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   43865   clinical trials with a EudraCT protocol, of which   7286   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

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

    < Back to search results

    Download PDF

    Clinical Trial Results:
    A Phase 3 Randomized, Double-Blind, Placebo- Controlled Study of Pembrolizumab (MK-3475) in Combination With Epacadostat or Placebo in Subjects with Unresectable or Metastatic Melanoma (KEYNOTE-252 / ECHO-301)

    Summary
    EudraCT number
    		 2015-004991-31
    Trial protocol
    		 SE   NL   DK   IE   ES   PL   FR   BE   GB   IT  
    Global end of trial date
    16 Aug 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Aug 2020
    First version publication date
    15 Aug 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    INCB24360-301/MK3475-252/Keynote252
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02752074
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 INCB24360-301: Study ID
    Sponsors
    Sponsor organisation name
    Incyte Corporation
    Sponsor organisation address
    1801 Augustine Cut-Off, Wilmington,, United States, 19803
    Public contact
    Incyte Corporation Call Centre, Incyte Corporation, +44 (0)330 100 3677, globalmedinfo@incyte.com
    Scientific contact
    Incyte Corporation Call Centre, Incyte Corporation, +44 (0)330 100 3677, globalmedinfo@incyte.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    16 Aug 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Aug 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the progression-free survival (PFS) of the combination of pembrolizumab and epacadostat versus pembrolizumab and placebo (i.e. 2 treatment groups) based on RECIST 1.1 by independent central review; and To compare overall survival (OS) of the 2 treatment groups.
    Protection of trial subjects
    Participants should receive appropriate supportive care measures as deemed necessary by the treating investigator, including, but not limited to, the items outlined below. -Nausea/vomiting: Nausea and vomiting should be treated aggressively, and consideration should be given in subsequent cycles to the administration of prophylactic antiemetic therapy according to standard institutional practice. Subjects should be strongly encouraged to maintain liberal oral fluid intake. -Anti-infectives: Subjects with a documented infectious complication should receive oral or IV antibiotics or other anti-infective agents as considered appropriate by the treating investigator for a given infectious condition, according to standard institutional practice.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    31 May 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 60
    Country: Number of subjects enrolled
    Canada: 33
    Country: Number of subjects enrolled
    Chile: 38
    Country: Number of subjects enrolled
    Israel: 10
    Country: Number of subjects enrolled
    Italy: 48
    Country: Number of subjects enrolled
    Japan: 44
    Country: Number of subjects enrolled
    Korea, Democratic People's Republic of: 29
    Country: Number of subjects enrolled
    Mexico: 10
    Country: Number of subjects enrolled
    New Zealand: 10
    Country: Number of subjects enrolled
    Russian Federation: 30
    Country: Number of subjects enrolled
    South Africa: 42
    Country: Number of subjects enrolled
    Switzerland: 18
    Country: Number of subjects enrolled
    United Kingdom: 7
    Country: Number of subjects enrolled
    United States: 56
    Country: Number of subjects enrolled
    Netherlands: 4
    Country: Number of subjects enrolled
    Poland: 10
    Country: Number of subjects enrolled
    Spain: 52
    Country: Number of subjects enrolled
    Sweden: 31
    Country: Number of subjects enrolled
    Belgium: 15
    Country: Number of subjects enrolled
    Denmark: 14
    Country: Number of subjects enrolled
    France: 91
    Country: Number of subjects enrolled
    Germany: 46
    Country: Number of subjects enrolled
    Ireland: 8
    Worldwide total number of subjects
    706
    EEA total number of subjects
    326
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    376
    From 65 to 84 years
    317
    85 years and over
    13

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 This study was conducted at 135 centers in 23 countries

    Pre-assignment
    Screening details
    		 This study was conducted at one hundred and thirty-five (135) centers, screened 928 participants and 706 participants enrolled in the study.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Pembrolizumab + Epacadostat
    Arm description
    		 Pembrolizumab will be administered intravenously every 3 weeks starting at Day 1 (Week 1). Epacadostat will be administered orally daily starting at Day 1 (Week 1).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Epacadostat
    Investigational medicinal product code
    Other name
    INCB024360
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Epacadostat will be administered orally daily starting at Day 1 (Week 1) for a maximum duration of treatment(35 infusions)

    Investigational medicinal product name
    pembrolizumab
    Investigational medicinal product code
    Other name
    MK-3475, KEYTRUDA®
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pembrolizumab will be administered intravenously every 3 weeks starting at Day 1 (Week 1) for a maximum duration treatment (35 infusions)

    Arm title
    		 Pembrolizumab + Placebo
    Arm description
    		 Pembrolizumab will be administered intravenously every 3 weeks starting at Day 1 (Week 1). Placebo will be administered orally daily starting at Day 1 (Week 1).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matching Placebo will be administered orally daily starting at Day 1 (Week 1) for a maximum duration of treatment(35 infusions)

    Investigational medicinal product name
    pembrolizumab
    Investigational medicinal product code
    Other name
    MK-3475, KEYTRUDA®
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pembrolizumab will be administered intravenously every 3 weeks starting at Day 1 (Week 1) for a maximum duration of treatment (35 infusions).

