russian Federation: 37
    Country: Number of subjects enrolled
    Spain: 35
    Country: Number of subjects enrolled
    Taiwan: 21
    Country: Number of subjects enrolled
    Türkiye: 41
    Country: Number of subjects enrolled
    Ukraine: 70
    Country: Number of subjects enrolled
    United Kingdom: 38
    Country: Number of subjects enrolled
    United States: 78
    Worldwide total number of subjects
    882
    EEA total number of subjects
    235
    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)
    688
    From 65 to 84 years
    193
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 35 participants were randomized to Part 1 (Safety Run-in) of the study, and 847 participants were randomized in Part 2 (phase 3) of the study. Twelve participants randomized to the Part 2: Pembrolizumab + Chemotherapy arm received a second course of pembrolizumab at the investigator's discretion.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Part 1: Pembrolizumab + Nab-Paclitaxel
    Arm description
    		 Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 21-day cycle PLUS nab-paclitaxel IV on Days 1, 8 and 15 of each 28-day cycle.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nab-paclitaxel
    Investigational medicinal product code
    Other name
    ABRAXANE®
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Nab-paclitaxel 100 mg/m^2 IV on Days 1, 8 and 15 of each 28-day cycle.

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    MK-3475 KEYTRUDA®
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants receive pembrolizumab 200 mg intravenously (IV) on Day 1 of each 21-day cycle

    Arm title
    		 Part 1: Pembrolizumab + Paclitaxel
    Arm description
    		 Participants received pembrolizumab 200 mg IV on Day 1 of each 21-day cycle PLUS paclitaxel IV on Days 1, 8 and 15 of each 28-day cycle.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    TAXOL®
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    paclitaxel 90 mg/m^2 IV on Days 1, 8 and 15 of each 28-day cycle.

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    MK-3475 KEYTRUDA®
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants receive pembrolizumab 200 mg intravenously (IV) on Day 1 of each 21-day cycle

    Arm title
    		 Part 1: Pembrolizumab + Gemcitabine/Carboplatin
    Arm description
    		 Participants received pembrolizumab 200 mg IV on Day 1 of each 21-day cycle PLUS gemcitabine/carboplatin (gemcitabine) and an Area Under the Curve (AUC) 2 (carboplatin) on Days 1 and 8 of each 21-day cycle.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    MK-3475 KEYTRUDA®
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants receive pembrolizumab 200 mg intravenously (IV) on Day 1 of each 21-day cycle

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    PARAPLATIN®
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Area Under the Curve (AUC) 2 on Days 1 and 8 of each 21-day cycle.

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    GEMZAR®
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Gemcitabine1000 mg/m^2 on Days 1 and 8 of each 21-day cycle.

    Arm title
    		 Part 2: Pembrolizumab + Chemotherapy
    Arm description
    		 Participants received pembrolizumab 200 mg IV on Day 1 of each 21-day cycle PLUS one of three background chemotherapy regimens at investigator's discretion: 1) nab-paclitaxel IV on Days 1, 8 and 15 of each 28-day cycle, 2) paclitaxel IV on Days 1, 8 and 15 of each 28-day cycle, OR 3) gemcitabine/carboplatin (gemcitabine) and an AUC 2 (carboplatin) on Days 1 and 8 of each 21-day cycle. Qualified participants who received first course of pembrolizumab but continued to experience disease progression were eligible to initiate a second course of pembrolizumab IV Q3W for up to 17 administrations (up to ~1 year).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    MK-3475 KEYTRUDA®
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants receive pembrolizumab 200 mg intravenously (IV) on Day 1 of each 21-day cycle

    Investigational medicinal product name
    Chemotherapy
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    one of three background chemotherapy regimens at investigator's discretion: 1) nabpaclitaxel 100 mg/m^2 IV on Days 1, 8 and 15 of each 28-day cycle, 2) paclitaxel 90 mg/m^2 IV on Days 1, 8 and 15 of each 28- day cycle, OR 3) gemcitabine/carboplatin 1000 mg/m^2 (gemcitabine) and an AUC 2 (carboplatin) on Days 1 and 8 of each 21-day cycle.

    Arm title
    		 Part 2: Placebo + Chemotherapy
    Arm description
    		 Participants received placebo (normal saline) IV on Day 1 of each 21-day cycle PLUS one of three background chemotherapy regimens at investigator's discretion: 1) nab-paclitaxel 100 mg/m^2 IV on Days 1, 8 and 15 of each 28-day cycle, 2) paclitaxel 90 mg/m^2 IV on Days 1, 8 and 15 of each 28-day cycle, OR 3) gemcitabine/carboplatin 1000 mg/m^2 (gemcitabine) and an AUC 2 (carboplatin) on Days 1 and 8 of each 21-day cycle
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Chemotherapy
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    one of three background chemotherapy regimens at investigator's discretion: 1) nabpaclitaxel 100 mg/m^2 IV on Days 1, 8 and 15 of each 28-day cycle, 2) paclitaxel 90 mg/m^2 IV on Days 1, 8 and 15 of each 28- day cycle, OR 3) gemcitabine/carboplatin 1000 mg/m^2 (gemcitabine) and an AUC 2 (carboplatin) on Days 1 and 8 of each 21-day cycle.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants receive placebo (normal saline) IV on Day 1 of each 21-day cycle

    Number of subjects in period 1
    		Part 1: Pembrolizumab + Nab-Paclitaxel Part 1: Pembrolizumab + Paclitaxel Part 1: Pembrolizumab + Gemcitabine/Carboplatin Part 2: Pembrolizumab + Chemotherapy Part 2: Placebo + Chemotherapy
    Started
    11
    14
    10
    566
    281
    Completed
    0
    0
    0
    0
    0
    Not completed
    11
    14
    10
    566
    281
         Adverse event, serious fatal
    9
    12
    9
    475
    244
         Consent withdrawn by subject
    -
    -
    -
    25
    8
         Sponsor Decision
    1
    1
    -
    34
    17
         Transferred to extension study
    1
    1
    1
    32
    11
         Lost to follow-up
    -
    -
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part 1: Pembrolizumab + Nab-Paclitaxel
    Reporting group description
    		 Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 21-day cycle PLUS nab-paclitaxel IV on Days 1, 8 and 15 of each 28-day cycle.

    Reporting group title
    Part 1: Pembrolizumab + Paclitaxel
    Reporting group description
    		 Participants received pembrolizumab 200 mg IV on Day 1 of each 21-day cycle PLUS paclitaxel IV on Days 1, 8 and 15 of each 28-day cycle.

    Reporting group title
    Part 1: Pembrolizumab + Gemcitabine/Carboplatin
    Reporting group description
    		 Participants received pembrolizumab 200 mg IV on Day 1 of each 21-day cycle PLUS gemcitabine/carboplatin (gemcitabine) and an Area Under the Curve (AUC) 2 (carboplatin) on Days 1 and 8 of each 21-day cycle.

    Reporting group title
    Part 2: Pembrolizumab + Chemotherapy
    Reporting group description
    		 Participants received pembrolizumab 200 mg IV on Day 1 of each 21-day cycle PLUS one of three background chemotherapy regimens at investigator's discretion: 1) nab-paclitaxel IV on Days 1, 8 and 15 of each 28-day cycle, 2) paclitaxel IV on Days 1, 8 and 15 of each 28-day cycle, OR 3) gemcitabine/carboplatin (gemcitabine) and an AUC 2 (carboplatin) on Days 1 and 8 of each 21-day cycle. Qualified participants who received first course of pembrolizumab but continued to experience disease progression were eligible to initiate a second course of pembrolizumab IV Q3W for up to 17 administrations (up to ~1 year).

    Reporting group title
    Part 2: Placebo + Chemotherapy
    Reporting group description
    		 Participants received placebo (normal saline) IV on Day 1 of each 21-day cycle PLUS one of three background chemotherapy regimens at investigator's discretion: 1) nab-paclitaxel 100 mg/m^2 IV on Days 1, 8 and 15 of each 28-day cycle, 2) paclitaxel 90 mg/m^2 IV on Days 1, 8 and 15 of each 28-day cycle, OR 3) gemcitabine/carboplatin 1000 mg/m^2 (gemcitabine) and an AUC 2 (carboplatin) on Days 1 and 8 of each 21-day cycle

    Reporting group values
    		 Part 1: Pembrolizumab + Nab-Paclitaxel Part 1: Pembrolizumab + Paclitaxel Part 1: Pembrolizumab + Gemcitabine/Carboplatin Part 2: Pembrolizumab + Chemotherapy Part 2: Placebo + Chemotherapy Total
    Number of subjects
    		 11 14 10 566 281 882
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0 0
        Adults (18-64 years)
    		 7 8 6 443 224 688
        From 65-84 years
    		 4 6 4 122 57 193
        85 years and over
    		 0 0 0 1 0 1
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 54.6 ( 13.5 ) 60.4 ( 15.3 ) 59.6 ( 11.7 ) 53.5 ( 12.7 ) 53.0 ( 12.7 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 11 14 10 566 281 882
        Male
    		 0 0 0 0 0 0
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 11 1 12
        Asian
    		 4 7 4 123 52 190
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0 0
        Black or African American
    		 1 0 0 20 17 38
        White
    		 6 7 6 384 195 598
        More than one race
    		 0 0 0 11 8 19
        Unknown or Not Reported
    		 0 0 0 17 8 25
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 1 0 0 116 48 165
        Not Hispanic or Latino
    		 9 14 10 423 218 674
        Unknown or Not Reported
    		 1 0 0 27 15 43
    Programmed Cell Death Ligand 1 (PD-L1) Status (Combined Positive Score [CPS] Cutoff of 1)
    PD-L1 protein expression in triple-negative breast cancer (TNBC) is determined by using CPS, which is the number of PD-L1 staining cells (tumor cells, lymphocytes, macrophages) divided by the total number of viable tumor cells, multiplied by 100. The number of participants with PD-L1 Status CPS<1 and CPS≥1 at baseline is presented.
    Units: Subjects
        PD-L1 CPS ≥1
    		 8 12 7 425 211 663
        PD-L1 CPS <1
    		 3 2 3 141 70 219
    PD-L1 Status (CPS Cutoff of 10)
    PD-L1 protein expression in TNBC is determined by using CPS, which is the number of PD-L1 staining cells (tumor cells, lymphocytes, macrophages) divided by the total number of viable tumor cells, multiplied by 100. The number of participants with PD-L1 Status CPS<10 and CPS≥10 at baseline is presented.
    Units: Subjects
        PD-L1 CPS ≥10
    		 1 9 4 220 103 337
        PD-L1 CPS <10
    		 10 5 6 346 178 545

    End points

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    End points reporting groups
    Reporting group title
    Part 1: Pembrolizumab + Nab-Paclitaxel
    Reporting group description
    		 Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 21-day cycle PLUS nab-paclitaxel IV on Days 1, 8 and 15 of each 28-day cycle.

    Reporting group title
    Part 1: Pembrolizumab + Paclitaxel
    Reporting group description
    		 Participants received pembrolizumab 200 mg IV on Day 1 of each 21-day cycle PLUS paclitaxel IV on Days 1, 8 and 15 of each 28-day cycle.

