Flag of the European Union EU Clinical Trials Register Help

Clinical trials

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

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

    The EU Clinical Trials Register currently displays   43862   clinical trials with a EudraCT protocol, of which   7285   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

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

    < Back to search results

    Download PDF

    Clinical Trial Results:
    Randomized, Phase II Study of Pembrolizumab (MK-3475) versus Chemotherapy in Patients with Advanced Melanoma (KEYNOTE 002)

    Summary
    EudraCT number
    		 2012-003030-17
    Trial protocol
    		 ES   DE   NO   SE   IT   NL   FR   Outside EU/EEA  
    Global end of trial date
    31 Jan 2019

    Results information
    Results version number
    		 v2(current)
    This version publication date
    28 Aug 2019
    First version publication date
    22 Feb 2017
    Other versions
    		 v1
    Version creation reason

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    P08719
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01704287
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 MK-3475-002: Merck Protocol Number
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme Corp.
    Sponsor organisation address
    2000 Galloping Hill Road, Kenilworth, NJ, United States, 07033
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    31 Jan 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Nov 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Jan 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This study was conducted to compare survival using pembrolizumab (SCH 900475, MK-3475) or standard chemotherapy in participants with advanced melanoma (MEL) who had progressed after prior therapy. Initial Treatment Period: Participants were initially randomized to low-dose (2 mg/kg) pembrolizumab, higher dose (10 mg/kg) pembrolizumab or Investigator-choice chemotherapy (ICC: carboplatin+paclitaxel, paclitaxel alone, dacarbazine, or temozolomide). With Amendment 3, all ongoing pembrolizumab participants were to be treated with open label, fixed dose pembrolizumab 200 mg, instead of a weight-based dosing of pembrolizumab. Switch-to-Pembrolizumab Treatment Period: Participants randomized to ICC who experienced progressive disease (PD) may have been eligible to switch to either pembrolizumab 2 mg/kg or pembrolizumab 10 mg/kg. With Amendment 3, all switch-to-pembrolizumab participants were to be treated with open label, fixed dose pembrolizumab 200 mg.
    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
    20 Nov 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 2
    Country: Number of subjects enrolled
    Australia: 10
    Country: Number of subjects enrolled
    France: 16
    Country: Number of subjects enrolled
    Germany: 79
    Country: Number of subjects enrolled
    Israel: 36
    Country: Number of subjects enrolled
    Italy: 20
    Country: Number of subjects enrolled
    Netherlands: 36
    Country: Number of subjects enrolled
    Norway: 5
    Country: Number of subjects enrolled
    Spain: 16
    Country: Number of subjects enrolled
    Sweden: 5
    Country: Number of subjects enrolled
    Switzerland: 36
    Country: Number of subjects enrolled
    United States: 279
    Worldwide total number of subjects
    540
    EEA total number of subjects
    177
    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)
    1
    Adults (18-64 years)
    304
    From 65 to 84 years
    230
    85 years and over
    5

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 This end of trial analysis is based on a trial closure database cutoff date of 31-Jan-2019.

    Period 1
    Period 1 title
    Initial Treatment Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Pembrolizumab 2 mg/kg
    Arm description
    		 Participants were initially randomized to receive pembrolizumab 2 mg/kg intravenously (IV) once every 3 weeks (Q3W). With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    MK-3475, SCH 900475
    Other name
    KEYTRUDA®
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pembrolizumab 2 mg/kg via IV infusion on Day 1 of each 3-week cycle

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    MK-3475, SCH 900475
    Other name
    KEYTRUDA®
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pembrolizumab 200 mg via IV infusion on Day 1 of each 3-week cycle

    Arm title
    		 Pembrolizumab 10 mg/kg
    Arm description
    		 Participants were initially randomized to receive pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    MK-3475, SCH 900475
    Other name
    KEYTRUDA®
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pembrolizumab 10 mg/kg via IV infusion on Day 1 of each 3-week cycle

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    MK-3475, SCH 900475
    Other name
    KEYTRUDA®
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pembrolizumab 200 mg via IV infusion on Day 1 of each 3-week cycle

    Arm title
    		 Investigator-Choice Chemotherapy (ICC)
    Arm description
    		 Participants were initially randomized to receive 1 of 4 possible chemotherapy regimens decided at the treating institution (carboplatin+paclitaxel, paclitaxel alone, dacarbazine, or temozolomide). Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    PARAPLATIN®
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Carboplatin per institutional standard

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    TAXOL®
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel per institutional standard

    Investigational medicinal product name
    Dacarbazine
    Investigational medicinal product code
    Other name
    DTIC
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dacarbazine per institutional standard

    Investigational medicinal product name
    Temozolomide
    Investigational medicinal product code
    MK-7365
    Other name
    TEMODAR®
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Temozolomide per institutional standard

    Number of subjects in period 1
    		Pembrolizumab 2 mg/kg Pembrolizumab 10 mg/kg Investigator-Choice Chemotherapy (ICC)
    Started
    180
    181
    179
    Treated
    178
    179
    171
    Completed
    33
    47
    104
    Not completed
    147
    134
    75
         Consent withdrawn by subject
    3
    2
    4
         Death
    139
    129
    71
         Lost to follow-up
    5
    3
    -
    Period 2
    Period 2 title
    Switch-to-Pembrolizumab Treatment Period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 ICC→Pembrolizumab 2 mg/kg
    Arm description
    		 Participants who were initially randomized to ICC, subsequently experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg. Participants received pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to PD, toxicity, or choice. (Up to ~66 months)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    MK-3475, SCH 900475
    Other name
    KEYTRUDA®
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pembrolizumab 2 mg/kg via IV infusion on Day 1 of each 3-week cycle

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    MK-3475, SCH 900475
    Other name
    KEYTRUDA®
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pembrolizumab 200 mg via IV infusion on Day 1 of each 3-week cycle

    Arm title
    		 ICC→Pembrolizumab 10 mg/kg
    Arm description
    		 Participants who were assigned to ICC, experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg. Participants received pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to PD, toxicity, or choice. (Up to ~66 months)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    MK-3475, SCH 900475
    Other name
    KEYTRUDA®
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pembrolizumab 200 mg via IV infusion on Day 1 of each 3-week cycle

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    MK-3475, SCH 900475
    Other name
    KEYTRUDA®
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pembrolizumab 10 mg/kg via IV infusion on Day 1 of each 3-week cycle

    Number of subjects in period 2 [1]
    		ICC→Pembrolizumab 2 mg/kg ICC→Pembrolizumab 10 mg/kg
    Started
    53
    45
    Completed
    15
    7
    Not completed
    38
    38
         Consent withdrawn by subject
    1
    -
         Death
    35
    37
         Lost to follow-up
    2
    1
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: 98 participants who were initially randomized to the ICC treatment group and experienced progressive disease were switched to either the Pembrolizumab 2 mg/kg or Pembrolizumab 10 mg/kg treatment groups.

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Pembrolizumab 2 mg/kg
    Reporting group description
    		 Participants were initially randomized to receive pembrolizumab 2 mg/kg intravenously (IV) once every 3 weeks (Q3W). With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)

    Reporting group title
    Pembrolizumab 10 mg/kg
    Reporting group description
    		 Participants were initially randomized to receive pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)

    Reporting group title
    Investigator-Choice Chemotherapy (ICC)
    Reporting group description
    		 Participants were initially randomized to receive 1 of 4 possible chemotherapy regimens decided at the treating institution (carboplatin+paclitaxel, paclitaxel alone, dacarbazine, or temozolomide). Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)

    Reporting group values
    		 Pembrolizumab 2 mg/kg Pembrolizumab 10 mg/kg Investigator-Choice Chemotherapy (ICC) Total
    Number of subjects
    		 180 181 179 540
    Age categorical
    Units: Subjects
        Adolescents (12-17 years)
    		 1 0 0 1
        Adults (18-64 years)
    		 101 106 97 304
        From 65-84 years
    		 77 72 81 230
        85 years and over
    		 1 3 1 5
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 59.5 ( 14.9 ) 60.1 ( 13.3 ) 60.5 ( 12.7 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 76 72 65 213
        Male
    		 104 109 114 327
    Programmed Cell Death-Ligand 1 (PD-L1) Tumor Expression Status
    Membranous PD-L1 expression in tumor and tumor-associated immune cells was assessed by immunohistochemistry assay and scored on a unique melanoma (Allred Proportion Score [APS]/Melanoma [MEL]) scale of 0 to 5. Participants with an APS score of ≥2 (membranous staining in ≥1% of cells) were considered to be PD-L1 Positive and participants with an APS score of 0 or 1 were considered to be PD-L1 Negative.
    Units: Subjects
        PD-L1 Positive
    		 99 97 98 294
        PD-L1 Negative
    		 48 46 40 134
        Unknown
    		 33 38 41 112

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Pembrolizumab 2 mg/kg
    Reporting group description
    		 Participants were initially randomized to receive pembrolizumab 2 mg/kg intravenously (IV) once every 3 weeks (Q3W). With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)