    Number of subjects in period 1
    		Pembrolizumab + Epacadostat Pembrolizumab + Placebo
    Started
    354
    352
    Treated
    353
    352
    Completed
    198
    209
    Not completed
    156
    143
         Consent withdrawn by subject
    9
    10
         Deaths
    146
    129
         Lost to follow-up
    1
    4

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Pembrolizumab + Epacadostat
    Reporting group description
    		 Pembrolizumab will be administered intravenously every 3 weeks starting at Day 1 (Week 1). Epacadostat will be administered orally daily starting at Day 1 (Week 1).

    Reporting group title
    Pembrolizumab + Placebo
    Reporting group description
    		 Pembrolizumab will be administered intravenously every 3 weeks starting at Day 1 (Week 1). Placebo will be administered orally daily starting at Day 1 (Week 1).

    Reporting group values
    		 Pembrolizumab + Epacadostat Pembrolizumab + Placebo Total
    Number of subjects
    		 354 352 706
    Age Categorical
    Units:
        < 65 years
    		 183 193 376
        ≥ 65 years
    		 171 159 330
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 61.4 ( 13.9 ) 61.6 ( 13.7 ) -
    Sex: Female, Male
    Units:
        Female
    		 137 146 283
        Male
    		 217 206 423
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 36 27 63
        Not Hispanic or Latino
    		 302 306 608
        Unknown or Not Reported
    		 16 19 35
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 40 36 76
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 0 0 0
        White
    		 311 315 626
        More than one race
    		 2 1 3
        Unknown or Not Reported
    		 1 0 1
    Eastern Cooperative Oncology Group (ECOG)
    Units: Subjects
        Fully active
    		 261 267 528
        Restricted in physically strenuous activity
    		 93 85 178

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Pembrolizumab + Epacadostat
    Reporting group description
    		 Pembrolizumab will be administered intravenously every 3 weeks starting at Day 1 (Week 1). Epacadostat will be administered orally daily starting at Day 1 (Week 1).

    Reporting group title
    Pembrolizumab + Placebo
    Reporting group description
    		 Pembrolizumab will be administered intravenously every 3 weeks starting at Day 1 (Week 1). Placebo will be administered orally daily starting at Day 1 (Week 1).

    Primary: Progression-free survival

    		 Close Top of page
    End point title
    		 Progression-free survival
    End point description
    Progression-free survival, defined as the time from date of randomization until the earliest date of disease progression, as determined by independent central review of objective radiographic disease assessments per RECIST 1.1, or death from any cause, whichever comes first.
    End point type
    Primary
    End point timeframe
    Assessed every 9 weeks for duration of study participation which is estimated to be 24 months
    End point values
    		 Pembrolizumab + Epacadostat Pembrolizumab + Placebo
    Number of subjects analysed
    354
    352
    Units: months
        median (confidence interval 95%)
    4.7 (2.9 to 6.8)
    4.9 (2.9 to 6.8)
    Statistical analysis title
    		 Progression Free Survival
    Comparison groups
    Pembrolizumab + Placebo v Pembrolizumab + Epacadostat
    Number of subjects included in analysis
    706
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.51711 [1]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.83
         upper limit
    		 1.21
    Notes
    [1] - One-sided p-value based on log-rank test.

    Primary: Overall survival (OS) rate at 6 months

    		 Close Top of page
    End point title
    		 Overall survival (OS) rate at 6 months
    End point description
    Defined as time from date of randomization to date of death due to any cause. OS was calculated using product-limit (Kaplan-Meier) method for censored data.
    End point type
    Primary
    End point timeframe
    Assessed every 9 weeks of study participation which is estimated to be 24 months. The OS rate at Month 6 was calculated.
    End point values
    		 Pembrolizumab + Epacadostat Pembrolizumab + Placebo
    Number of subjects analysed
    354
    352
    Units: percent probability
        median (confidence interval 95%)
    84.1 (79.8 to 87.5)
    87.2 (83.2 to 90.3)
    Statistical analysis title
    		 Progession Free Survival
    Comparison groups
    Pembrolizumab + Epacadostat v Pembrolizumab + Placebo
    Number of subjects included in analysis
    706
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.80666 [2]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.86
         upper limit
    		 1.49
    Notes
    [2] - One-sided p-value based on log-rank test.