    Reporting group title
    Part 1: Pembrolizumab + Gemcitabine/Carboplatin
    Reporting group description
    		 Participants received pembrolizumab 200 mg IV on Day 1 of each 21-day cycle PLUS gemcitabine/carboplatin (gemcitabine) and an Area Under the Curve (AUC) 2 (carboplatin) on Days 1 and 8 of each 21-day cycle.

    Reporting group title
    Part 2: Pembrolizumab + Chemotherapy
    Reporting group description
    		 Participants received pembrolizumab 200 mg IV on Day 1 of each 21-day cycle PLUS one of three background chemotherapy regimens at investigator's discretion: 1) nab-paclitaxel IV on Days 1, 8 and 15 of each 28-day cycle, 2) paclitaxel IV on Days 1, 8 and 15 of each 28-day cycle, OR 3) gemcitabine/carboplatin (gemcitabine) and an AUC 2 (carboplatin) on Days 1 and 8 of each 21-day cycle. Qualified participants who received first course of pembrolizumab but continued to experience disease progression were eligible to initiate a second course of pembrolizumab IV Q3W for up to 17 administrations (up to ~1 year).

    Reporting group title
    Part 2: Placebo + Chemotherapy
    Reporting group description
    		 Participants received placebo (normal saline) IV on Day 1 of each 21-day cycle PLUS one of three background chemotherapy regimens at investigator's discretion: 1) nab-paclitaxel 100 mg/m^2 IV on Days 1, 8 and 15 of each 28-day cycle, 2) paclitaxel 90 mg/m^2 IV on Days 1, 8 and 15 of each 28-day cycle, OR 3) gemcitabine/carboplatin 1000 mg/m^2 (gemcitabine) and an AUC 2 (carboplatin) on Days 1 and 8 of each 21-day cycle

    Subject analysis set title
    As treated: Pembrolizumab + Nab-Paclitaxel
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    One participant randomized did not receive treatment. 3 participants randomized to Pembrolizumab + Paclitaxel group received Pembrolizumab + Nab-Paclitaxel treatment in error

    Subject analysis set title
    As Treated: Pembrolizumab + Paclitaxel
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    3 participants randomized to Pembrolizumab + Paclitaxel received pembrolizumab + Nab-Paclitaxel in error; 1 participant received Pembrolizumab + Gemcitabine/Carboplatin in error

    Subject analysis set title
    As treated: Pembrolizumab + Gemcitabine/Carboplatin
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    1 participant randomized to Pembrolizumab + Paclitaxel group received Pembrolizumab + Gemcitabine/Carboplatin in error

    Subject analysis set title
    As treated: Pembrolizumab + Chemotherapy
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    4 participants were randomized but not treated

    Subject analysis set title
    As Treated: Placebo + Chemotherapy
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All participants as treated

    Primary: Part 1: Percentage of Participants Who Experienced an Adverse Event (AE) - All Participants

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    End point title
    		 Part 1: Percentage of Participants Who Experienced an Adverse Event (AE) - All Participants [1]
    End point description
    An AE is defined as any unfavorable and unintended sign, symptom, disease, or worsening of preexisting condition temporally associated with study treatment and irrespective of causality to study treatment. The population analyzed included all randomly assigned participants who received at least 1 dose of study intervention were included in the group corresponding to the study intervention actually received. Four participants assigned to the pembrolizumab + paclitaxel group received incorrect chemotherapy in error: 3 participants received pembrolizumab + nab-paclitaxel and 1 received pembrolizumab + gemcitabine/carboplatin.
    End point type
    Primary
    End point timeframe
    Up to approximately 39 months
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Per protocol, the end point only included participants in Part 2 of the study.
    End point values
    		 As treated: Pembrolizumab + Nab-Paclitaxel As Treated: Pembrolizumab + Paclitaxel As treated: Pembrolizumab + Gemcitabine/Carboplatin
    Number of subjects analysed
    13
    10
    11
    Units: Percentage of Participants
        number (not applicable)
    100.0
    100.0
    100.0
    No statistical analyses for this end point

    Primary: Part 1: Percentage of Participants Who Discontinued Study Drug Due to an AE - All Participants

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    End point title
    		 Part 1: Percentage of Participants Who Discontinued Study Drug Due to an AE - All Participants [2]
    End point description
    An AE is defined as any unfavorable and unintended sign, symptom, disease, or worsening of preexisting condition temporally associated with study treatment and irrespective of causality to study treatment. The population analyzed included all randomly assigned participants who received at least 1 dose of study intervention were included in the group corresponding to the study intervention actually received. Four participants assigned to the pembrolizumab + paclitaxel group received incorrect chemotherapy in error: 3 participants received pembrolizumab + nab-paclitaxel and 1 received pembrolizumab + gemcitabine/carboplatin.
    End point type
    Primary
    End point timeframe
    Up to approximately 39 months
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Per protocol, the end point only included participants in Part 2 of the study.
    End point values
    		 As treated: Pembrolizumab + Nab-Paclitaxel As Treated: Pembrolizumab + Paclitaxel As treated: Pembrolizumab + Gemcitabine/Carboplatin
    Number of subjects analysed
    13
    10
    11
    Units: Percentage of Participants
        number (not applicable)
    38.5
    50.0
    27.3
    No statistical analyses for this end point

    Primary: Part 2: Progression-Free Survival (PFS) - All Participants

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    End point title
    		 Part 2: Progression-Free Survival (PFS) - All Participants [3]
    End point description
    Progression-free survival was defined as the time from randomization to the first documented progressive disease (PD) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) based on assessments by blinded independent central review (BICR) or death due to any cause, whichever occurs 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 must also have demonstrated an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. Participants were analyzed in the treatment arm to which they were randomly assigned, regardless of whether they received treatment
    End point type
    Primary
    End point timeframe
    Up to approximately 53 months
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, the end point only included participants in Part 2 of the study.
    End point values
    		 Part 2: Pembrolizumab + Chemotherapy Part 2: Placebo + Chemotherapy
    Number of subjects analysed
    566
    281
    Units: Months
        median (confidence interval 95%)
    7.5 (6.3 to 7.7)
    5.6 (5.4 to 7.2)
    Statistical analysis title
    		 Hazard Ratio of PFS
    Statistical analysis description
    Based on Cox regression model with treatment as a covariate stratified by chemotherapy on study, tumor PD-L1 status, and prior treatment with same class of chemotherapy in the (neo)adjuvant setting.
    Comparison groups
    Part 2: Pembrolizumab + Chemotherapy v Part 2: Placebo + Chemotherapy
    Number of subjects included in analysis
    847
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.012 [4]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 0.98
    Notes
    [4] - One-sided p-value based on log-rank test stratified by chemotherapy (taxane versus [vs] gemcitabine/carboplatin), tumor PD-L1 status (CPS ≥1 vs CPS <1) and prior treatment with same class of chemotherapy in the (neo)adjuvant setting (yes vs. no).

    Primary: Part 2: Overall Survival (OS) - All Participants

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    End point title
    		 Part 2: Overall Survival (OS) - All Participants [5]
    End point description
    Overall survival is defined as the time from randomization to death due to any cause. Participants without documented death at the time of the analysis were censored at the date of the last follow-up. Participants were analyzed in the treatment arm to which they were randomly assigned, regardless of whether they received treatment.
    End point type
    Primary
    End point timeframe
    Up to approximately 53 months
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, the end point only included participants in Part 2 of the study.
    End point values
    		 Part 2: Pembrolizumab + Chemotherapy Part 2: Placebo + Chemotherapy
    Number of subjects analysed
    566
    281
    Units: Months
        median (confidence interval 95%)
    17.2 (15.3 to 19.0)
    15.5 (13.9 to 17.2)
    Statistical analysis title
    		 Hazard Ratio of OS
    Statistical analysis description
    One-sided p-value based on log-rank test stratified by chemotherapy on study (taxane vs gemcitabine/carboplatin), tumor PD-L1 status (CPS ≥1 vs CPS <1) and prior treatment with same class of chemotherapy in the (neo)adjuvant setting (yes vs no).
    Comparison groups
    Part 2: Pembrolizumab + Chemotherapy v Part 2: Placebo + Chemotherapy
    Number of subjects included in analysis
    847
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0797 [6]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.76
         upper limit
    		 1.05
    Notes
    [6] - One-sided p-value based on log-rank test stratified by chemotherapy on study (taxane vs gemcitabine/carboplatin), tumor PD-L1 status (CPS ≥1 vs CPS <1) and prior treatment with same class of chemotherapy in the (neo)adjuvant setting (yes vs no).

    Primary: Part 2: PFS - Participants with Programmed Cell Death-Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥1 Tumors

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    End point title
    		 Part 2: PFS - Participants with Programmed Cell Death-Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥1 Tumors [7]
    End point description
    Progression-free survival was defined as the time from randomization to the first documented PD per RECIST 1.1 based on assessments by BICR or death due to any cause, whichever occurs 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 must also have demonstrated an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. Participants with PD-L1 CPS ≥1 tumors were analyzed in the treatment arm to which they were randomly assigned, regardless of whether they received treatment.
    End point type
    Primary
    End point timeframe
    Up to approximately 53 months
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, the end point only included participants in Part 2 of the study.
    End point values
    		 Part 2: Pembrolizumab + Chemotherapy Part 2: Placebo + Chemotherapy
    Number of subjects analysed
    425
    211
    Units: Months
        median (confidence interval 95%)
    7.6 (6.6 to 8.0)
    5.6 (5.4 to 7.4)
    Statistical analysis title
    		 Hazard Ratio of PFS
    Statistical analysis description
    Based on Cox regression model with treatment as a covariate stratified by chemotherapy on study, and prior treatment with same class of chemotherapy in the (neo)adjuvant setting.
    Comparison groups
    Part 2: Pembrolizumab + Chemotherapy v Part 2: Placebo + Chemotherapy
    Number of subjects included in analysis
    636
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0016 [8]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.62
         upper limit
    		 0.91
    Notes
    [8] - One-sided p-value based on log-rank test stratified by chemotherapy on study (taxane vs gemcitabine/carboplatin), and prior treatment with same class of chemotherapy in the (neo)adjuvant setting (yes vs no).

    Primary: Part 2: PFS - Participants with PD-L1 CPS ≥10 Tumors

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    End point title
    		 Part 2: PFS - Participants with PD-L1 CPS ≥10 Tumors
    End point description
    Progression-free survival was defined as the time from randomization to the first documented PD per RECIST 1.1 based on assessments by BICR or death due to any cause, whichever occurs 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 must also have demonstrated an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. Participants with PD-L1 CPS ≥10 tumors were analyzed in the treatment arm to which they were randomly assigned, regardless of whether they received treatment,
    End point type
    Primary
    End point timeframe
    Up to approximately 53 months
    End point values
    		 As treated: Pembrolizumab + Chemotherapy As Treated: Placebo + Chemotherapy
    Number of subjects analysed
    220
    103
    Units: Months
        median (confidence interval 95%)
    9.7 (7.6 to 11.3)
    5.6 (5.3 to 7.5)
    Statistical analysis title
    		 Hazard Ratio of PFS
    Statistical analysis description
    Based on Cox regression model with treatment as a covariate stratified by chemotherapy on study, and prior treatment with same class of chemotherapy in the (neo)adjuvant setting.
    Comparison groups
    As Treated: Placebo + Chemotherapy v As treated: Pembrolizumab + Chemotherapy
    Number of subjects included in analysis
    323
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0018 [9]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 0.88
    Notes
    [9] - One-sided p-value based on log-rank test stratified by chemotherapy on study (taxane vs gemcitabine/carboplatin), and prior treatment with same class of chemotherapy in the (neo)adjuvant setting (yes vs no).