    Reporting group title
    Pembrolizumab 10 mg/kg
    Reporting group description
    		 Participants were initially randomized to receive pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)

    Reporting group title
    Investigator-Choice Chemotherapy (ICC)
    Reporting group description
    		 Participants were initially randomized to receive 1 of 4 possible chemotherapy regimens decided at the treating institution (carboplatin+paclitaxel, paclitaxel alone, dacarbazine, or temozolomide). Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)
    Reporting group title
    ICC→Pembrolizumab 2 mg/kg
    Reporting group description
    		 Participants who were initially randomized to ICC, subsequently experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg. Participants received pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to PD, toxicity, or choice. (Up to ~66 months)

    Reporting group title
    ICC→Pembrolizumab 10 mg/kg
    Reporting group description
    		 Participants who were assigned to ICC, experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg. Participants received pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to PD, toxicity, or choice. (Up to ~66 months)

    Subject analysis set title
    Investigator-Choice Chemotherapy (ICC) Only
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants were randomized to receive 1 of 4 possible chemotherapy regimens decided at the treating institution (carboplatin+paclitaxel, paclitaxel alone, dacarbazine, or temozolomide). This treatment group included the participants who remained on ICC through the database cutoff date. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)

    Subject analysis set title
    ICC→Pembrolizumab 2 mg/kg (Before Switch to Pembrolizumab)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants who were initially randomized to ICC, subsequently experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg. Participants received pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to PD, toxicity, or choice. (Up to ~66 months)

    Subject analysis set title
    ICC→Pembrolizumab 10 mg/kg (Before Switch to Pembrolizumab)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants who were initially randomized to ICC, subsequently experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg. Participants received pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to PD, toxicity, or choice. (Up to ~66 months)

    Subject analysis set title
    ICC→Pembrolizumab 2 mg/kg (After Switch to Pembrolizumab)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants who were initially randomized to ICC, subsequently experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg. Participants received pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to PD, toxicity, or choice. (Up to ~66 months)

    Subject analysis set title
    ICC→Pembrolizumab 10 mg/kg (After Switch to Pembrolizumab)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants who were initially randomized to ICC, subsequently experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg. Participants received pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to PD, toxicity, or choice. (Up to ~66 months)

    Subject analysis set title
    Pembrolizumab 2 mg/kg PD-L1-Positive
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants were initially randomized to receive pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)

    Subject analysis set title
    Pembrolizumab 10 mg/kg PD-L1-Positive
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants were initially randomized to receive pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)

    Subject analysis set title
    Investigator-Choice Chemotherapy (ICC) PD-L1 Positive
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants were randomized to receive 1 of 4 possible chemotherapy regimens decided at the treating institution (carboplatin+paclitaxel, paclitaxel alone, dacarbazine, or temozolomide). (Up to ~66 months)

    Subject analysis set title
    Pembrolizumab 2 mg/kg PD-L1-Negative
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants were initially randomized to receive pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)

    Subject analysis set title
    Pembrolizumab 10 mg/kg PD-L1-Negative
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants were initially randomized to receive pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)

    Subject analysis set title
    Investigator-Choice Chemotherapy (ICC) PD-L1 Negative
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants were randomized to receive 1 of 4 possible chemotherapy regimens decided at the treating institution (carboplatin+paclitaxel, paclitaxel alone, dacarbazine, or temozolomide). (Up to ~66 months)

    Primary: Progression-free Survival (PFS) – Initial Treatment Period

    		 Close Top of page
    End point title
    		 Progression-free Survival (PFS) – Initial Treatment Period
    End point description
    PFS was defined as the time from randomization to the 1st documented progressive disease (PD) or death due to any cause, whichever occurred first. Per Response Criteria in Solid Tumors version 1.1 (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 have also demonstrated an absolute increase of ≥5 mm. Note: The appearance of ≥1 new lesions was also considered PD. Analysis of PFS was based on an integrated radiology & oncology (IRO) assessment & was not planned or conducted for the switch-to-pembrolizumab treatment groups. Median PFS based on the product limit (Kaplan-Meier) method for censored data is presented. This was the final analysis for PFS. The analysis population consisted of all randomized participants. Participants were included in the initial treatment group to which they were randomized for efficacy analysis.
    End point type
    Primary
    End point timeframe
    Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015)
    End point values
    		 Pembrolizumab 2 mg/kg Pembrolizumab 10 mg/kg Investigator-Choice Chemotherapy (ICC)
    Number of subjects analysed
    180
    181
    179
    Units: Months
        median (confidence interval 95%)
    2.9 (2.8 to 3.8)
    3.0 (2.8 to 5.2)
    2.8 (2.6 to 2.8)
    Statistical analysis title
    		 PFS - Initial Treatment Period
    Statistical analysis description
    Cox regression model with treatment as covariate stratified by Eastern Cooperative Oncology Group (ECOG) performance status (0 vs. 1); lactate dehydrogenase (LDH) levels (normal vs. elevated LDH levels [=110% Upper Limit of Normal (ULN)]); & BRAF mutational status (mutant vs. wild-type)
    Comparison groups
    Investigator-Choice Chemotherapy (ICC) v Pembrolizumab 2 mg/kg
    Number of subjects included in analysis
    359
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 < 0.0001 [2]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.46
         upper limit
    		 0.73
    Notes
    [1] - Numerator=Pembrolizumab 2 mg/kg Denominator=ICC
    [2] - One-sided p-value based on stratified log rank test
    Statistical analysis title
    		 PFS - Initial Treatment Period
    Statistical analysis description
    Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels [=110% ULN]); & BRAF mutational status (mutant vs. wild-type)
    Comparison groups
    Pembrolizumab 10 mg/kg v Investigator-Choice Chemotherapy (ICC)
    Number of subjects included in analysis
    360
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 < 0.0001 [4]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.47
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.37
         upper limit
    		 0.6
    Notes
    [3] - Numerator=Pembrolizumab 10 mg/kg Denominator=ICC
    [4] - One-sided p-value based on stratified log rank test
    Statistical analysis title
    		 PFS - Initial Treatment Period
    Statistical analysis description
    Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels [=110% ULN]); & BRAF mutational status (mutant vs. wild-type)
    Comparison groups
    Pembrolizumab 2 mg/kg v Pembrolizumab 10 mg/kg
    Number of subjects included in analysis
    361
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.1247 [6]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.66
         upper limit
    		 1.05
    Notes
    [5] - Numerator=Pembrolizumab 10 mg/kg Denominator=Pembrolizumab 2 mg/kg
    [6] - Two-sided p-value based on stratified log rank test

    Primary: Interim Overall Survival (OS) – Initial Treatment Period

    		 Close Top of page
    End point title
    		 Interim Overall Survival (OS) – Initial Treatment Period
    End point description
    OS was defined as the time from randomization to death due to any cause. Analysis of OS was not planned or conducted for the switch-to-pembrolizumab treatment groups. Median OS based on the product-limit (Kaplan-Meier) method for censored data is presented. This was the interim analysis for OS. The analysis population consisted of all randomized participants. Participants were included in the initial treatment group to which they were randomized for the efficacy analysis.
    End point type
    Primary
    End point timeframe
    Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015)
    End point values
    		 Pembrolizumab 2 mg/kg Pembrolizumab 10 mg/kg Investigator-Choice Chemotherapy (ICC)
    Number of subjects analysed
    180
    181
    179
    Units: Months
        median (confidence interval 95%)
    13.4 (11.0 to 16.4)
    14.7 (11.3 to 19.5)
    11.0 (8.9 to 13.8)
    Statistical analysis title
    		 Interim OS - Initial Treatment Period
    Statistical analysis description
    Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels [=110% ULN]); & BRAF mutational status (mutant vs. wild-type)
    Comparison groups
    Pembrolizumab 2 mg/kg v Investigator-Choice Chemotherapy (ICC)
    Number of subjects included in analysis
    359
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 = 0.1173 [8]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.67
         upper limit
    		 1.1
    Notes
    [7] - Numerator=Pembrolizumab 2 mg/kg Denominator=ICC
    [8] - One-sided p-value based on stratified log rank test
    Statistical analysis title
    		 Interim OS - Initial Treatment Period
    Statistical analysis description
    Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels [=110% ULN]); & BRAF mutational status (mutant vs. wild-type)
    Comparison groups
    Pembrolizumab 2 mg/kg v Pembrolizumab 10 mg/kg
    Number of subjects included in analysis
    361
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 = 0.2905 [10]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.67
         upper limit
    		 1.12
    Notes
    [9] - Numerator=Pembrolizumab 10 mg/kg Denominator=Pembrolizumab 2 mg/kg
    [10] - Two-sided p-value based on stratified log rank test
    Statistical analysis title
    		 Interim OS - Initial Treatment Period
    Statistical analysis description
    Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels [=110% ULN]); & BRAF mutational status (mutant vs. wild-type)
    Comparison groups
    Pembrolizumab 10 mg/kg v Investigator-Choice Chemotherapy (ICC)
    Number of subjects included in analysis
    360
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 = 0.0106 [12]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.57
         upper limit
    		 0.96
    Notes
    [11] - Numerator=Pembrolizumab 10 mg/kg Denominator=ICC
    [12] - One-sided p-value based on stratified log rank test

    Primary: Final Overall Survival (OS) – Initial Treatment Period

    		 Close Top of page
    End point title
    		 Final Overall Survival (OS) – Initial Treatment Period
    End point description
    OS was defined as the time from randomization to death due to any cause. Analysis of OS was not planned or conducted for the switch-to-pembrolizumab treatment groups. Median OS based on the product-limit (Kaplan-Meier) method for censored data is presented. This was the final analysis for OS. The analysis population consisted of all randomized participants. Participants were included in the initial treatment group to which they were randomized for the efficacy analysis.
    End point type
    Primary
    End point timeframe
    Up to approximately 75 months (Through End of Trial Analysis database cutoff date of 31-Jan-2019)
    End point values
    		 Pembrolizumab 2 mg/kg Pembrolizumab 10 mg/kg Investigator-Choice Chemotherapy (ICC)
    Number of subjects analysed
    180
    181
    179
    Units: Months
        median (confidence interval 95%)
    13.4 (11.0 to 16.4)
    14.7 (11.3 to 19.5)
    11.0 (8.9 to 13.8)
    Statistical analysis title
    		 Final OS - Initial Treatment Period
    Statistical analysis description
    Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels [=110% ULN]); & BRAF mutational status (mutant vs. wild-type)
    Comparison groups
    Pembrolizumab 2 mg/kg v Investigator-Choice Chemotherapy (ICC)
    Number of subjects included in analysis
    359
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority [13]
    P-value
    		 = 0.1146 [14]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.68
         upper limit
    		 1.1
    Notes
    [13] - Numerator=Pembrolizumab 2 mg/kg Denominator=ICC
    [14] - One-sided p-value based on stratified log rank test
    Statistical analysis title
    		 Final OS - Initial Treatment Period
    Statistical analysis description
    Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels [=110% ULN]); & BRAF mutational status (mutant vs. wild-type)
    Comparison groups
    Pembrolizumab 10 mg/kg v Investigator-Choice Chemotherapy (ICC)
    Number of subjects included in analysis
    360
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority [15]
    P-value
    		 = 0.0023 [16]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.55
         upper limit
    		 0.9
    Notes
    [15] - Numerator=Pembrolizumab 10 mg/kg Denominator=ICC
    [16] - One-sided p-value based on stratified log rank test
    Statistical analysis title
    		 Final OS - Initial Treatment Period
    Statistical analysis description
    Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels [=110% ULN]); & BRAF mutational status (mutant vs. wild-type)
    Comparison groups
    Pembrolizumab 2 mg/kg v Pembrolizumab 10 mg/kg
    Number of subjects included in analysis
    361
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority [17]
    P-value
    		 = 0.149 [18]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.66
         upper limit
    		 1.07
    Notes
    [17] - Numerator=Pembrolizumab 10 mg/kg Denominator=Pembrolizumab 2 mg/kg
    [18] - Two-sided p-value based on stratified log rank test

    Secondary: Overall Survival (OS) By Programmed Cell Death-Ligand 1 (PD-L1) Tumor Expression Status – Initial Treatment Period

    		 Close Top of page
    End point title
    		 Overall Survival (OS) By Programmed Cell Death-Ligand 1 (PD-L1) Tumor Expression Status – Initial Treatment Period
    End point description
    OS was defined as the time from randomization to death due to any cause. Participants with a Allred Proportion Score (APS) ≥2 (membranous staining in ≥1% of cells for PD-L1) were considered to be PD-L1 Positive and participants with a APS of 0 or 1 were considered to be PD-L1 Negative. Analysis of OS was not planned or conducted for the switch-to-pembrolizumab treatment groups. Median OS based on the product-limit (Kaplan-Meier) method for censored data by PD-L1 tumor expression status is presented. The analysis population consisted of all randomized participants who had a PD-L1 APS assessment. Participants were included in the initial treatment group to which they were randomized for efficacy analysis.
    End point type
    Secondary
    End point timeframe
    Up to approximately 75 months (Through End of Trial Analysis database cutoff date of 31-Jan-2019)
    End point values
    		 Pembrolizumab 2 mg/kg PD-L1-Positive Pembrolizumab 10 mg/kg PD-L1-Positive Investigator-Choice Chemotherapy (ICC) PD-L1 Positive Pembrolizumab 2 mg/kg PD-L1-Negative Pembrolizumab 10 mg/kg PD-L1-Negative Investigator-Choice Chemotherapy (ICC) PD-L1 Negative
    Number of subjects analysed
    99
    97
    98
    48
    46
    40
    Units: Months
        median (confidence interval 95%)
    15.0 (10.9 to 20.9)
    17.5 (13.7 to 28.9)
    12.1 (7.7 to 18.2)
    10.5 (6.4 to 13.5)
    13.4 (4.6 to 23.3)
    9.3 (5.1 to 14.2)
    Statistical analysis title
    		 Final OS by PD-L1 Tumor Expression Status
    Statistical analysis description
    Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels [=110% ULN]); & BRAF mutational status (mutant vs. wild-type)
    Comparison groups
    Pembrolizumab 2 mg/kg PD-L1-Positive v Investigator-Choice Chemotherapy (ICC) PD-L1 Positive
    Number of subjects included in analysis
    197
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [19]
    P-value
    		 = 0.3113 [20]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.66
         upper limit
    		 1.28
    Notes
    [19] - PD-L1-Positive Participants Numerator=Pembrolizumab 2 mg/kg Denominator=ICC
    [20] - One-sided p-value based on stratified log rank test
    Statistical analysis title
    		 Final OS by PD-L1 Tumor Expression Status
    Statistical analysis description
    Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels [=110% ULN]); & BRAF mutational status (mutant vs. wild-type)
    Comparison groups
    Pembrolizumab 10 mg/kg PD-L1-Positive v Investigator-Choice Chemotherapy (ICC) PD-L1 Positive
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [21]
    P-value
    		 = 0.0208 [22]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 0.99
    Notes
    [21] - PD-L1 Positive Participants Numerator=Pembrolizumab 10 mg/kg Denominator=ICC
    [22] - One-sided p-value based on stratified log rank test
    Statistical analysis title
    		 Final OS by PD-L1 Tumor Expression Status
    Statistical analysis description
    Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels [=110% ULN]); & BRAF mutational status (mutant vs. wild-type)
    Comparison groups
    Pembrolizumab 2 mg/kg PD-L1-Positive v Pembrolizumab 10 mg/kg PD-L1-Positive
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [23]
    P-value
    		 = 0.0496 [24]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 1
    Notes
    [23] - PD-L1 Positive Participants Numerator=Pembrolizumab 10 mg/kg Denominator=Pembrolizumab 2 mg/kg
    [24] - Two-sided p-value based on stratified log rank test
    Statistical analysis title
    		 Final OS by PD-L1 Tumor Expression Status
    Statistical analysis description
    Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels [=110% ULN]); & BRAF mutational status (mutant vs. wild-type)
    Comparison groups
    Pembrolizumab 2 mg/kg PD-L1-Negative v Investigator-Choice Chemotherapy (ICC) PD-L1 Negative
    Number of subjects included in analysis
    88
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [25]
    P-value
    		 = 0.6043 [26]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.65
         upper limit
    		 1.76
    Notes
    [25] - PD-L1 Negative Participants Numerator=Pembrolizumab 2 mg/kg Denominator=ICC
    [26] - One-sided p-value based on stratified log rank test
    Statistical analysis title
    		 Final OS by PD-L1 Tumor Expression Status
    Statistical analysis description
    Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels [=110% ULN]); & BRAF mutational status (mutant vs. wild-type)
    Comparison groups
    Pembrolizumab 10 mg/kg PD-L1-Negative v Investigator-Choice Chemotherapy (ICC) PD-L1 Negative
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [27]
    P-value
    		 = 0.0335 [28]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.37
         upper limit
    		 1.04
    Notes
    [27] - PD-L1 Negative Participants Numerator=Pembrolizumab 10 mg/kg Denominator=ICC
    [28] - One-sided p-value based on stratified log rank test
    Statistical analysis title
    		 Final OS by PD-L1 Tumor Expression Status
    Statistical analysis description
    Cox regression model with treatment as covariate stratified by ECOG performance status (0 vs. 1); LDH levels (normal vs. elevated LDH levels [=110% ULN]); & BRAF mutational status (mutant vs. wild-type)
    Comparison groups
    Pembrolizumab 2 mg/kg PD-L1-Negative v Pembrolizumab 10 mg/kg PD-L1-Negative
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [29]
    P-value
    		 = 0.1504 [30]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.44
         upper limit
    		 1.13
    Notes
    [29] - PD-L1 Negative Participants Numerator=Pembrolizumab 10 mg/kg Denominator=Pembrolizumab 2 mg/kg
    [30] - Two-sided p-value based on stratified log rank test