    Primary: Part 2: OS - Participants with PD-L1 CPS ≥1 Tumors

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    End point title
    		 Part 2: OS - Participants with PD-L1 CPS ≥1 Tumors [10]
    End point description
    Overall survival is defined as the time from randomization to death due to any cause. Participants without documented death at the time of the analysis were censored at the date of the last follow-up. Participants with PD-L1 CPS ≥1 tumors were analyzed in the treatment arm to which they were randomly assigned, regardless of whether they received treatment
    End point type
    Primary
    End point timeframe
    Up to approximately 53 months
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, the end point only included participants in Part 2 of the study.
    End point values
    		 Part 2: Pembrolizumab + Chemotherapy Part 2: Placebo + Chemotherapy
    Number of subjects analysed
    425
    211
    Units: Months
        median (confidence interval 95%)
    17.6 (15.5 to 19.5)
    16.0 (12.8 to 17.4)
    Statistical analysis title
    		 Hazard Ratio of OS
    Statistical analysis description
    Based on Cox regression model with treatment as a covariate stratified by chemotherapy on study, and prior treatment with same class of chemotherapy in the (neo)adjuvant setting.
    Comparison groups
    Part 2: Pembrolizumab + Chemotherapy v Part 2: Placebo + Chemotherapy
    Number of subjects included in analysis
    636
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0563 [11]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.72
         upper limit
    		 1.04
    Notes
    [11] - One-sided p-value based on log-rank test stratified by chemotherapy on study (taxane vs gemcitabine/carboplatin), and prior treatment with same class of chemotherapy in the (neo)adjuvant setting (yes vs no).

    Primary: Part 2: OS - Participants with PD-L1 CPS ≥10 Tumors

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    End point title
    		 Part 2: OS - Participants with PD-L1 CPS ≥10 Tumors [12]
    End point description
    Overall survival is defined as the time from randomization to death due to any cause. Participants without documented death at the time of the analysis were censored at the date of the last follow-up. Participants with PD-L1 CPS ≥10 tumors were analyzed in the treatment arm to which they were randomly assigned, regardless of whether they received treatment.
    End point type
    Primary
    End point timeframe
    Up to approximately 53 months
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, the end point only included participants in Part 2 of the study.
    End point values
    		 Part 2: Pembrolizumab + Chemotherapy Part 2: Placebo + Chemotherapy
    Number of subjects analysed
    220
    103
    Units: Months
        median (confidence interval 95%)
    23.0 (19.0 to 26.3)
    16.1 (12.6 to 18.8)
    Statistical analysis title
    		 Hazard Ratio of OS
    Statistical analysis description
    Based on Cox regression model with treatment as a covariate stratified by chemotherapy on study, and prior treatment with same class of chemotherapy in the (neo)adjuvant setting.
    Comparison groups
    Part 2: Pembrolizumab + Chemotherapy v Part 2: Placebo + Chemotherapy
    Number of subjects included in analysis
    323
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0093 [13]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.55
         upper limit
    		 0.95
    Notes
    [13] - One-sided p-value based on log-rank test stratified by chemotherapy on study (taxane vs gemcitabine/carboplatin), and prior treatment with same class of chemotherapy in the (neo)adjuvant setting (yes vs no).

    Secondary: Part 2: Objective Response Rate (ORR) - All Participants

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    End point title
    		 Part 2: Objective Response Rate (ORR) - All Participants [14]
    End point description
    Objective response rate is defined as the percentage of participants in the analysis population who have a complete response (CR: disappearance of all target lesions) or partial response (PR: at least a 30% decrease in the sum of diameters of target lesions). The percentage of participants who experienced a CR or PR as assessed by BICR based on RECIST 1.1 is presented. Participants were analyzed in the treatment arm to which they were randomly assigned, regardless of whether they received treatment.
    End point type
    Secondary
    End point timeframe
    Up to approximately 53 months
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, the end point only included participants in Part 2 of the study.
    End point values
    		 Part 2: Pembrolizumab + Chemotherapy Part 2: Placebo + Chemotherapy
    Number of subjects analysed
    566
    281
    Units: Percentage of Participants
        number (confidence interval 95%)
    40.8 (36.7 to 45.0)
    37.0 (31.4 to 42.9)
    Statistical analysis title
    		 Difference in ORR (%) vs. Control
    Statistical analysis description
    Based on Miettinen & Nurminen method stratified by chemotherapy on study (taxane vs gemcitabine/carboplatin), tumor PD-L1 status (CPS ≥1 vs CPS <1) and prior treatment with same class of chemotherapy in the (neo)adjuvant setting (yes vs no).
    Comparison groups
    Part 2: Pembrolizumab + Chemotherapy v Part 2: Placebo + Chemotherapy
    Number of subjects included in analysis
    847
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1413
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in ORR (%) vs. Control
    Point estimate
    3.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.2
         upper limit
    		 10.6

    Secondary: Part 2: ORR - Participants With PD-L1 CPS ≥10 Tumors

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    End point title
    		 Part 2: ORR - Participants With PD-L1 CPS ≥10 Tumors [15]
    End point description
    Objective response rate is defined as the percentage of participants in the analysis population who have a complete response (CR: disappearance of all target lesions) or partial response (PR: at least a 30% decrease in the sum of diameters of target lesions). The percentage of participants who experienced a CR or PR as assessed by BICR based on RECIST 1.1 is presented. Participants with PD-L1 CPS ≥10 tumors were analyzed in the treatment arm to which they were randomly assigned, regardless of whether they received treatment.
    End point type
    Secondary
    End point timeframe
    Up to approximately 53 months
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, the end point only included participants in Part 2 of the study.
    End point values
    		 Part 2: Pembrolizumab + Chemotherapy Part 2: Placebo + Chemotherapy
    Number of subjects analysed
    220
    103
    Units: Percentage of Participants
        number (confidence interval 95%)
    52.7 (45.9 to 59.5)
    40.8 (31.2 to 50.9)
    Statistical analysis title
    		 Difference in ORR(%) vs. Control
    Statistical analysis description
    Based on Miettinen & Nurminen method stratified by chemotherapy on study (taxane vs gemcitabine/carboplatin) and prior treatment with same class of chemotherapy in the (neo)adjuvant setting (yes vs no).
    Comparison groups
    Part 2: Pembrolizumab + Chemotherapy v Part 2: Placebo + Chemotherapy
    Number of subjects included in analysis
    323
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0213
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in ORR(%) vs. Control
    Point estimate
    12.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4
         upper limit
    		 23.4

    Secondary: Part 2: ORR - Participants With PD-L1 CPS ≥1 Tumors

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    End point title
    		 Part 2: ORR - Participants With PD-L1 CPS ≥1 Tumors [16]
    End point description
    Objective response rate is defined as the percentage of participants in the analysis population who have a complete response (CR: disappearance of all target lesions) or partial response (PR: at least a 30% decrease in the sum of diameters of target lesions). The percentage of participants who experienced a CR or PR as assessed by BICR based on RECIST 1.1 is presented. Participants with PD-L1 CPS ≥1 tumors were analyzed in the treatment arm to which they were randomly assigned, regardless of whether they received treatment
    End point type
    Secondary
    End point timeframe
    Up to approximately 53 months
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, the end point only included participants in Part 2 of the study.
    End point values
    		 Part 2: Pembrolizumab + Chemotherapy Part 2: Placebo + Chemotherapy
    Number of subjects analysed
    425
    211
    Units: Percentage of Participants
        number (confidence interval 95%)
    44.9 (40.1 to 49.8)
    38.9 (32.2 to 45.8)
    Statistical analysis title
    		 Difference in ORR (%) vs. Control
    Statistical analysis description
    Based on Miettinen & Nurminen method stratified by chemotherapy on study (taxane vs gemcitabine/carboplatin), and prior treatment with same class of chemotherapy in the (neo)adjuvant setting (yes vs no).
    Comparison groups
    Part 2: Pembrolizumab + Chemotherapy v Part 2: Placebo + Chemotherapy
    Number of subjects included in analysis
    636
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0725
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in ORR (%) vs. Control
    Point estimate
    6.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.1
         upper limit
    		 14

    Secondary: Part 2: DOR – Participants With PD-L1 CPS ≥10 Tumors

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    End point title
    		 Part 2: DOR – Participants With PD-L1 CPS ≥10 Tumors [17]
    End point description
    For participants who demonstrate a confirmed CR (Disappearance of all target lesions) or confirmed PR (At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1, DOR is defined as the time from first documented evidence of CR or PR until progressive disease (PD) or death due to any cause, whichever occurs first. 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 must also have demonstrated an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered PD. A value of 9999 indicates median, upper limit, lower limit not reached due to insufficient number of responding participants with relapse. The population analyzed included all randomized participants, regardless of whether they received study treatment, who demonstrated a confirmed response (CR or PR). Participants were included in the treatment arm to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Up to approximately 53 months
    Notes
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, the end point only included participants in Part 2 of the study.
    End point values
    		 Part 2: Pembrolizumab + Chemotherapy Part 2: Placebo + Chemotherapy
    Number of subjects analysed
    116
    42
    Units: Months
        median (full range (min-max))
    9999 (9999 to 9999)
    7.3 (1.5 to 9999)
    No statistical analyses for this end point

    Secondary: Part 2: DOR – Participants With PD-L1 CPS ≥1 Tumors

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    End point title
    		 Part 2: DOR – Participants With PD-L1 CPS ≥1 Tumors [18]
    End point description
    For participants who demonstrate a confirmed CR (Disappearance of all target lesions) or confirmed PR (At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1, DOR is defined as the time from first documented evidence of CR or PR until progressive disease (PD) or death due to any cause, whichever occurs first. 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 must also have demonstrated an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered PD. A value of 9999 indicates median, upper limit, lower limit not reached due to insufficient number of responding participants with relapse. The population analyzed included all randomized participants, regardless of whether they received study treatment, who demonstrated a confirmed response (CR or PR). Participants were included in the treatment arm to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Up to approximately 53 months
    Notes
    [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, the end point only included participants in Part 2 of the study.
    End point values
    		 Part 2: Pembrolizumab + Chemotherapy Part 2: Placebo + Chemotherapy
    Number of subjects analysed
    191
    82
    Units: Months
        median (full range (min-max))
    9999 (9999 to 9999)
    6.8 (1.5 to 9999)
    No statistical analyses for this end point