    Secondary: Overall Response Rate (ORR) – Initial Treatment Period

    		 Close Top of page
    End point title
    		 Overall Response Rate (ORR) – Initial Treatment Period
    End point description
    ORR was defined as the percentage of participants who had a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions) as assessed using RECIST 1.1. Analysis of ORR was not planned or conducted for the switch-to-pembrolizumab participants. The percentage of participants who experienced a CR or PR is presented. This was the final analysis for ORR. The analysis population consisted of all randomized participants. Participants were included in the initial treatment group to which they were randomized for efficacy analysis.
    End point type
    Secondary
    End point timeframe
    Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015)
    End point values
    		 Pembrolizumab 2 mg/kg Pembrolizumab 10 mg/kg Investigator-Choice Chemotherapy (ICC)
    Number of subjects analysed
    180
    181
    179
    Units: Percentage of Participants
        number (confidence interval 95%)
    22.2 (16.4 to 29.0)
    27.6 (21.3 to 34.7)
    4.5 (1.9 to 8.6)
    No statistical analyses for this end point

    Secondary: Best Overall Response (BOR) - Initial Treatment Period

    		 Close Top of page
    End point title
    		 Best Overall Response (BOR) - Initial Treatment Period
    End point description
    BOR was assessed by independent radiology review using RECIST 1.1 and was recorded from randomization until the last imaging assessment in this period. Response categories included: Complete Response (CR): disappearance of all target lesions; Partial Response (PR): at least a 30% decrease in the sum of diameters of target lesions; Progressive Disease (PD): at least a 20% increase in the sum of diameters of target lesions; and Stable Disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. BOR for the Initial Treatment Period was based on IRO and is presented for participants during the Initial Treatment Period. The analysis population consisted of all randomized participants. Participants were included in the initial treatment group to which they were randomized for this efficacy analysis.
    End point type
    Secondary
    End point timeframe
    Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015)
    End point values
    		 Pembrolizumab 2 mg/kg Pembrolizumab 10 mg/kg Investigator-Choice Chemotherapy (ICC)
    Number of subjects analysed
    180
    181
    179
    Units: Percentage of Participants
    number (not applicable)
        Complete Response
    3.3
    7.2
    0.0
        Partial Response
    18.9
    20.4
    4.5
        Stable Disease
    16.7
    14.9
    19.0
        Progressive Disease
    46.7
    47.5
    61.5
        Not Evaluable
    13.3
    9.9
    15.1
        No Disease
    0.6
    0.0
    0.0
        No Assessment
    0.6
    0.0
    0.0
    No statistical analyses for this end point

    Secondary: Best Overall Response (BOR) - Switch-to-Pembrolizumab Treatment Period

    		 Close Top of page
    End point title
    		 Best Overall Response (BOR) - Switch-to-Pembrolizumab Treatment Period
    End point description
    BOR was assessed using RECIST 1.1 & was recorded from the start of the second line of study drug (pembrolizumab) until the last imaging assessment in this period. Response categories included: Complete Response (CR): disappearance of all target lesions; Partial Response (PR): ≥30% decrease in the sum of diameters of target lesions; Progressive Disease (PD): ≥20% increase in the sum of diameters of target lesions; & Stable Disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. For the switch-to-pembrolizumab treatment groups, BOR was based on independent review committee (IRC) assessment and is presented for the switch-to-pembrolizumab treatment groups. The analysis population consisted of all randomized participants in ICC who switched to receiving pembrolizumab. Participants were included in the treatment group to which they were re-randomized (switched) for this efficacy analysis.
    End point type
    Secondary
    End point timeframe
    Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015)
    End point values
    		 ICC→Pembrolizumab 2 mg/kg ICC→Pembrolizumab 10 mg/kg
    Number of subjects analysed
    53
    45
    Units: Percentage of Participants
    number (not applicable)
        Complete Response
    1.9
    4.4
        Partial Response
    17.0
    13.3
        Stable Disease
    15.1
    11.1
        Progressive Disease
    54.7
    55.6
        Not Evaluable
    11.3
    13.3
        No Assessment
    0.0
    2.2
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR) – Initial Treatment Period

    		 Close Top of page
    End point title
    		 Duration of Response (DOR) – Initial Treatment Period
    End point description
    For participants who demonstrated a confirmed response (Complete Response [CR]: disappearance of all target lesions or Partial Response [PR]: ≥30% decrease in the sum of diameters of target lesions) per RECIST 1.1, DOR was defined as the time from 1st documented evidence of CR or PR until disease progression or death. DOR for participants who had not progressed or died at the time of analysis was to be censored at the date of their last tumor assessment. DOR analysis was based on IRO assessment. Analysis of DOR was not planned or analyzed for the switch-to-pembrolizumab treatment groups. Median DOR is presented. The analysis population consisted of all randomized participants who demonstrated a confirmed response (CR or PR) per RECIST 1.1. Participants were included in the treatment group to which they were randomized for efficacy. (99999=DOR Median not reached; 99999=DOR Upper Limit not reached: no progressive disease by time of last assessment)
    End point type
    Secondary
    End point timeframe
    Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015)
    End point values
    		 Pembrolizumab 2 mg/kg Pembrolizumab 10 mg/kg Investigator-Choice Chemotherapy (ICC)
    Number of subjects analysed
    40
    50
    8
    Units: Months
        median (full range (min-max))
    22.8 (1.4 to 25.3)
    99999 (1.1 to 99999)
    6.8 (2.8 to 11.3)
    No statistical analyses for this end point

    Secondary: Number of Participants Who Experienced an Adverse Event (AE) - Overall Study

    		 Close Top of page
    End point title
    		 Number of Participants Who Experienced an Adverse Event (AE) - Overall Study [31]
    End point description
    An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of study drug, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition which was temporally associated with the use of study drug, was also an AE. Participants were included in the treatment group in which an AE was experienced. The number of participants who experienced at least one AE is presented. The analysis population consisted of all participants who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    Up to approximately 75 months (Through End of Trial Analysis database cutoff date of 31-Jan-2019)
    Notes
    [31] - 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: The initial ICC treatment group was broken out into 5 treatment groups for analysis of safety.
    End point values
    		 Pembrolizumab 2 mg/kg Pembrolizumab 10 mg/kg Investigator-Choice Chemotherapy (ICC) Only ICC→Pembrolizumab 2 mg/kg (Before Switch to Pembrolizumab) ICC→Pembrolizumab 10 mg/kg (Before Switch to Pembrolizumab) ICC→Pembrolizumab 2 mg/kg (After Switch to Pembrolizumab) ICC→Pembrolizumab 10 mg/kg (After Switch to Pembrolizumab)
    Number of subjects analysed
    178
    179
    73
    53
    45
    53
    45
    Units: Participants
    172
    179
    71
    52
    45
    53
    41
    No statistical analyses for this end point

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

    		 Close Top of page
    End point title
    		 Number of Participants Who Discontinued Study Drug Due to an Adverse Event (AE) - Overall Study [32]
    End point description
    An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study drug, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition which is temporally associated with the use of study drug, was also an AE. The number of participants who discontinued study drug due to an AE is presented. The analysis population consisted of all participants who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    Up to approximately 75 months (Through End of Trial Analysis database cutoff date of 31-Jan-2019)
    Notes
    [32] - 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: The initial ICC treatment group was broken out into 5 treatment groups for analysis of tolerability.
    End point values
    		 Pembrolizumab 2 mg/kg Pembrolizumab 10 mg/kg Investigator-Choice Chemotherapy (ICC) Only ICC→Pembrolizumab 2 mg/kg (Before Switch to Pembrolizumab) ICC→Pembrolizumab 10 mg/kg (Before Switch to Pembrolizumab) ICC→Pembrolizumab 2 mg/kg (After Switch to Pembrolizumab) ICC→Pembrolizumab 10 mg/kg (After Switch to Pembrolizumab)
    Number of subjects analysed
    178
    179
    73
    53
    45
    53
    45
    Units: Participants
    29
    33
    13
    1
    1
    4
    4
    No statistical analyses for this end point

    Adverse events

    		 Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    Up to approximately 75 months (Through End of Trial Analysis database cutoff date of 31-Jan-2019)
    Adverse event reporting additional description
    Safety Population: All participants who received ≥1 dose of study drug. Per protocol, disease progression of cancer under study was not considered an AE unless related to study drug. Therefore, MedDRA preferred terms "Neoplasm progression", "Malignant neoplasm progression" and "Disease progression" not related to study drug are excluded as AEs.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Investigator-Choice Chemotherapy (ICC) Only
    Reporting group description
    		 Participants received one of four possible chemotherapy regimens decided at the treating institution (carboplatin + paclitaxel, paclitaxel alone, dacarbazine, or temozolomide). This treatment group included the participants who remained on ICC through the final analysis. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to approximately 66 months)

    Reporting group title
    ICC→Pembrolizumab 10 mg/kg (Before Switch to Pembrolizumab)
    Reporting group description
    		 Participants who were assigned to ICC, experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg in a double-blind fashion. Participants received pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to approximately 66 months)