    Secondary: Part 2: Duration of Response (DOR) - All Participants

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    End point title
    		 Part 2: Duration of Response (DOR) - All Participants [19]
    End point description
    For participants who demonstrate a confirmed CR (Disappearance of all target lesions) or confirmed PR (At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1, DOR is defined as the time from first documented evidence of CR or PR until progressive disease (PD) or death due to any cause, whichever occurs first. 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 must also have demonstrated an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered PD. A value of 9999 indicates median, upper limit, lower limit not reached due to insufficient number of responding participants with relapse. The population analyzed included all randomized participants, regardless of whether they received study treatment, who demonstrated a confirmed response (CR or PR). Participants were included in the treatment arm to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Up to approximately 53 months
    Notes
    [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, the end point only included participants in Part 2 of the study.
    End point values
    		 Part 2: Pembrolizumab + Chemotherapy Part 2: Placebo + Chemotherapy
    Number of subjects analysed
    231
    104
    Units: Months
        median (full range (min-max))
    9999 (9999 to 9999)
    6.5 (1.5 to 9999)
    No statistical analyses for this end point

    Secondary: Part 2: Disease Control Rate (DCR) - All Participants

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    End point title
    		 Part 2: Disease Control Rate (DCR) - All Participants [20]
    End point description
    Disease control rate is defined as the percentage of participants who have achieved CR (disappearance of all target lesions) or PR (At least a 30% decrease in the sum of diameters of target lesions) or have demonstrated stable disease (SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease [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 is also considered PD]) for at least 24 weeks, based on assessments by BICR per RECIST 1.1.
    End point type
    Secondary
    End point timeframe
    Up to approximately 53 months
    Notes
    [20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, the end point only included participants in Part 2 of the study.
    End point values
    		 Part 2: Pembrolizumab + Chemotherapy Part 2: Placebo + Chemotherapy
    Number of subjects analysed
    566
    281
    Units: Percentage of Participants
        number (confidence interval 95%)
    56.0 (51.8 to 60.1)
    51.2 (45.2 to 57.2)
    Statistical analysis title
    		 Difference in DCR (%) vs. control
    Statistical analysis description
    Based on Miettinen & Nurminen method stratified by chemotherapy on study (taxane vs gemcitabine/carboplatin), tumor PD-L1 status (CPS ≥1 vs CPS <1) and prior treatment with same class of chemotherapy in the (neo) adjuvant setting (yes vs no).
    Comparison groups
    Part 2: Pembrolizumab + Chemotherapy v Part 2: Placebo + Chemotherapy
    Number of subjects included in analysis
    847
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0966
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in DCR (%) vs. control
    Point estimate
    4.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.4
         upper limit
    		 11.8

    Secondary: Part 2: DCR – Participants With PD-L1 CPS ≥1 Tumors

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    End point title
    		 Part 2: DCR – Participants With PD-L1 CPS ≥1 Tumors [21]
    End point description
    Disease control rate is defined as the percentage of participants who have achieved CR (disappearance of all target lesions) or PR (At least a 30% decrease in the sum of diameters of target lesions) or have demonstrated stable disease (SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease [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 is also considered PD]) for at least 24 weeks, based on assessments by BICR per RECIST 1.1.
    End point type
    Secondary
    End point timeframe
    Up to approximately 53 months
    Notes
    [21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, the end point only included participants in Part 2 of the study.
    End point values
    		 Part 2: Pembrolizumab + Chemotherapy Part 2: Placebo + Chemotherapy
    Number of subjects analysed
    425
    211
    Units: Percentage of Participants
        number (confidence interval 95%)
    58.6 (53.7 to 63.3)
    53.6 (46.6 to 60.4)
    Statistical analysis title
    		 Difference in DCR (%) vs. Control
    Statistical analysis description
    Based on Miettinen & Nurminen method stratified by chemotherapy on study (taxane vs gemcitabine/carboplatin) and prior treatment with same class of chemotherapy in the (neo) adjuvant setting (yes vs no).
    Comparison groups
    Part 2: Pembrolizumab + Chemotherapy v Part 2: Placebo + Chemotherapy
    Number of subjects included in analysis
    636
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1164
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in DCR (%) vs. Control
    Point estimate
    5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.2
         upper limit
    		 13.1

    Secondary: Part 2: Percentage of Participants Who Discontinued Study Drug Due to an AE- All Participants

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    End point title
    		 Part 2: Percentage of Participants Who Discontinued Study Drug Due to an AE- All Participants [22]
    End point description
    An AE is defined as any unfavorable and unintended sign, symptom, disease, or worsening of preexisting condition temporally associated with study treatment and irrespective of causality to study treatment.
    End point type
    Secondary
    End point timeframe
    Up to approximately 81 months
    Notes
    [22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, the end point only included participants in Part 2 of the study.
    End point values
    		 Part 2: Pembrolizumab + Chemotherapy Part 2: Placebo + Chemotherapy
    Number of subjects analysed
    562
    281
    Units: Percentage of Participants
        number (not applicable)
    20.5
    13.2
    No statistical analyses for this end point

    Secondary: Part 2: DCR – Participants With PD-L1 CPS ≥10 Tumors

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    End point title
    		 Part 2: DCR – Participants With PD-L1 CPS ≥10 Tumors [23]
    End point description
    Disease control rate is defined as the percentage of participants who have achieved CR (disappearance of all target lesions) or PR (At least a 30% decrease in the sum of diameters of target lesions) or have demonstrated stable disease (SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease [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 is also considered PD]) for at least 24 weeks, based on assessments by BICR per RECIST 1.1.
    End point type
    Secondary
    End point timeframe
    Up to approximately 53 months
    Notes
    [23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, the end point only included participants in Part 2 of the study.
    End point values
    		 Part 2: Pembrolizumab + Chemotherapy Part 2: Placebo + Chemotherapy
    Number of subjects analysed
    220
    103
    Units: Percentage of Participants
        number (confidence interval 95%)
    65.0 (58.3 to 71.3)
    54.4 (44.3 to 64.2)
    Statistical analysis title
    		 Difference in DCR (%) vs. Control
    Statistical analysis description
    Based on Miettinen & Nurminen method stratified by chemotherapy on study (taxane vs gemcitabine/carboplatin) and prior treatment with same class of chemotherapy in the (neo) adjuvant setting (yes vs no).
    Comparison groups
    Part 2: Pembrolizumab + Chemotherapy v Part 2: Placebo + Chemotherapy
    Number of subjects included in analysis
    323
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0327
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in DCR (%) vs. Control
    Point estimate
    10.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.7
         upper limit
    		 22.3

    Secondary: Part 2: Percentage of Participants Who Experienced an AE- All Participants

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    End point title
    		 Part 2: Percentage of Participants Who Experienced an AE- All Participants [24]
    End point description
    An AE is defined as any unfavorable and unintended sign, symptom, disease, or worsening of preexisting condition temporally associated with study treatment and irrespective of causality to study treatment.
    End point type
    Secondary
    End point timeframe
    Up to approximately 81 months
    Notes
    [24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, the end point only included participants in Part 2 of the study.
    End point values
    		 Part 2: Pembrolizumab + Chemotherapy Part 2: Placebo + Chemotherapy
    Number of subjects analysed
    562
    281
    Units: Percentage of Participants
        number (not applicable)
    98.6
    98.2
    No statistical analyses for this end point

    Secondary: Part 2: Change from Baseline to Week 15 in Systemic Therapy Side Effects Using the EORTC QLQ-BR23 - Participants with PD-L1 CPS ≥1 Tumors

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    End point title
    		 Part 2: Change from Baseline to Week 15 in Systemic Therapy Side Effects Using the EORTC QLQ-BR23 - Participants with PD-L1 CPS ≥1 Tumors [25]
    End point description
    EORTC-QLQ-BR23 is a 23-item breast cancer-specific companion module to the EORTC-QLQ-C30 and consists of four functional scales (body image, sexual enjoyment, sexual functioning, future perspective) and four symptom scales (systemic therapy side effects, upset by hair loss, arm symptoms, breast symptoms). Participant responses to 7 questions about their systemic therapy side effects were scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A higher score denotes worse symptoms for the systemic therapy side effects symptom scale. The change from baseline in systemic therapy side effects (EORTC QLQ-BR23 Items 1-4, 6, 7, and 8) score is presented.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 15
    Notes
    [25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, the end point only included participants in Part 2 of the study.
    End point values
    		 Part 2: Pembrolizumab + Chemotherapy Part 2: Placebo + Chemotherapy
    Number of subjects analysed
    415
    208
    Units: Scores on a scale
        least squares mean (confidence interval 95%)
    13.00 (11.08 to 14.91)
    11.86 (9.17 to 14.55)
    No statistical analyses for this end point

    Secondary: Part 2: Change from Baseline to Week 15 in Systemic Therapy Side Effects Using the EORTC Breast Cancer-Specific Quality of Life Questionnaire (QLQ-BR23)-All Participants

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    End point title
    		 Part 2: Change from Baseline to Week 15 in Systemic Therapy Side Effects Using the EORTC Breast Cancer-Specific Quality of Life Questionnaire (QLQ-BR23)-All Participants [26]
    End point description
    EORTC-QLQ-BR23 is a 23-item breast cancer-specific companion module to the EORTC-QLQ-C30 and consists of four functional scales (body image, sexual enjoyment, sexual functioning, future perspective) and four symptom scales (systemic therapy side effects, upset by hair loss, arm symptoms, breast symptoms). Participant responses to 7 questions about their systemic therapy side effects were scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A higher score denotes worse symptoms for the systemic therapy side effects symptom scale. The change from baseline in systemic therapy side effects (EORTC QLQ-BR23 Items 1-4, 6, 7, and 8) score is presented.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 15
    Notes
    [26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, the end point only included participants in Part 2 of the study.
    End point values
    		 Part 2: Pembrolizumab + Chemotherapy Part 2: Placebo + Chemotherapy
    Number of subjects analysed
    554
    278
    Units: Scores on a scale
        least squares mean (confidence interval 95%)
    12.50 (10.84 to 14.15)
    12.36 (10.06 to 14.65)
    No statistical analyses for this end point

    Secondary: Part 2: Change from Baseline to Week 15 in European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status (Item 29) and Quality of Life (Item 30) Combined Score- All Participants

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    End point title
    		 Part 2: Change from Baseline to Week 15 in European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status (Item 29) and Quality of Life (Item 30) Combined Score- All Participants [27]
    End point description
    The EORTC QLQ-C30 is a questionnaire to assess the overall quality of life of cancer patients. Participant responses to the questions "How would you rate your overall health during the past week?" (Item 29) and “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 range from 0 to 100. A higher score indicates a better overall health status. The change from baseline in EORTC QLQ-C30 Items 29 and 30 combined score are presented.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 15
    Notes
    [27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, the end point only included participants in Part 2 of the study.
    End point values
    		 Part 2: Pembrolizumab + Chemotherapy Part 2: Placebo + Chemotherapy
    Number of subjects analysed
    554
    278
    Units: Scores on a scale
        least squares mean (confidence interval 95%)
    -3.52 (-5.61 to -1.42)
    -2.15 (-4.97 to 0.67)
    No statistical analyses for this end point

    Secondary: Part 2: Change from Baseline to Week 15 in EORTC QLQ-C30 Global Health Status (Item 29) and Quality of Life (Item 30) Combined Score - Participants With PD-L1 CPS ≥1 Tumors

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    End point title
    		 Part 2: Change from Baseline to Week 15 in EORTC QLQ-C30 Global Health Status (Item 29) and Quality of Life (Item 30) Combined Score - Participants With PD-L1 CPS ≥1 Tumors [28]
    End point description
    The EORTC QLQ-C30 is a questionnaire to assess the overall quality of life of cancer patients. Participant responses to the questions "How would you rate your overall health during the past week?" (Item 29) and “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 range from 0 to 100. A higher score indicates a better overall health status. The change from baseline in EORTC QLQ-C30 Items 29 and 30 combined score are presented.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 15
    Notes
    [28] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, the end point only included participants in Part 2 of the study.
    End point values
    		 Part 2: Pembrolizumab + Chemotherapy Part 2: Placebo + Chemotherapy
    Number of subjects analysed
    415
    208
    Units: Scores on a scale
        least squares mean (confidence interval 95%)
    -3.92 (-6.42 to -1.44)
    -3.15 (-6.54 to 0.24)
    No statistical analyses for this end point

    Secondary: Part 2: Change from Baseline to Week 15 in EORTC QLQ-C30 Global Health Status (Item 29) and Quality of Life (Item 30) Combined Score-Participants With PD-L1 CPS ≥10 Tumors

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    End point title
    		 Part 2: Change from Baseline to Week 15 in EORTC QLQ-C30 Global Health Status (Item 29) and Quality of Life (Item 30) Combined Score-Participants With PD-L1 CPS ≥10 Tumors [29]
    End point description
    The EORTC QLQ-C30 is a questionnaire to assess the overall quality of life of cancer patients. Participant responses to the questions "How would you rate your overall health during the past week?" (Item 29) and “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 range from 0 to 100. A higher score indicates a better overall health status. The change from baseline in EORTC QLQ-C30 Items 29 and 30 combined score are presented.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 15
    Notes
    [29] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, the end point only included participants in Part 2 of the study.
    End point values
    		 Part 2: Pembrolizumab + Chemotherapy Part 2: Placebo + Chemotherapy
    Number of subjects analysed
    216
    100
    Units: Scores on a scale
        least squares mean (confidence interval 95%)
    -2.69 (-5.86 to 0.48)
    -0.88 (-5.41 to 3.64)
    No statistical analyses for this end point

    Secondary: Part 2: Change from Baseline to Week 15 in Systemic Therapy Side Effects Using the EORTC QLQ-BR23- Participants with PD-L1 CPS ≥10 Tumors

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    End point title
    		 Part 2: Change from Baseline to Week 15 in Systemic Therapy Side Effects Using the EORTC QLQ-BR23- Participants with PD-L1 CPS ≥10 Tumors [30]
    End point description
    EORTC-QLQ-BR23 is a 23-item breast cancer-specific companion module to the EORTC-QLQ-C30 and consists of four functional scales (body image, sexual enjoyment, sexual functioning, future perspective) and four symptom scales (systemic therapy side effects, upset by hair loss, arm symptoms, breast symptoms). Participant responses to 7 questions about their systemic therapy side effects are scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A higher score denotes worse symptoms for the systemic therapy side effects symptom scale. The change from baseline in systemic therapy side effects (EORTC QLQ-BR23 Items 1-4, 6, 7, and 8) score is presented.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 15
    Notes
    [30] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, the end point only included participants in Part 2 of the study.
    End point values
    		 Part 2: Pembrolizumab + Chemotherapy Part 2: Placebo + Chemotherapy
    Number of subjects analysed
    216
    100
    Units: Scores on a scale
        least squares mean (confidence interval 95%)
    13.56 (10.88 to 16.23)
    13.26 (9.28 to 17.25)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to approximately 81 months
    Adverse event reporting additional description
    All participants who received > or =1 dose of study intervention corresponding to the intervention received. 4 participants assigned to the pembrolizumab + paclitaxel group received incorrect chemotherapy in error. Per protocol, “Neoplasm progression", "Malignant neoplasm progression" and "Disease progression" not related to the drug are excluded.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.1
    Reporting groups
    Reporting group title
    Part 1: Pembrolizumab + Nab-Paclitaxel
    Reporting group description
    		 Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 21-day cycle PLUS nab-paclitaxel IV on Days 1, 8 and 15 of each 28-day cycle.

    Reporting group title
    Part 1: Pembrolizumab + Paclitaxel
    Reporting group description
    		 Participants received pembrolizumab 200 mg IV on Day 1 of each 21-day cycle PLUS paclitaxel IV on Days 1, 8 and 15 of each 28-day cycle.

    Reporting group title
    Part 2: Placebo + Chemotherapy
    Reporting group description
    		 Participants received placebo (normal saline) IV on Day 1 of each 21-day cycle PLUS one of three background chemotherapy regimens at investigator's discretion: 1) nab-paclitaxel 100 mg/m^2 IV on Days 1, 8 and 15 of each 28-day cycle, 2) paclitaxel 90 mg/m^2 IV on Days 1, 8 and 15 of each 28-day cycle, OR 3) gemcitabine/carboplatin 1000 mg/m^2 (gemcitabine) and an AUC 2 (carboplatin) on Days 1 and 8 of each 21-day cycle

    Reporting group title
    Part 2: Pembrolizumab + Chemotherapy (First Course)
    Reporting group description
    		 Participants received pembrolizumab 200 mg IV on Day 1 of each 21-day cycle PLUS one of three background chemotherapy regimens at investigator's discretion: 1) nab-paclitaxel IV on Days 1, 8 and 15 of each 28-day cycle, 2) paclitaxel IV on Days 1, 8 and 15 of each 28-day cycle, OR 3) gemcitabine/carboplatin (gemcitabine) and an AUC 2 (carboplatin) on Days 1 and 8 of each 21-day cycle. Qualified participants who received first course of pembrolizumab but continued to experience disease progression were eligible to initiate a second course of pembrolizumab IV Q3W for up to 17 administrations (up to ~1 year).

    Reporting group title
    Part 2: Pembrolizumab + Chemotherapy (Second Course)
    Reporting group description
    		 Eligible participants received up to 17 additional administrations (up to approximately 1year) of pembrolizumab 200 mg IV on day 1 of each 21-day cycle.

    Reporting group title
    Part 1: Pembrolizumab + Gemcitabine/Carboplatin
    Reporting group description
    		 Participants received pembrolizumab 200 mg IV on Day 1 of each 21-day cycle PLUS gemcitabine/carboplatin (gemcitabine) and an Area Under the Curve (AUC) 2 (carboplatin) on Days 1 and 8 of each 21-day cycle.