    Reporting group title
    ICC→Pembrolizumab 2 mg/kg (Before Switch to Pembrolizumab)
    Reporting group description
    		 Participants who were assigned to ICC, experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg in a double-blind fashion. Participants received pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to approximately 66 months)

    Reporting group title
    Pembrolizumab 2 mg/kg
    Reporting group description
    		 Participants initially received pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to approximately 66 months)

    Reporting group title
    Pembrolizumab 10 mg/kg
    Reporting group description
    		 Participants initially received pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to approximately 66 months)

    Reporting group title
    ICC→Pembrolizumab 2 mg/kg (After Switch to Pembrolizumab)
    Reporting group description
    		 Participants who were assigned to ICC, experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg in a double-blind fashion. Participants received pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to approximately 66 months)

    Reporting group title
    ICC→Pembrolizumab 10 mg/kg (After Switch to Pembrolizumab)
    Reporting group description
    		 Participants who were assigned to ICC, experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg in a double-blind fashion. Participants received pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to approximately 66 months)

    Serious adverse events
    		 Investigator-Choice Chemotherapy (ICC) Only ICC→Pembrolizumab 10 mg/kg (Before Switch to Pembrolizumab) ICC→Pembrolizumab 2 mg/kg (Before Switch to Pembrolizumab) Pembrolizumab 2 mg/kg Pembrolizumab 10 mg/kg ICC→Pembrolizumab 2 mg/kg (After Switch to Pembrolizumab) ICC→Pembrolizumab 10 mg/kg (After Switch to Pembrolizumab)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    33 / 73 (45.21%)
    9 / 45 (20.00%)
    15 / 53 (28.30%)
    91 / 178 (51.12%)
    78 / 179 (43.58%)
    18 / 53 (33.96%)
    18 / 45 (40.00%)
         number of deaths (all causes)
    71
    0
    0
    139
    129
    35
    37
         number of deaths resulting from adverse events
    7
    0
    0
    11
    8
    1
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    2 / 178 (1.12%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cancer pain
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Colon cancer metastatic
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Intracranial tumour haemorrhage
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    0 / 179 (0.00%)
    1 / 53 (1.89%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    3 / 178 (1.69%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to lymph nodes
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Oncologic complication
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Rectal cancer
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    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
    0 / 0
    Tumour pain
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 45 (2.22%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    1 / 53 (1.89%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal metastasis
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Metastases to meninges
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Metastasis
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Small cell carcinoma
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    1 / 53 (1.89%)
    1 / 178 (0.56%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    1 / 53 (1.89%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    1 / 53 (1.89%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymphoedema
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    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
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Phlebitis
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Poor venous access
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Thrombosis
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    2 / 178 (1.12%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Cyst
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Death
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    2 / 178 (1.12%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    2 / 2
    1 / 1
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Gait disturbance
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    6 / 179 (3.35%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    1 / 6
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    3 / 3
    0 / 0
    0 / 0
    Generalised oedema
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    3 / 178 (1.69%)
    0 / 179 (0.00%)
    1 / 53 (1.89%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    2 / 3
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Infusion site extravasation
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Oedema
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 73 (1.37%)
    1 / 45 (2.22%)
    0 / 53 (0.00%)
    3 / 178 (1.69%)
    4 / 179 (2.23%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 4
    1 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Cytokine release syndrome
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    1 / 53 (1.89%)
    2 / 178 (1.12%)
    0 / 179 (0.00%)
    1 / 53 (1.89%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Dyspnoea
         subjects affected / exposed
    3 / 73 (4.11%)
    1 / 45 (2.22%)
    0 / 53 (0.00%)
    2 / 178 (1.12%)
    5 / 179 (2.79%)
    1 / 53 (1.89%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
    1 / 2
    0 / 5
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Laryngeal inflammation
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    3 / 179 (1.68%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    3 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 73 (2.74%)
    0 / 45 (0.00%)
    2 / 53 (3.77%)
    2 / 178 (1.12%)
    1 / 179 (0.56%)
    1 / 53 (1.89%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 2
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary thrombosis
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    0 / 179 (0.00%)
    1 / 53 (1.89%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Alveolitis allergic
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    0 / 179 (0.00%)
    1 / 53 (1.89%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    2 / 178 (1.12%)
    3 / 179 (1.68%)
    1 / 53 (1.89%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 2
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Mental status changes
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    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
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    2 / 73 (2.74%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    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
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    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
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    1 / 53 (1.89%)
    0 / 178 (0.00%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Fracture displacement
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Spinal fracture
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Traumatic intracranial haemorrhage
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Limb injury
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Radiation necrosis
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Accidental overdose
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    0 / 179 (0.00%)
    1 / 53 (1.89%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Cardiac ventricular disorder
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    1 / 53 (1.89%)
    0 / 178 (0.00%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Nervous system disorders
    Ataxia
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    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
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    1 / 179 (0.56%)
    1 / 53 (1.89%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    2 / 178 (1.12%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Hemiplegia
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Lumbar radiculopathy
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Meningitis noninfective
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Myasthenic syndrome
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Myoclonus
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    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
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Paraesthesia
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Partial seizures
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    2 / 178 (1.12%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    1 / 53 (1.89%)
    2 / 45 (4.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    2 / 178 (1.12%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
    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
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    0 / 0
    Aphasia
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Brain oedema
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Peripheral motor neuropathy
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 73 (4.11%)
    0 / 45 (0.00%)
    1 / 53 (1.89%)
    7 / 178 (3.93%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
    1 / 1
    2 / 7
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    2 / 73 (2.74%)
    0 / 45 (0.00%)
    1 / 53 (1.89%)
    0 / 178 (0.00%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    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
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    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
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    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
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    2 / 73 (2.74%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    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
    0 / 0
    Ear and labyrinth disorders
    Vertigo positional
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Eye disorders
    Eye movement disorder
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Iritis
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    4 / 179 (2.23%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    1 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    1 / 53 (1.89%)
    0 / 178 (0.00%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Autoimmune colitis
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    1 / 53 (1.89%)
    2 / 178 (1.12%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 45 (2.22%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    4 / 179 (2.23%)
    1 / 53 (1.89%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    4 / 4
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulum
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    1 / 53 (1.89%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric disorder
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Gastrointestinal disorder
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Gastrointestinal pain
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Haematochezia
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    1 / 53 (1.89%)
    0 / 178 (0.00%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    2 / 179 (1.12%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Intussusception
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Large intestinal ulcer
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Malabsorption
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Nausea
         subjects affected / exposed
    3 / 73 (4.11%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    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
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    1 / 179 (0.56%)
    1 / 53 (1.89%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    2 / 2
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
    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
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Small intestinal perforation
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    1 / 1
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    2 / 178 (1.12%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    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
    0 / 0
    Diverticular perforation
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    0 / 179 (0.00%)
    1 / 53 (1.89%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    2 / 45 (4.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Hepatobiliary disorders
    Autoimmune hepatitis
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Cholangitis
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    3 / 178 (1.69%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    0 / 0
    Hepatic necrosis
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    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
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 45 (2.22%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 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
    0 / 0
    Bile duct obstruction
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Skin and subcutaneous tissue disorders
    Lichenoid keratosis
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Skin mass
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Stevens-Johnson syndrome
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Purpura
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    1 / 53 (1.89%)
    1 / 178 (0.56%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 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
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Postrenal failure
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Tubulointerstitial nephritis
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Endocrine disorders
    Addison's disease
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    1 / 53 (1.89%)
    0 / 178 (0.00%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Adrenal insufficiency
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Adrenocortical insufficiency acute
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Hyperparathyroidism
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Hypophysitis
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Hypopituitarism
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    2 / 179 (1.12%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Secondary adrenocortical insufficiency
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Inappropriate antidiuretic hormone secretion
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    0 / 179 (0.00%)
    1 / 53 (1.89%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    2 / 179 (1.12%)
    0 / 53 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    2 / 179 (1.12%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Groin pain
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Neck pain
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Osteolysis
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 45 (2.22%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    0 / 0
    Spondylolisthesis
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Cervical spine stenosis
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    0 / 179 (0.00%)
    1 / 53 (1.89%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis perforated
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    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
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    2 / 178 (1.12%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Candida infection
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    0 / 0
    Cellulitis streptococcal
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Enterocolitis infectious
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    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
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 45 (0.00%)
    1 / 53 (1.89%)
    2 / 178 (1.12%)
    2 / 179 (1.12%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 2
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Infected cyst
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Infection
         subjects affected / exposed
    2 / 73 (2.74%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    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
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 45 (2.22%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    0 / 0
    Mastitis
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Pelvic abscess
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 73 (4.11%)
    2 / 45 (4.44%)
    0 / 53 (0.00%)
    2 / 178 (1.12%)
    3 / 179 (1.68%)
    3 / 53 (5.66%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 2
    0 / 0
    0 / 2
    2 / 5
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 45 (2.22%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 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
    0 / 0
    Salmonellosis
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 73 (2.74%)
    0 / 45 (0.00%)
    1 / 53 (1.89%)
    1 / 178 (0.56%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 1
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    2 / 178 (1.12%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    1 / 53 (1.89%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Streptococcal sepsis
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 73 (2.74%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    2 / 178 (1.12%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    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
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 45 (2.22%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 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
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral rash
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Abdominal abscess
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    0 / 179 (0.00%)
    1 / 53 (1.89%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    0 / 179 (0.00%)
    1 / 53 (1.89%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    1 / 53 (1.89%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 45 (0.00%)
    1 / 53 (1.89%)
    4 / 178 (2.25%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
    0 / 4
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetic metabolic decompensation
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    1 / 53 (1.89%)
    0 / 178 (0.00%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    1 / 178 (0.56%)
    3 / 179 (1.68%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    1 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    0 / 179 (0.00%)
    0 / 53 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Type 1 diabetes mellitus
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    0 / 179 (0.00%)
    1 / 53 (1.89%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Investigator-Choice Chemotherapy (ICC) Only ICC→Pembrolizumab 10 mg/kg (Before Switch to Pembrolizumab) ICC→Pembrolizumab 2 mg/kg (Before Switch to Pembrolizumab) Pembrolizumab 2 mg/kg Pembrolizumab 10 mg/kg ICC→Pembrolizumab 2 mg/kg (After Switch to Pembrolizumab) ICC→Pembrolizumab 10 mg/kg (After Switch to Pembrolizumab)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    66 / 73 (90.41%)
    44 / 45 (97.78%)
    52 / 53 (98.11%)
    158 / 178 (88.76%)
    176 / 179 (98.32%)
    48 / 53 (90.57%)
    36 / 45 (80.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain
         subjects affected / exposed
    4 / 73 (5.48%)
    3 / 45 (6.67%)
    4 / 53 (7.55%)
    2 / 178 (1.12%)
    8 / 179 (4.47%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    4
    3
    4
    2
    8
    0
    0
    Melanocytic naevus
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    0 / 179 (0.00%)
    3 / 53 (5.66%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    5
    0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    5 / 178 (2.81%)
    11 / 179 (6.15%)
    2 / 53 (3.77%)
    3 / 45 (6.67%)
         occurrences all number
    1
    0
    0
    7
    11
    2
    5
    Hypertension
         subjects affected / exposed
    1 / 73 (1.37%)
    1 / 45 (2.22%)
    2 / 53 (3.77%)
    2 / 178 (1.12%)
    9 / 179 (5.03%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    1
    1
    2
    2
    9
    0
    0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    0 / 179 (0.00%)
    3 / 53 (5.66%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    0
    Lymphoedema
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    0 / 179 (0.00%)
    3 / 53 (5.66%)
    1 / 45 (2.22%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    10 / 73 (13.70%)
    2 / 45 (4.44%)
    4 / 53 (7.55%)
    19 / 178 (10.67%)