    Serious adverse events
    		 Part 1: Pembrolizumab + Nab-Paclitaxel Part 1: Pembrolizumab + Paclitaxel Part 2: Placebo + Chemotherapy Part 2: Pembrolizumab + Chemotherapy (First Course) Part 2: Pembrolizumab + Chemotherapy (Second Course) Part 1: Pembrolizumab + Gemcitabine/Carboplatin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 13 (23.08%)
    4 / 10 (40.00%)
    68 / 281 (24.20%)
    169 / 562 (30.07%)
    3 / 12 (25.00%)
    9 / 11 (81.82%)
         number of deaths (all causes)
    11
    9
    249
    480
    5
    9
         number of deaths resulting from adverse events
    0
    1
    5
    17
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of colon
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 10 (10.00%)
    0 / 281 (0.00%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cancer pain
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 281 (0.36%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour necrosis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endometrial adenocarcinoma
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myelodysplastic syndrome
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    0 / 562 (0.00%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic lymphocytic leukaemia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 281 (0.36%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 281 (0.36%)
    2 / 562 (0.36%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertensive emergency
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 281 (0.36%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Varicose vein
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Shock haemorrhagic
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Surgical and medical procedures
    Assisted suicide
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    2 / 281 (0.71%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    2 / 562 (0.36%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Drug withdrawal syndrome
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 281 (0.36%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 281 (0.36%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Fat necrosis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Face oedema
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    3 / 562 (0.53%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    2 / 562 (0.36%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    4 / 281 (1.42%)
    7 / 562 (1.25%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    3 / 6
    7 / 8
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abnormal uterine bleeding
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine haemorrhage
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 281 (0.36%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchostenosis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Pleurisy
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 10 (10.00%)
    1 / 281 (0.36%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Obstructive airways disorder
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 281 (0.36%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    3 / 281 (1.07%)
    5 / 562 (0.89%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    1 / 6
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleuritic pain
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 10 (10.00%)
    0 / 281 (0.00%)
    6 / 562 (1.07%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    8 / 8
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    2 / 281 (0.71%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 281 (0.36%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 281 (0.36%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    3 / 281 (1.07%)
    7 / 562 (1.25%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    2 / 7
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 281 (0.36%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 281 (0.36%)
    4 / 562 (0.71%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    4 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood corticotrophin increased
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    0 / 562 (0.00%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 281 (0.36%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Cortisol decreased
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 281 (0.36%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 281 (0.36%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 281 (0.36%)
    4 / 562 (0.71%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    4 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatic enzymes increased
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    2 / 281 (0.71%)
    5 / 562 (0.89%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    6 / 6
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ligament sprain
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Limb injury
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Procedural pneumothorax
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Traumatic intracranial haemorrhage
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 281 (0.36%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 281 (0.36%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Transfusion reaction
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Transfusion-related acute lung injury
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    2 / 281 (0.71%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular access complication
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 10 (10.00%)
    0 / 281 (0.00%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 281 (0.36%)
    2 / 562 (0.36%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    2 / 562 (0.36%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinus bradycardia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocarditis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Nervous system disorders
    Brain oedema
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebellar haemorrhage
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 281 (0.36%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Chronic inflammatory demyelinating polyradiculoneuropathy
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 281 (0.36%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Cerebral venous sinus thrombosis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral haematoma
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Guillain-Barre syndrome
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 281 (0.36%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    2 / 281 (0.71%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral motor neuropathy
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 281 (0.36%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intracranial pressure increased
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myelopathy
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Parkinsonism
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 281 (0.36%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Hepatic encephalopathy
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    2 / 281 (0.71%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    4 / 562 (0.71%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    6 / 6
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 10 (10.00%)
    3 / 281 (1.07%)
    7 / 562 (1.25%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    3 / 3
    6 / 7
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    6 / 281 (2.14%)
    11 / 562 (1.96%)
    0 / 12 (0.00%)
    2 / 11 (18.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    6 / 8
    12 / 12
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    4 / 281 (1.42%)
    5 / 562 (0.89%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    4 / 4
    7 / 7
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myelosuppression
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymphopenia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 281 (0.36%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombotic microangiopathy
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    4 / 281 (1.42%)
    11 / 562 (1.96%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    6 / 7
    12 / 14
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Papilloedema
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Cheilitis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    2 / 562 (0.36%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    3 / 562 (0.53%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    3 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Food poisoning
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 281 (0.36%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal pseudo-obstruction
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 281 (0.36%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer haemorrhage
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 281 (0.36%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    3 / 281 (1.07%)
    3 / 562 (0.53%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 3
    3 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    6 / 281 (2.14%)
    10 / 562 (1.78%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    4 / 7
    10 / 12
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Liver disorder
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 281 (0.36%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Hepatitis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    3 / 562 (0.53%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    5 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Autoimmune hepatitis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 281 (0.36%)
    2 / 562 (0.36%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Steatohepatitis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Drug eruption
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subcutaneous emphysema
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Hydronephrosis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    2 / 562 (0.36%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 281 (0.36%)
    3 / 562 (0.53%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    2 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Kidney enlargement
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephritis
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 10 (10.00%)
    0 / 281 (0.00%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    2 / 562 (0.36%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 281 (0.36%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 281 (0.36%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Endocrine disorders
    Inappropriate antidiuretic hormone secretion
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Adrenal insufficiency
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    4 / 562 (0.71%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    3 / 4
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypothyroidism
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    2 / 11 (18.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    2 / 562 (0.36%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myositis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Scleroderma
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 281 (0.36%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Pathological fracture
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Polyarthritis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 10 (10.00%)
    1 / 281 (0.36%)
    2 / 562 (0.36%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal abscess
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 281 (0.36%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Abscess
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 281 (0.36%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Biliary tract infection
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast cellulitis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 281 (0.36%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Device related sepsis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    2 / 562 (0.36%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 281 (0.36%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 10 (10.00%)
    1 / 281 (0.36%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 281 (0.36%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    2 / 562 (0.36%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 281 (0.36%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 13 (15.38%)
    0 / 10 (0.00%)
    7 / 281 (2.49%)
    11 / 562 (1.96%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    1 / 7
    2 / 11
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    1 / 2
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningitis aseptic
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mastitis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia staphylococcal
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Pneumonia mycoplasmal
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 281 (0.36%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia streptococcal
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 281 (0.36%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pseudomonal sepsis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 10 (0.00%)
    3 / 281 (1.07%)
    6 / 562 (1.07%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    2 / 3
    2 / 6
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 281 (0.36%)
    2 / 562 (0.36%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    Superinfection
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Streptococcal sepsis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    3 / 562 (0.53%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular device infection
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 281 (0.36%)
    0 / 562 (0.00%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 10 (10.00%)
    1 / 281 (0.36%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 281 (0.36%)
    2 / 562 (0.36%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    2 / 562 (0.36%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 281 (0.36%)
    2 / 562 (0.36%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Type 1 diabetes mellitus
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 10 (10.00%)
    0 / 281 (0.00%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    2 / 281 (0.71%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    2 / 281 (0.71%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 281 (0.36%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Part 1: Pembrolizumab + Nab-Paclitaxel Part 1: Pembrolizumab + Paclitaxel Part 2: Placebo + Chemotherapy Part 2: Pembrolizumab + Chemotherapy (First Course) Part 2: Pembrolizumab + Chemotherapy (Second Course) Part 1: Pembrolizumab + Gemcitabine/Carboplatin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 13 (100.00%)
    10 / 10 (100.00%)
    273 / 281 (97.15%)
    551 / 562 (98.04%)
    11 / 12 (91.67%)
    11 / 11 (100.00%)
    Vascular disorders
    Haematoma
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 10 (0.00%)
    2 / 281 (0.71%)
    5 / 562 (0.89%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    2
    6
    0
    0
    Flushing
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 10 (10.00%)
    3 / 281 (1.07%)
    11 / 562 (1.96%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    3
    22
    0
    0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 281 (0.36%)
    9 / 562 (1.60%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    10
    1
    0
    Hypotension
         subjects affected / exposed
    3 / 13 (23.08%)
    0 / 10 (0.00%)
    9 / 281 (3.20%)
    11 / 562 (1.96%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    3
    0
    10
    11
    0
    0
    Hot flush
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 10 (10.00%)
    10 / 281 (3.56%)
    21 / 562 (3.74%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    2
    14
    22
    0
    0
    Lymphoedema
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    11 / 281 (3.91%)
    16 / 562 (2.85%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    11
    17
    0
    1
    General disorders and administration site conditions
    Injection site reaction
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 281 (0.36%)
    2 / 562 (0.36%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    2
    0
    1
    Infusion site pain
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 281 (0.36%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Infusion site extravasation
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    3 / 562 (0.53%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    0
    0
    3
    0
    1
    Fatigue
         subjects affected / exposed
    1 / 13 (7.69%)
    2 / 10 (20.00%)
    96 / 281 (34.16%)
    180 / 562 (32.03%)
    1 / 12 (8.33%)
    1 / 11 (9.09%)
         occurrences all number
    1
    3
    119
    258
    1
    1
    Chills
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 10 (10.00%)
    7 / 281 (2.49%)
    16 / 562 (2.85%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences all number
    1
    1
    7
    18
    1
    0
    Chest pain
         subjects affected / exposed
    2 / 13 (15.38%)
    1 / 10 (10.00%)
    17 / 281 (6.05%)
    25 / 562 (4.45%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    2
    1
    20
    27
    0
    0
    Asthenia
         subjects affected / exposed
    6 / 13 (46.15%)
    3 / 10 (30.00%)
    47 / 281 (16.73%)
    108 / 562 (19.22%)
    0 / 12 (0.00%)
    3 / 11 (27.27%)
         occurrences all number
    16
    8
    84
    194
    0
    6
    Thirst
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 10 (10.00%)
    1 / 281 (0.36%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    2
    1
    0
    0
    Oedema peripheral
         subjects affected / exposed
    5 / 13 (38.46%)
    0 / 10 (0.00%)
    29 / 281 (10.32%)
    65 / 562 (11.57%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    5