    20 / 179 (11.17%)
    2 / 53 (3.77%)
    3 / 45 (6.67%)
         occurrences all number
    11
    2
    4
    25
    44
    2
    3
    Chest pain
         subjects affected / exposed
    3 / 73 (4.11%)
    1 / 45 (2.22%)
    3 / 53 (5.66%)
    7 / 178 (3.93%)
    11 / 179 (6.15%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    3
    1
    4
    8
    15
    0
    0
    Chills
         subjects affected / exposed
    0 / 73 (0.00%)
    5 / 45 (11.11%)
    3 / 53 (5.66%)
    10 / 178 (5.62%)
    11 / 179 (6.15%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    5
    3
    11
    13
    0
    0
    Fatigue
         subjects affected / exposed
    28 / 73 (38.36%)
    26 / 45 (57.78%)
    27 / 53 (50.94%)
    74 / 178 (41.57%)
    91 / 179 (50.84%)
    15 / 53 (28.30%)
    16 / 45 (35.56%)
         occurrences all number
    34
    33
    36
    106
    117
    17
    24
    Influenza like illness
         subjects affected / exposed
    1 / 73 (1.37%)
    1 / 45 (2.22%)
    1 / 53 (1.89%)
    9 / 178 (5.06%)
    14 / 179 (7.82%)
    4 / 53 (7.55%)
    3 / 45 (6.67%)
         occurrences all number
    2
    1
    1
    13
    17
    4
    6
    Malaise
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    3 / 53 (5.66%)
    7 / 178 (3.93%)
    2 / 179 (1.12%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    3
    9
    2
    0
    0
    Oedema peripheral
         subjects affected / exposed
    4 / 73 (5.48%)
    1 / 45 (2.22%)
    5 / 53 (9.43%)
    17 / 178 (9.55%)
    21 / 179 (11.73%)
    6 / 53 (11.32%)
    2 / 45 (4.44%)
         occurrences all number
    4
    1
    5
    19
    24
    7
    2
    Pain
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 45 (2.22%)
    4 / 53 (7.55%)
    6 / 178 (3.37%)
    7 / 179 (3.91%)
    3 / 53 (5.66%)
    0 / 45 (0.00%)
         occurrences all number
    0
    1
    5
    7
    7
    3
    0
    Pyrexia
         subjects affected / exposed
    7 / 73 (9.59%)
    5 / 45 (11.11%)
    5 / 53 (9.43%)
    23 / 178 (12.92%)
    30 / 179 (16.76%)
    3 / 53 (5.66%)
    8 / 45 (17.78%)
         occurrences all number
    7
    6
    7
    33
    43
    4
    8
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    9 / 73 (12.33%)
    6 / 45 (13.33%)
    13 / 53 (24.53%)
    37 / 178 (20.79%)
    42 / 179 (23.46%)
    7 / 53 (13.21%)
    5 / 45 (11.11%)
         occurrences all number
    9
    8
    13
    50
    50
    7
    6
    Dyspnoea
         subjects affected / exposed
    9 / 73 (12.33%)
    1 / 45 (2.22%)
    10 / 53 (18.87%)
    18 / 178 (10.11%)
    29 / 179 (16.20%)
    7 / 53 (13.21%)
    4 / 45 (8.89%)
         occurrences all number
    10
    1
    10
    20
    33
    7
    4
    Pleural effusion
         subjects affected / exposed
    4 / 73 (5.48%)
    0 / 45 (0.00%)
    1 / 53 (1.89%)
    3 / 178 (1.69%)
    3 / 179 (1.68%)
    4 / 53 (7.55%)
    1 / 45 (2.22%)
         occurrences all number
    4
    0
    1
    3
    3
    4
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    4 / 73 (5.48%)
    1 / 45 (2.22%)
    4 / 53 (7.55%)
    10 / 178 (5.62%)
    8 / 179 (4.47%)
    3 / 53 (5.66%)
    1 / 45 (2.22%)
         occurrences all number
    6
    1
    4
    10
    8
    3
    1
    Depression
         subjects affected / exposed
    4 / 73 (5.48%)
    1 / 45 (2.22%)
    4 / 53 (7.55%)
    7 / 178 (3.93%)
    12 / 179 (6.70%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    4
    1
    4
    7
    13
    0
    0
    Insomnia
         subjects affected / exposed
    8 / 73 (10.96%)
    3 / 45 (6.67%)
    2 / 53 (3.77%)
    9 / 178 (5.06%)
    11 / 179 (6.15%)
    3 / 53 (5.66%)
    1 / 45 (2.22%)
         occurrences all number
    8
    3
    2
    10
    12
    3
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 73 (0.00%)
    3 / 45 (6.67%)
    2 / 53 (3.77%)
    9 / 178 (5.06%)
    13 / 179 (7.26%)
    3 / 53 (5.66%)
    2 / 45 (4.44%)
         occurrences all number
    0
    4
    2
    10
    18
    4
    4
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 45 (2.22%)
    1 / 53 (1.89%)
    11 / 178 (6.18%)
    14 / 179 (7.82%)
    3 / 53 (5.66%)
    1 / 45 (2.22%)
         occurrences all number
    0
    1
    2
    11
    17
    4
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    2 / 73 (2.74%)
    2 / 45 (4.44%)
    1 / 53 (1.89%)
    12 / 178 (6.74%)
    10 / 179 (5.59%)
    4 / 53 (7.55%)
    2 / 45 (4.44%)
         occurrences all number
    2
    2
    1
    13
    16
    4
    2
    Blood bilirubin increased
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 45 (0.00%)
    3 / 53 (5.66%)
    6 / 178 (3.37%)
    2 / 179 (1.12%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    1
    0
    3
    11
    5
    0
    0
    Blood cholesterol increased
         subjects affected / exposed
    0 / 73 (0.00%)
    3 / 45 (6.67%)
    2 / 53 (3.77%)
    5 / 178 (2.81%)
    7 / 179 (3.91%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    3
    2
    9
    14
    0
    0
    Lymphocyte count decreased
         subjects affected / exposed
    4 / 73 (5.48%)
    2 / 45 (4.44%)
    3 / 53 (5.66%)
    6 / 178 (3.37%)
    7 / 179 (3.91%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    4
    2
    4
    17
    8
    0
    0
    Neutrophil count decreased
         subjects affected / exposed
    3 / 73 (4.11%)
    4 / 45 (8.89%)
    3 / 53 (5.66%)
    2 / 178 (1.12%)
    1 / 179 (0.56%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    3
    5
    4
    10
    5
    0
    0
    Platelet count decreased
         subjects affected / exposed
    5 / 73 (6.85%)
    5 / 45 (11.11%)
    4 / 53 (7.55%)
    2 / 178 (1.12%)
    5 / 179 (2.79%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    7
    8
    9
    9
    9
    0
    0
    Weight decreased
         subjects affected / exposed
    1 / 73 (1.37%)
    3 / 45 (6.67%)
    4 / 53 (7.55%)
    12 / 178 (6.74%)
    17 / 179 (9.50%)
    4 / 53 (7.55%)
    1 / 45 (2.22%)
         occurrences all number
    1
    3
    5
    12
    17
    5
    1
    White blood cell count decreased
         subjects affected / exposed
    5 / 73 (6.85%)
    3 / 45 (6.67%)
    3 / 53 (5.66%)
    4 / 178 (2.25%)
    3 / 179 (1.68%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    6
    3
    3
    12
    3
    0
    0
    Blood creatinine increased
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    0 / 179 (0.00%)
    3 / 53 (5.66%)
    2 / 45 (4.44%)
         occurrences all number
    0
    0
    0
    0
    0
    7
    2
    Lipase increased
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    0 / 179 (0.00%)
    3 / 53 (5.66%)
    1 / 45 (2.22%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    1
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    4 / 73 (5.48%)
    0 / 45 (0.00%)
    2 / 53 (3.77%)
    3 / 178 (1.69%)
    7 / 179 (3.91%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    4
    0
    3
    4
    7
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    9 / 73 (12.33%)
    3 / 45 (6.67%)
    4 / 53 (7.55%)
    19 / 178 (10.67%)
    18 / 179 (10.06%)
    3 / 53 (5.66%)
    7 / 45 (15.56%)
         occurrences all number
    9
    3
    4
    25
    27
    4
    7
    Dysgeusia
         subjects affected / exposed
    2 / 73 (2.74%)
    4 / 45 (8.89%)
    5 / 53 (9.43%)
    3 / 178 (1.69%)
    2 / 179 (1.12%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    2
    4
    5
    3
    2
    0
    0
    Headache
         subjects affected / exposed
    8 / 73 (10.96%)
    7 / 45 (15.56%)
    9 / 53 (16.98%)
    21 / 178 (11.80%)
    30 / 179 (16.76%)
    8 / 53 (15.09%)
    6 / 45 (13.33%)
         occurrences all number
    8
    10
    11
    33
    45
    11
    10
    Neuropathy peripheral
         subjects affected / exposed
    6 / 73 (8.22%)
    5 / 45 (11.11%)
    7 / 53 (13.21%)
    4 / 178 (2.25%)
    3 / 179 (1.68%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    6
    7
    7
    4
    3
    0
    0
    Paraesthesia
         subjects affected / exposed
    3 / 73 (4.11%)
    3 / 45 (6.67%)
    5 / 53 (9.43%)
    4 / 178 (2.25%)
    4 / 179 (2.23%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    3
    3
    6
    4
    4
    0
    0
    Tremor
         subjects affected / exposed
    0 / 73 (0.00%)
    3 / 45 (6.67%)
    1 / 53 (1.89%)
    3 / 178 (1.69%)
    5 / 179 (2.79%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    3
    1
    3
    5
    0
    0
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 73 (1.37%)
    3 / 45 (6.67%)
    2 / 53 (3.77%)
    1 / 178 (0.56%)
    2 / 179 (1.12%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    1
    3
    2
    1
    2
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    21 / 73 (28.77%)
    10 / 45 (22.22%)
    15 / 53 (28.30%)
    30 / 178 (16.85%)
    26 / 179 (14.53%)
    12 / 53 (22.64%)
    8 / 45 (17.78%)
         occurrences all number
    26
    10
    25
    43
    31
    13
    21
    Leukopenia
         subjects affected / exposed
    8 / 73 (10.96%)
    4 / 45 (8.89%)
    3 / 53 (5.66%)
    0 / 178 (0.00%)
    2 / 179 (1.12%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    8
    7
    6
    0
    3
    0
    0
    Neutropenia
         subjects affected / exposed
    2 / 73 (2.74%)
    5 / 45 (11.11%)
    7 / 53 (13.21%)
    1 / 178 (0.56%)
    2 / 179 (1.12%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    2
    8
    14
    1
    4
    0
    0
    Thrombocytopenia
         subjects affected / exposed
    9 / 73 (12.33%)
    2 / 45 (4.44%)
    7 / 53 (13.21%)
    3 / 178 (1.69%)
    3 / 179 (1.68%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    12
    2
    10
    5
    5
    0
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    3 / 73 (4.11%)
    0 / 45 (0.00%)
    1 / 53 (1.89%)
    4 / 178 (2.25%)
    10 / 179 (5.59%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    3
    0
    1
    8
    11
    0
    0
    Eye disorders
    Dry eye
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    0 / 179 (0.00%)
    3 / 53 (5.66%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 45 (0.00%)
    3 / 53 (5.66%)
    11 / 178 (6.18%)
    9 / 179 (5.03%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    1
    0
    3
    13
    10
    0
    0
    Abdominal pain
         subjects affected / exposed
    8 / 73 (10.96%)
    4 / 45 (8.89%)
    1 / 53 (1.89%)
    28 / 178 (15.73%)
    27 / 179 (15.08%)
    7 / 53 (13.21%)
    2 / 45 (4.44%)
         occurrences all number
    10
    4
    2
    38
    33
    7
    3
    Abdominal pain upper
         subjects affected / exposed
    2 / 73 (2.74%)
    2 / 45 (4.44%)