    0
    42
    83
    0
    0
    Oedema
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    0
    0
    1
    0
    1
    Mucosal inflammation
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 10 (0.00%)
    14 / 281 (4.98%)
    31 / 562 (5.52%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    21
    41
    0
    0
    Mucosal dryness
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 10 (0.00%)
    1 / 281 (0.36%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Malaise
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 10 (10.00%)
    14 / 281 (4.98%)
    25 / 562 (4.45%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    25
    38
    0
    3
    Pyrexia
         subjects affected / exposed
    3 / 13 (23.08%)
    2 / 10 (20.00%)
    55 / 281 (19.57%)
    99 / 562 (17.62%)
    2 / 12 (16.67%)
    2 / 11 (18.18%)
         occurrences all number
    3
    2
    85
    150
    2
    5
    Immune system disorders
    Contrast media allergy
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    0 / 562 (0.00%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    Drug hypersensitivity
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 281 (0.36%)
    3 / 562 (0.53%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    4
    1
    0
    Hypersensitivity
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 10 (20.00%)
    8 / 281 (2.85%)
    8 / 562 (1.42%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences all number
    0
    3
    16
    9
    2
    0
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 10 (0.00%)
    14 / 281 (4.98%)
    24 / 562 (4.27%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    0
    14
    29
    0
    1
    Female genital tract fistula
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    0 / 562 (0.00%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 281 (0.36%)
    2 / 562 (0.36%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    2
    0
    1
    Bronchostenosis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Cough
         subjects affected / exposed
    2 / 13 (15.38%)
    4 / 10 (40.00%)
    49 / 281 (17.44%)
    118 / 562 (21.00%)
    0 / 12 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    2
    4
    60
    154
    0
    2
    Epistaxis
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 10 (20.00%)
    17 / 281 (6.05%)
    20 / 562 (3.56%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    3
    20
    26
    0
    0
    Haemoptysis
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 10 (10.00%)
    2 / 281 (0.71%)
    2 / 562 (0.36%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    2
    2
    0
    0
    Hydrothorax
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 281 (0.36%)
    0 / 562 (0.00%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    Nasal dryness
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 281 (0.36%)
    1 / 562 (0.18%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    1
    1
    0
    Nasal pruritus
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    0 / 562 (0.00%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    18 / 281 (6.41%)
    29 / 562 (5.16%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    25
    32
    0
    1
    Pneumothorax
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    3 / 281 (1.07%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    3
    1
    0
    1
    Productive cough
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 10 (10.00%)
    13 / 281 (4.63%)
    12 / 562 (2.14%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    1
    15
    12
    0
    0
    Pulmonary embolism
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 10 (0.00%)
    4 / 281 (1.42%)
    2 / 562 (0.36%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    2
    0
    4
    2
    0
    0
    Sinus congestion
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Dysphonia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    4 / 281 (1.42%)
    22 / 562 (3.91%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    4
    23
    1
    0
    Dyspnoea
         subjects affected / exposed
    1 / 13 (7.69%)
    2 / 10 (20.00%)
    37 / 281 (13.17%)
    69 / 562 (12.28%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    3
    44
    82
    0
    1
    Dyspnoea exertional
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 10 (10.00%)
    5 / 281 (1.78%)
    5 / 562 (0.89%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    6
    5
    0
    0
    Throat irritation
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    2 / 562 (0.36%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    2
    0
    1
    Psychiatric disorders
    Depressed mood
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    2 / 281 (0.71%)
    3 / 562 (0.53%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    4
    4
    0
    1
    Anxiety
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 10 (20.00%)
    11 / 281 (3.91%)
    23 / 562 (4.09%)
    0 / 12 (0.00%)
    3 / 11 (27.27%)
         occurrences all number
    0
    2
    11
    23
    0
    4
    Stress
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Persistent depressive disorder
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Insomnia
         subjects affected / exposed
    1 / 13 (7.69%)
    2 / 10 (20.00%)
    28 / 281 (9.96%)
    48 / 562 (8.54%)
    0 / 12 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    2
    2
    32
    53
    0
    2
    Depression
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 10 (0.00%)
    13 / 281 (4.63%)
    20 / 562 (3.56%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    13
    20
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 10 (10.00%)
    55 / 281 (19.57%)
    139 / 562 (24.73%)
    2 / 12 (16.67%)
    2 / 11 (18.18%)
         occurrences all number
    1
    2
    84
    242
    2
    28
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    0 / 562 (0.00%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Amylase increased
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 10 (10.00%)
    0 / 281 (0.00%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 10 (10.00%)
    46 / 281 (16.37%)
    131 / 562 (23.31%)
    1 / 12 (8.33%)
    2 / 11 (18.18%)
         occurrences all number
    1
    2
    69
    225
    1
    17
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 10 (0.00%)
    22 / 281 (7.83%)
    50 / 562 (8.90%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    28
    79
    1
    0
    Blood cholesterol increased
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 281 (0.36%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    1
    0
    3
    Blood corticotrophin increased
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    0 / 562 (0.00%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Blood iron decreased
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 281 (0.36%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    16 / 281 (5.69%)
    31 / 562 (5.52%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    17
    34
    0
    0
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 10 (0.00%)
    3 / 281 (1.07%)
    10 / 562 (1.78%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    3
    10
    0
    0
    Cortisol decreased
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 10 (0.00%)
    1 / 281 (0.36%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 10 (0.00%)
    8 / 281 (2.85%)
    20 / 562 (3.56%)
    0 / 12 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    1
    0
    11
    35
    0
    2
    Haemoglobin decreased
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    3 / 281 (1.07%)
    14 / 562 (2.49%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    4
    19
    0
    3
    Lipase increased
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 10 (0.00%)
    1 / 281 (0.36%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    0
    1
    1
    0
    1
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 13 (0.00%)
    3 / 10 (30.00%)
    11 / 281 (3.91%)
    30 / 562 (5.34%)
    2 / 12 (16.67%)
    1 / 11 (9.09%)
         occurrences all number
    0
    7
    32
    88
    17
    1
    Weight increased
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 10 (10.00%)
    7 / 281 (2.49%)
    14 / 562 (2.49%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    8
    14
    0
    2
    White blood cell count decreased
         subjects affected / exposed
    0 / 13 (0.00%)
    5 / 10 (50.00%)
    55 / 281 (19.57%)
    106 / 562 (18.86%)
    4 / 12 (33.33%)
    2 / 11 (18.18%)
         occurrences all number
    0
    20
    211
    502
    29
    3
    Weight decreased
         subjects affected / exposed
    1 / 13 (7.69%)
    4 / 10 (40.00%)
    12 / 281 (4.27%)
    50 / 562 (8.90%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    2
    5
    13
    55
    0
    1
    Lymphocyte percentage decreased
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    0
    38
    Neutrophil count decreased
         subjects affected / exposed
    2 / 13 (15.38%)
    5 / 10 (50.00%)
    76 / 281 (27.05%)
    128 / 562 (22.78%)
    4 / 12 (33.33%)
    1 / 11 (9.09%)
         occurrences all number
    2
    17
    310
    668
    29
    1
    Neutrophil percentage decreased
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 10 (10.00%)
    1 / 281 (0.36%)
    6 / 562 (1.07%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    9
    24
    0
    0
    Platelet count decreased
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    44 / 281 (15.66%)
    87 / 562 (15.48%)
    2 / 12 (16.67%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    125
    350
    10
    0
    Injury, poisoning and procedural complications
    Limb injury
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 10 (0.00%)
    1 / 281 (0.36%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    1
    1
    0
    0
    Incision site pain
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    2 / 562 (0.36%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    2
    0
    0
    Fracture
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Contusion
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    3 / 281 (1.07%)
    9 / 562 (1.60%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    3
    10
    0
    1
    Wound complication
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 10 (0.00%)
    1 / 281 (0.36%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Thermal burn
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    4 / 562 (0.71%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    4
    0
    2
    Animal bite
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    3 / 281 (1.07%)
    8 / 562 (1.42%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    3
    11
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 13 (15.38%)
    5 / 10 (50.00%)
    66 / 281 (23.49%)
    111 / 562 (19.75%)
    1 / 12 (8.33%)
    1 / 11 (9.09%)
         occurrences all number
    3
    7
    104
    184
    1
    1
    Dysgeusia
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 10 (0.00%)
    15 / 281 (5.34%)
    54 / 562 (9.61%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    18
    63
    0
    0
    Dizziness
         subjects affected / exposed
    1 / 13 (7.69%)
    3 / 10 (30.00%)
    24 / 281 (8.54%)
    52 / 562 (9.25%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    4
    33
    61
    0
    0
    Dementia Alzheimer's type
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 10 (10.00%)
    0 / 281 (0.00%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Ataxia
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 10 (10.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Lethargy
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 10 (0.00%)
    3 / 281 (1.07%)
    11 / 562 (1.96%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    2
    0
    5
    15
    0
    1
    Mental impairment
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Taste disorder
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 10 (0.00%)
    5 / 281 (1.78%)
    8 / 562 (1.42%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    5
    9
    0
    0
    Somnolence
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 10 (10.00%)
    6 / 281 (2.14%)
    9 / 562 (1.60%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    8
    9
    0
    0
    Presyncope
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 10 (0.00%)
    4 / 281 (1.42%)
    4 / 562 (0.71%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    5
    6
    0
    0
    Polyneuropathy
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    12 / 562 (2.14%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    12
    0
    0
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 13 (7.69%)
    3 / 10 (30.00%)
    20 / 281 (7.12%)
    49 / 562 (8.72%)
    0 / 12 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    1
    4
    22
    55
    0
    2
    Peripheral motor neuropathy
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    2 / 281 (0.71%)
    2 / 562 (0.36%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    2
    2
    0
    1
    Paraesthesia
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 10 (0.00%)
    15 / 281 (5.34%)
    24 / 562 (4.27%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    15
    31
    0
    0
    Neurotoxicity
         subjects affected / exposed
    2 / 13 (15.38%)
    1 / 10 (10.00%)
    4 / 281 (1.42%)
    4 / 562 (0.71%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    3
    2
    7
    7
    0
    0
    Neuropathy peripheral
         subjects affected / exposed
    4 / 13 (30.77%)
    2 / 10 (20.00%)
    35 / 281 (12.46%)
    62 / 562 (11.03%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    6
    2
    50
    72
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    5 / 13 (38.46%)
    5 / 10 (50.00%)
    140 / 281 (49.82%)
    294 / 562 (52.31%)
    4 / 12 (33.33%)
    8 / 11 (72.73%)
         occurrences all number
    5
    15
    258
    633
    22
    12
    Thrombocytopenia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    56 / 281 (19.93%)
    110 / 562 (19.57%)
    0 / 12 (0.00%)
    5 / 11 (45.45%)
         occurrences all number
    0
    0
    155
    346
    0
    89
    Neutropenia
         subjects affected / exposed
    2 / 13 (15.38%)
    1 / 10 (10.00%)
    109 / 281 (38.79%)
    232 / 562 (41.28%)
    2 / 12 (16.67%)
    7 / 11 (63.64%)
         occurrences all number
    3
    21
    384
    936
    4
    90
    Lymphopenia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    4 / 281 (1.42%)
    30 / 562 (5.34%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    15
    62
    0
    0
    Leukopenia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    50 / 281 (17.79%)
    111 / 562 (19.75%)
    0 / 12 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    0
    0
    158
    461
    0
    64
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 10 (10.00%)
    12 / 281 (4.27%)
    20 / 562 (3.56%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    1
    13
    22
    0
    0
    Eye disorders
    Diplopia
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 10 (10.00%)
    5 / 281 (1.78%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    5
    1
    0
    0
    Dry eye
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 10 (0.00%)
    8 / 281 (2.85%)
    20 / 562 (3.56%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    0
    8
    20
    0
    1
    Eye pain
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    3 / 562 (0.53%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    3
    0
    0
    Eye swelling
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 10 (0.00%)
    1 / 281 (0.36%)
    2 / 562 (0.36%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    1
    2
    0
    0
    Eyelid cyst
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 10 (10.00%)
    0 / 281 (0.00%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Ocular discomfort
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    Vision blurred
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    8 / 281 (2.85%)
    9 / 562 (1.60%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    8
    11
    0
    1
    Eye pruritus
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    6 / 281 (2.14%)
    3 / 562 (0.53%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    6
    3
    0
    1
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 10 (10.00%)
    6 / 281 (2.14%)
    2 / 562 (0.36%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    6
    2
    0
    2
    Diarrhoea
         subjects affected / exposed
    5 / 13 (38.46%)
    2 / 10 (20.00%)
    66 / 281 (23.49%)
    155 / 562 (27.58%)
    1 / 12 (8.33%)
    6 / 11 (54.55%)
         occurrences all number
    9
    3
    134
    305
    2
    6
    Dental caries
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 10 (10.00%)
    2 / 281 (0.71%)
    6 / 562 (1.07%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    2
    6
    0
    0
    Constipation
         subjects affected / exposed
    3 / 13 (23.08%)
    3 / 10 (30.00%)
    77 / 281 (27.40%)
    155 / 562 (27.58%)
    0 / 12 (0.00%)
    6 / 11 (54.55%)
         occurrences all number
    3
    3
    97
    212
    0
    10
    Colitis
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 10 (10.00%)
    3 / 281 (1.07%)
    8 / 562 (1.42%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    3
    9
    0
    0
    Anal fissure
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 10 (10.00%)
    2 / 281 (0.71%)
    4 / 562 (0.71%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    3
    4
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 10 (10.00%)
    16 / 281 (5.69%)
    45 / 562 (8.01%)
    1 / 12 (8.33%)
    1 / 11 (9.09%)
         occurrences all number
    1
    1
    19
    64
    1
    1
    Abdominal pain
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 10 (10.00%)
    25 / 281 (8.90%)
    43 / 562 (7.65%)
    0 / 12 (0.00%)
    3 / 11 (27.27%)
         occurrences all number
    0
    1
    28
    57
    0
    6
    Abdominal distension
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    6 / 281 (2.14%)
    11 / 562 (1.96%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    7