    0 / 53 (0.00%)
    6 / 178 (3.37%)
    12 / 179 (6.70%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    2
    2
    0
    6
    12
    0
    0
    Constipation
         subjects affected / exposed
    16 / 73 (21.92%)
    8 / 45 (17.78%)
    12 / 53 (22.64%)
    40 / 178 (22.47%)
    42 / 179 (23.46%)
    12 / 53 (22.64%)
    6 / 45 (13.33%)
         occurrences all number
    19
    10
    17
    47
    57
    14
    6
    Diarrhoea
         subjects affected / exposed
    13 / 73 (17.81%)
    11 / 45 (24.44%)
    11 / 53 (20.75%)
    40 / 178 (22.47%)
    41 / 179 (22.91%)
    16 / 53 (30.19%)
    9 / 45 (20.00%)
         occurrences all number
    20
    17
    17
    52
    67
    23
    22
    Dry mouth
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    9 / 178 (5.06%)
    7 / 179 (3.91%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    1
    0
    0
    11
    10
    0
    0
    Dyspepsia
         subjects affected / exposed
    2 / 73 (2.74%)
    3 / 45 (6.67%)
    2 / 53 (3.77%)
    3 / 178 (1.69%)
    4 / 179 (2.23%)
    4 / 53 (7.55%)
    2 / 45 (4.44%)
         occurrences all number
    2
    3
    3
    3
    5
    4
    2
    Nausea
         subjects affected / exposed
    23 / 73 (31.51%)
    19 / 45 (42.22%)
    29 / 53 (54.72%)
    44 / 178 (24.72%)
    49 / 179 (27.37%)
    12 / 53 (22.64%)
    10 / 45 (22.22%)
         occurrences all number
    30
    23
    44
    74
    56
    12
    17
    Vomiting
         subjects affected / exposed
    17 / 73 (23.29%)
    13 / 45 (28.89%)
    10 / 53 (18.87%)
    19 / 178 (10.67%)
    38 / 179 (21.23%)
    6 / 53 (11.32%)
    2 / 45 (4.44%)
         occurrences all number
    22
    14
    14
    26
    58
    7
    2
    Dysphagia
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    0 / 179 (0.00%)
    3 / 53 (5.66%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    4
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    10 / 73 (13.70%)
    11 / 45 (24.44%)
    15 / 53 (28.30%)
    7 / 178 (3.93%)
    2 / 179 (1.12%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    10
    11
    18
    8
    4
    0
    0
    Dry skin
         subjects affected / exposed
    4 / 73 (5.48%)
    0 / 45 (0.00%)
    1 / 53 (1.89%)
    18 / 178 (10.11%)
    18 / 179 (10.06%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    4
    0
    1
    24
    18
    0
    0
    Night sweats
         subjects affected / exposed
    2 / 73 (2.74%)
    3 / 45 (6.67%)
    4 / 53 (7.55%)
    4 / 178 (2.25%)
    10 / 179 (5.59%)
    1 / 53 (1.89%)
    4 / 45 (8.89%)
         occurrences all number
    2
    4
    5
    4
    11
    1
    4
    Erythema
         subjects affected / exposed
    2 / 73 (2.74%)
    1 / 45 (2.22%)
    2 / 53 (3.77%)
    10 / 178 (5.62%)
    7 / 179 (3.91%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    2
    2
    2
    12
    8
    0
    0
    Pruritus
         subjects affected / exposed
    5 / 73 (6.85%)
    6 / 45 (13.33%)
    4 / 53 (7.55%)
    49 / 178 (27.53%)
    57 / 179 (31.84%)
    6 / 53 (11.32%)
    5 / 45 (11.11%)
         occurrences all number
    6
    6
    4
    77
    74
    7
    5
    Rash
         subjects affected / exposed
    6 / 73 (8.22%)
    3 / 45 (6.67%)
    4 / 53 (7.55%)
    29 / 178 (16.29%)
    33 / 179 (18.44%)
    11 / 53 (20.75%)
    7 / 45 (15.56%)
         occurrences all number
    7
    3
    5
    38
    49
    15
    9
    Rash maculo-papular
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    10 / 178 (5.62%)
    18 / 179 (10.06%)
    3 / 53 (5.66%)
    1 / 45 (2.22%)
         occurrences all number
    0
    0
    0
    11
    23
    4
    1
    Vitiligo
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 45 (2.22%)
    2 / 53 (3.77%)
    14 / 178 (7.87%)
    16 / 179 (8.94%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    1
    2
    19
    19
    0
    0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 45 (2.22%)
    0 / 53 (0.00%)
    16 / 178 (8.99%)
    15 / 179 (8.38%)
    4 / 53 (7.55%)
    3 / 45 (6.67%)
         occurrences all number
    0
    1
    0
    17
    16
    4
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 73 (6.85%)
    7 / 45 (15.56%)
    6 / 53 (11.32%)
    36 / 178 (20.22%)
    24 / 179 (13.41%)
    9 / 53 (16.98%)
    8 / 45 (17.78%)
         occurrences all number
    6
    9
    7
    52
    37
    13
    9
    Back pain
         subjects affected / exposed
    8 / 73 (10.96%)
    6 / 45 (13.33%)
    5 / 53 (9.43%)
    24 / 178 (13.48%)
    21 / 179 (11.73%)
    3 / 53 (5.66%)
    2 / 45 (4.44%)
         occurrences all number
    10
    6
    5
    31
    27
    3
    2
    Bone pain
         subjects affected / exposed
    1 / 73 (1.37%)
    3 / 45 (6.67%)
    2 / 53 (3.77%)
    2 / 178 (1.12%)
    8 / 179 (4.47%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    1
    3
    10
    2
    8
    0
    0
    Muscular weakness
         subjects affected / exposed
    3 / 73 (4.11%)
    2 / 45 (4.44%)
    5 / 53 (9.43%)
    5 / 178 (2.81%)
    9 / 179 (5.03%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    3
    3
    6
    5
    11
    0
    0
    Myalgia
         subjects affected / exposed
    3 / 73 (4.11%)
    4 / 45 (8.89%)
    4 / 53 (7.55%)
    19 / 178 (10.67%)
    14 / 179 (7.82%)
    3 / 53 (5.66%)
    3 / 45 (6.67%)
         occurrences all number
    3
    7
    4
    23
    15
    3
    3
    Musculoskeletal pain
         subjects affected / exposed
    3 / 73 (4.11%)
    1 / 45 (2.22%)
    4 / 53 (7.55%)
    18 / 178 (10.11%)
    15 / 179 (8.38%)
    4 / 53 (7.55%)
    2 / 45 (4.44%)
         occurrences all number
    3
    1
    4
    20
    15
    5
    2
    Pain in extremity
         subjects affected / exposed
    2 / 73 (2.74%)
    5 / 45 (11.11%)
    6 / 53 (11.32%)
    18 / 178 (10.11%)
    19 / 179 (10.61%)
    4 / 53 (7.55%)
    1 / 45 (2.22%)
         occurrences all number
    2
    5
    6
    25
    25
    4
    4
    Muscle spasms
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    0 / 179 (0.00%)
    1 / 53 (1.89%)
    3 / 45 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    6
    Neck pain
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    0 / 179 (0.00%)
    5 / 53 (9.43%)
    1 / 45 (2.22%)
         occurrences all number
    0
    0
    0
    0
    0
    5
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    2 / 73 (2.74%)
    1 / 45 (2.22%)
    4 / 53 (7.55%)
    10 / 178 (5.62%)
    20 / 179 (11.17%)
    4 / 53 (7.55%)
    0 / 45 (0.00%)
         occurrences all number
    2
    1
    4
    11
    36
    9
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 73 (1.37%)
    2 / 45 (4.44%)
    1 / 53 (1.89%)
    8 / 178 (4.49%)
    18 / 179 (10.06%)
    5 / 53 (9.43%)
    3 / 45 (6.67%)
         occurrences all number
    1
    2
    2
    12
    25
    6
    3
    Urinary tract infection
         subjects affected / exposed
    5 / 73 (6.85%)
    2 / 45 (4.44%)
    2 / 53 (3.77%)
    17 / 178 (9.55%)
    17 / 179 (9.50%)
    8 / 53 (15.09%)
    2 / 45 (4.44%)
         occurrences all number
    5
    2
    2
    19
    23
    8
    2
    Oral herpes
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    0 / 179 (0.00%)
    3 / 53 (5.66%)
    1 / 45 (2.22%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    20 / 73 (27.40%)
    11 / 45 (24.44%)
    8 / 53 (15.09%)
    36 / 178 (20.22%)
    51 / 179 (28.49%)
    9 / 53 (16.98%)
    8 / 45 (17.78%)
         occurrences all number
    21
    12
    10
    43
    55
    9
    8
    Dehydration
         subjects affected / exposed
    2 / 73 (2.74%)
    3 / 45 (6.67%)
    3 / 53 (5.66%)
    7 / 178 (3.93%)
    6 / 179 (3.35%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    3
    4
    7
    15
    7
    0
    0
    Hyperglycaemia
         subjects affected / exposed
    2 / 73 (2.74%)
    3 / 45 (6.67%)
    5 / 53 (9.43%)
    12 / 178 (6.74%)
    11 / 179 (6.15%)
    3 / 53 (5.66%)
    1 / 45 (2.22%)
         occurrences all number
    2
    3
    9
    21
    21
    7
    3
    Hypertriglyceridaemia
         subjects affected / exposed
    0 / 73 (0.00%)
    5 / 45 (11.11%)
    4 / 53 (7.55%)
    7 / 178 (3.93%)
    10 / 179 (5.59%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    7
    5
    18
    25
    0
    0
    Hypoalbuminaemia
         subjects affected / exposed
    5 / 73 (6.85%)
    2 / 45 (4.44%)
    3 / 53 (5.66%)
    5 / 178 (2.81%)
    12 / 179 (6.70%)
    0 / 53 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    5
    2
    4
    6
    13
    0
    0
    Hypokalaemia
         subjects affected / exposed
    3 / 73 (4.11%)
    3 / 45 (6.67%)
    4 / 53 (7.55%)
    9 / 178 (5.06%)
    8 / 179 (4.47%)
    4 / 53 (7.55%)
    3 / 45 (6.67%)
         occurrences all number
    3
    3
    5
    9
    10
    7
    3
    Hyponatraemia
         subjects affected / exposed
    4 / 73 (5.48%)
    2 / 45 (4.44%)
    3 / 53 (5.66%)
    19 / 178 (10.67%)
    10 / 179 (5.59%)
    6 / 53 (11.32%)
    3 / 45 (6.67%)
         occurrences all number
    6
    3
    3
    28
    11
    11
    4
    Hyperkalaemia
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 45 (0.00%)
    0 / 53 (0.00%)
    0 / 178 (0.00%)
    0 / 179 (0.00%)
    4 / 53 (7.55%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    4
    0

    More information

    		 Close Top of page

    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Apr 2013
    Amendment 01: The primary reasons for the amendment were to: 1) modify the primary and secondary objectives; 2) clarify inclusion and exclusion criteria; 3) modify the standard of care chemotherapy comparators permitted in this trial; and 4) modify the statistical analysis plan.
    02 Oct 2013
    Amendment 02: The primary reasons for the amendment were to: 1) modify the primary and secondary objectives; 2) clarify inclusion and exclusion criteria; 3) modify the standard of care chemotherapy comparators permitted in this trial; and 4) modify the statistical analysis plan.
    14 Jul 2016
    Amendment 03: The primary reason for the amendment was to modify the dosage of study treatment so that all participants will receive a fixed dose of pembrolizumab 200 mg every 3 weeks.
    22 Jan 2018
    Amendment 04: The primary reasons for this amendment were to clarify the follow-up durations for participants and remove the objectives relating to the pharmacokinetics (PK) analyses of pembrolizumab.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

    European Medicines Agency © 1995-Fri Apr 26 11:19:36 CEST 2024 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    EMA HMA