    13
    0
    1
    Dry mouth
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 10 (10.00%)
    10 / 281 (3.56%)
    22 / 562 (3.91%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    1
    14
    23
    0
    0
    Gastritis
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 10 (10.00%)
    7 / 281 (2.49%)
    18 / 562 (3.20%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    7
    18
    3
    0
    Flatulence
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 281 (0.36%)
    11 / 562 (1.96%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    13
    0
    1
    Dyspepsia
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 10 (0.00%)
    16 / 281 (5.69%)
    38 / 562 (6.76%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    0
    19
    45
    0
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    11 / 281 (3.91%)
    15 / 562 (2.67%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    12
    16
    0
    1
    Gingival bleeding
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    3 / 562 (0.53%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    3
    1
    0
    Vomiting
         subjects affected / exposed
    3 / 13 (23.08%)
    2 / 10 (20.00%)
    62 / 281 (22.06%)
    140 / 562 (24.91%)
    0 / 12 (0.00%)
    6 / 11 (54.55%)
         occurrences all number
    5
    2
    107
    248
    0
    8
    Stomatitis
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 10 (20.00%)
    19 / 281 (6.76%)
    54 / 562 (9.61%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    2
    22
    76
    0
    0
    Nausea
         subjects affected / exposed
    6 / 13 (46.15%)
    2 / 10 (20.00%)
    130 / 281 (46.26%)
    251 / 562 (44.66%)
    1 / 12 (8.33%)
    4 / 11 (36.36%)
         occurrences all number
    7
    3
    254
    522
    1
    9
    Large intestinal haemorrhage
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 10 (10.00%)
    0 / 281 (0.00%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Hepatobiliary disorders
    Hypertransaminasaemia
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 10 (0.00%)
    3 / 281 (1.07%)
    3 / 562 (0.53%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    3
    6
    0
    0
    Hepatic function abnormal
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    3 / 281 (1.07%)
    5 / 562 (0.89%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    3
    6
    1
    0
    Skin and subcutaneous tissue disorders
    Butterfly rash
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    Alopecia
         subjects affected / exposed
    4 / 13 (30.77%)
    5 / 10 (50.00%)
    97 / 281 (34.52%)
    190 / 562 (33.81%)
    0 / 12 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    4
    5
    97
    194
    0
    2
    Dermatitis acneiform
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    6 / 281 (2.14%)
    11 / 562 (1.96%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    7
    11
    0
    3
    Dermatitis contact
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    4 / 281 (1.42%)
    7 / 562 (1.25%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    4
    8
    0
    1
    Nail discolouration
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 10 (10.00%)
    10 / 281 (3.56%)
    7 / 562 (1.25%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    1
    10
    7
    0
    0
    Dry skin
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 10 (10.00%)
    10 / 281 (3.56%)
    16 / 562 (2.85%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    10
    18
    0
    1
    Dyshidrotic eczema
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    2 / 562 (0.36%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    2
    0
    1
    Erythema
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 10 (10.00%)
    11 / 281 (3.91%)
    23 / 562 (4.09%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    1
    18
    25
    0
    0
    Erythema nodosum
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Hyperhidrosis
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 10 (10.00%)
    4 / 281 (1.42%)
    7 / 562 (1.25%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    4
    7
    0
    0
    Drug eruption
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    2 / 562 (0.36%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    2
    1
    0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 10 (10.00%)
    2 / 281 (0.71%)
    3 / 562 (0.53%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    2
    3
    0
    0
    Onychalgia
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 10 (0.00%)
    3 / 281 (1.07%)
    3 / 562 (0.53%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    4
    3
    0
    0
    Nail dystrophy
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 10 (10.00%)
    1 / 281 (0.36%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    1
    1
    1
    0
    0
    Pigmentation disorder
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    Skin mass
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 10 (10.00%)
    0 / 281 (0.00%)
    2 / 562 (0.36%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    2
    0
    0
    Skin lesion
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 10 (0.00%)
    4 / 281 (1.42%)
    4 / 562 (0.71%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    4
    5
    1
    0
    Skin hyperpigmentation
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 10 (10.00%)
    1 / 281 (0.36%)
    7 / 562 (1.25%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    1
    7
    0
    0
    Rash pruritic
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    2 / 281 (0.71%)
    6 / 562 (1.07%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    2
    7
    0
    1
    Rash papular
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 10 (10.00%)
    0 / 281 (0.00%)
    3 / 562 (0.53%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    4
    0
    0
    Rash maculo-papular
         subjects affected / exposed
    0 / 13 (0.00%)
    3 / 10 (30.00%)
    10 / 281 (3.56%)
    25 / 562 (4.45%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    3
    10
    41
    0
    0
    Pruritus
         subjects affected / exposed
    3 / 13 (23.08%)
    3 / 10 (30.00%)
    32 / 281 (11.39%)
    85 / 562 (15.12%)
    1 / 12 (8.33%)
    1 / 11 (9.09%)
         occurrences all number
    3
    6
    39
    120
    1
    1
    Rash
         subjects affected / exposed
    2 / 13 (15.38%)
    2 / 10 (20.00%)
    34 / 281 (12.10%)
    110 / 562 (19.57%)
    0 / 12 (0.00%)
    3 / 11 (27.27%)
         occurrences all number
    2
    4
    44
    154
    0
    4
    Urticaria
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 10 (10.00%)
    3 / 281 (1.07%)
    11 / 562 (1.96%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    2
    4
    15
    0
    1
    Renal and urinary disorders
    Renal impairment
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 281 (0.36%)
    1 / 562 (0.18%)
    2 / 12 (16.67%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    4
    1
    2
    0
    Dysuria
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 10 (0.00%)
    3 / 281 (1.07%)
    12 / 562 (2.14%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    3
    12
    0
    0
    Polyuria
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 10 (10.00%)
    0 / 281 (0.00%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    1 / 13 (7.69%)
    2 / 10 (20.00%)
    4 / 281 (1.42%)
    25 / 562 (4.45%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    3
    4
    25
    0
    1
    Adrenal insufficiency
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    4 / 562 (0.71%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    4
    0
    0
    Hypophysitis
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Hypothyroidism
         subjects affected / exposed
    1 / 13 (7.69%)
    3 / 10 (30.00%)
    9 / 281 (3.20%)
    85 / 562 (15.12%)
    0 / 12 (0.00%)
    4 / 11 (36.36%)
         occurrences all number
    1
    3
    10
    96
    0
    5
    Thyroiditis
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 10 (10.00%)
    0 / 281 (0.00%)
    6 / 562 (1.07%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    6
    0
    0
    Musculoskeletal and connective tissue disorders
    Groin pain
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 10 (10.00%)
    1 / 281 (0.36%)
    5 / 562 (0.89%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    1
    6
    0
    0
    Joint swelling
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 281 (0.36%)
    2 / 562 (0.36%)
    0 / 12 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    0
    0
    1
    3
    0
    2
    Coccydynia
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Bone pain
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 10 (10.00%)
    17 / 281 (6.05%)
    22 / 562 (3.91%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    21
    25
    0
    0
    Back pain
         subjects affected / exposed
    2 / 13 (15.38%)
    0 / 10 (0.00%)
    41 / 281 (14.59%)
    72 / 562 (12.81%)
    1 / 12 (8.33%)
    1 / 11 (9.09%)
         occurrences all number
    2
    0
    48
    88
    2
    1
    Arthritis
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 10 (10.00%)
    3 / 281 (1.07%)
    6 / 562 (1.07%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    3
    8
    0
    0
    Arthralgia
         subjects affected / exposed
    4 / 13 (30.77%)
    1 / 10 (10.00%)
    48 / 281 (17.08%)
    122 / 562 (21.71%)
    0 / 12 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    4
    1
    73
    203
    0
    3
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 10 (10.00%)
    13 / 281 (4.63%)
    28 / 562 (4.98%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    1
    16
    31
    0
    0
    Spinal pain
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    2 / 281 (0.71%)
    5 / 562 (0.89%)
    0 / 12 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    0
    0
    2
    5
    0
    2
    Pain in jaw
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 10 (10.00%)
    2 / 281 (0.71%)
    10 / 562 (1.78%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    2
    11
    0
    0
    Pain in extremity
         subjects affected / exposed
    3 / 13 (23.08%)
    0 / 10 (0.00%)
    41 / 281 (14.59%)
    56 / 562 (9.96%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences all number
    3
    0
    47
    68
    1
    0
    Osteoporosis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    2 / 562 (0.36%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    2
    0
    1
    Neck pain
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 10 (10.00%)
    20 / 281 (7.12%)
    25 / 562 (4.45%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    23
    28
    0
    1
    Myalgia
         subjects affected / exposed
    0 / 13 (0.00%)
    3 / 10 (30.00%)
    34 / 281 (12.10%)
    59 / 562 (10.50%)
    0 / 12 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    0
    3
    57
    83
    0
    3
    Musculoskeletal stiffness
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 10 (10.00%)
    1 / 281 (0.36%)
    3 / 562 (0.53%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    1
    3
    0
    0
    Synovial cyst
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    0 / 562 (0.00%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 10 (0.00%)
    5 / 281 (1.78%)
    8 / 562 (1.42%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    6
    9
    0
    0
    Gastrointestinal infection
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Hordeolum
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 10 (0.00%)
    2 / 281 (0.71%)
    2 / 562 (0.36%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    2
    2
    0
    0
    Influenza
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 10 (10.00%)
    8 / 281 (2.85%)
    28 / 562 (4.98%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    10
    30
    0
    2
    Lip infection
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    3 / 13 (23.08%)
    0 / 10 (0.00%)
    21 / 281 (7.47%)
    53 / 562 (9.43%)
    1 / 12 (8.33%)
    1 / 11 (9.09%)
         occurrences all number
    3
    0
    28
    76
    1
    1
    Appendicitis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    COVID-19
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 281 (0.36%)
    2 / 562 (0.36%)
    1 / 12 (8.33%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    2
    1
    1
    Cellulitis
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 10 (0.00%)
    4 / 281 (1.42%)
    9 / 562 (1.60%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    5
    9
    0
    0
    Conjunctivitis
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 10 (10.00%)
    3 / 281 (1.07%)
    7 / 562 (1.25%)
    1 / 12 (8.33%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    13
    9
    1
    1
    Conjunctivitis viral
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Cystitis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    3 / 281 (1.07%)
    11 / 562 (1.96%)
    1 / 12 (8.33%)
    2 / 11 (18.18%)
         occurrences all number
    0
    0
    5
    13
    1
    2
    Erythema infectiosum
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Oral candidiasis
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 10 (10.00%)
    4 / 281 (1.42%)
    6 / 562 (1.07%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    6
    6
    0
    1
    Oropharyngeal candidiasis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    1 / 562 (0.18%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Vulvovaginitis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    0 / 562 (0.00%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 10 (0.00%)
    2 / 281 (0.71%)
    4 / 562 (0.71%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    2
    5
    0
    0
    Viral infection
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 10 (0.00%)
    4 / 281 (1.42%)
    9 / 562 (1.60%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    6
    14
    1
    0
    Viral diarrhoea
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 281 (0.00%)
    0 / 562 (0.00%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Urinary tract infection
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 10 (10.00%)
    13 / 281 (4.63%)
    49 / 562 (8.72%)
    1 / 12 (8.33%)
    1 / 11 (9.09%)
         occurrences all number
    2
    1
    14
    70
    1
    1
    Upper respiratory tract infection
         subjects affected / exposed
    5 / 13 (38.46%)
    3 / 10 (30.00%)
    26 / 281 (9.25%)
    58 / 562 (10.32%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    5
    4
    36
    94
    0
    9
    Tonsillitis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 281 (0.36%)
    8 / 562 (1.42%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    9
    0
    1
    Skin infection
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 10 (0.00%)
    4 / 281 (1.42%)
    6 / 562 (1.07%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    4
    7
    0
    0
    Pharyngitis
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 10 (10.00%)
    5 / 281 (1.78%)
    8 / 562 (1.42%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    8
    8
    0
    0
    Rash pustular
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 10 (0.00%)
    1 / 281 (0.36%)
    4 / 562 (0.71%)
    0 / 12 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    1
    4
    0
    0
    Rhinitis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    6 / 281 (2.14%)
    5 / 562 (0.89%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    8
    5
    0
    1
    Metabolism and nutrition disorders
    Hyperuricaemia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    8 / 281 (2.85%)
    9 / 562 (1.60%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    9
    13
    0
    48
    Hyperglycaemia
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 10 (10.00%)
    11 / 281 (3.91%)
    27 / 562 (4.80%)
    1 / 12 (8.33%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    11
    40
    1
    4
    Decreased appetite
         subjects affected / exposed
    8 / 13 (61.54%)
    2 / 10 (20.00%)
    39 / 281 (13.88%)
    118 / 562 (21.00%)
    0 / 12 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    12
    2
    49
    140
    0
    4
    Hyponatraemia
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 10 (0.00%)
    7 / 281 (2.49%)
    12 / 562 (2.14%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    0
    7
    14
    0
    1
    Hypomagnesaemia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    4 / 281 (1.42%)
    15 / 562 (2.67%)
    1 / 12 (8.33%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    6
    23
    1
    0
    Hypokalaemia
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 10 (10.00%)
    14 / 281 (4.98%)
    28 / 562 (4.98%)
    1 / 12 (8.33%)
    1 / 11 (9.09%)
         occurrences all number
    0
    4
    19
    46
    1
    2
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 10 (10.00%)
    11 / 281 (3.91%)
    18 / 562 (3.20%)
    0 / 12 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    0
    1
    11
    28
    0
    28
    Hypoglycaemia
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 10 (10.00%)
    0 / 281 (0.00%)
    2 / 562 (0.36%)
    0 / 12 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    0
    2
    0
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Dec 2016
    AM 1: Change in pneumonitis exclusion criteria
    13 Mar 2018
    AM 2: guidelines were added for dose modification in the event of myocarditis and updated guidelines for several other conditions.
    07 Sep 2018
    AM 3: Change in testing of primary endpoints at interim analysis 1
    11 Apr 2019
    AM 4: Change in timing of final analysis
    14 Oct 2019
    AM 5: The objectives, hypotheses, and statistical analysis plan were changed to include subjects with PD-L1 positive tumors with a higher combined positive score (CPS) cutoff of ≥10 (CPS ≥10).
    27 Oct 2021
    AM 6: To include language pertaining to the KN587 extension trial, as the plan is to transition current subjects over to KN587.
    12 Jul 2022
    Sponsor name and address change

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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