    Secondary: Objective response rate (ORR)

    		 Close Top of page
    End point title
    		 Objective response rate (ORR)
    End point description
    Objective response rate (ORR) is defined as the percentage of the participants in the analysis population who have a confirmed complete response (CR) or partial response (PR) based on RECIST 1.1 by independent central review.
    End point type
    Secondary
    End point timeframe
    Assessed every 9 weeks for duration of study participation which is estimated to be 24 months
    End point values
    		 Pembrolizumab + Epacadostat Pembrolizumab + Placebo
    Number of subjects analysed
    354
    352
    Units: Number of participants
    121
    111
    No statistical analyses for this end point

    Secondary: Safety and tolerability, as assessed by percentage of participants with adverse events

    		 Close Top of page
    End point title
    		 Safety and tolerability, as assessed by percentage of participants with adverse events
    End point description
    Safety and tolerability, as assessed by percentage of participants with adverse events and changes in laboratory parameters.
    End point type
    Secondary
    End point timeframe
    Through up to 90 days after end of treatment, up to 27 months
    End point values
    		 Pembrolizumab + Epacadostat Pembrolizumab + Placebo
    Number of subjects analysed
    353
    352
    Units: Number of participants
        With one or more adverse events
    346
    345
        Serious adverse events
    99
    100
    No statistical analyses for this end point

    Secondary: Duration of response (DOR)

    		 Close Top of page
    End point title
    		 Duration of response (DOR)
    End point description
    Defined as the time from the earliest date of qualifying response until earliest date of disease progression, per RECIST v1.1, or death from any cause, whichever comes first. Includes participants with complete response or partial response.
    End point type
    Secondary
    End point timeframe
    Assessed every 9 weeks for duration of study participation which is estimated to be 24 months
    End point values
    		 Pembrolizumab + Epacadostat Pembrolizumab + Placebo
    Number of subjects analysed
    354 [3]
    352 [4]
    Units: months
        median (full range (min-max))
    0.0 (0.0 to 14.7)
    0.0 (0.0 to 15.0)
    Notes
    [3] - Median not reached
    [4] - Median not reached
    No statistical analyses for this end point

    Secondary: Apparent oral clearance (CL/F) of epacadostat

    		 Close Top of page
    End point title
    		 Apparent oral clearance (CL/F) of epacadostat [5]
    End point description
    Defined as oral dose clearance.
    End point type
    Secondary
    End point timeframe
    Through up to 30 days after the end of treatment, up to 25 months
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: There is no hypothesis testing for this endpoint , descriptive analysis is provided.
    End point values
    		 Pembrolizumab + Epacadostat
    Number of subjects analysed
    340
    Units: Liter/hour (L/h)
        arithmetic mean (standard deviation)
    59.8 ( 17.5 )
    No statistical analyses for this end point

    Secondary: Apparent volume of distribution (Vd/F) of epacadostat

    		 Close Top of page
    End point title
    		 Apparent volume of distribution (Vd/F) of epacadostat [6]
    End point description
    Apparent volume of distribution after administration.
    End point type
    Secondary
    End point timeframe
    Through up to 30 days after the end of treatment, up to 25 months
    Notes
    [6] - 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: There is no hypothesis testing for this endpoint , descriptive analysis is provided.
    End point values
    		 Pembrolizumab + Epacadostat
    Number of subjects analysed
    340
    Units: Liter
        arithmetic mean (standard deviation)
    139 ( 22.5 )
    No statistical analyses for this end point

    Secondary: Clearance (CL) of pembrolizumab

    		 Close Top of page
    End point title
    		 Clearance (CL) of pembrolizumab
    End point description
    End point type
    Secondary
    End point timeframe
    Through up to 30 days after the end of treatment, up to 25 months
    End point values
    		 Pembrolizumab + Epacadostat Pembrolizumab + Placebo
    Number of subjects analysed
    0 [7]
    0 [8]
    Units: L/h
        arithmetic mean (standard deviation)
    ( )
    ( )
    Notes
    [7] - No data displayed because Outcome Measure has zero total analyzed
    [8] - No data displayed because Outcome Measure has zero total analyzed
    No statistical analyses for this end point

    Secondary: Volume of distribution (V) of pembrolizumab

    		 Close Top of page
    End point title
    		 Volume of distribution (V) of pembrolizumab
    End point description
    End point type
    Secondary
    End point timeframe
    Through up to 30 days after the end of treatment, up to 25 months
    End point values
    		 Pembrolizumab + Epacadostat Pembrolizumab + Placebo
    Number of subjects analysed
    0 [9]
    0 [10]
    Units: Liter
        arithmetic mean (standard deviation)
    ( )
    ( )
    Notes
    [9] - No data displayed because Outcome Measure has zero total analyzed
    [10] - No data displayed because Outcome Measure has zero total analyzed
    No statistical analyses for this end point

    Secondary: Formation of anti-pembrolizumab antibodies

    		 Close Top of page
    End point title
    		 Formation of anti-pembrolizumab antibodies
    End point description
    Evaluate the measurement of anti-drug antibodies (ADA).
    End point type
    Secondary
    End point timeframe
    Through up to 30 days after the end of treatment, up to 25 months
    End point values
    		 Pembrolizumab + Epacadostat Pembrolizumab + Placebo
    Number of subjects analysed
    0 [11]
    0 [12]
    Units: ng/ml
        arithmetic mean (standard deviation)
    ( )
    ( )
    Notes
    [11] - No data displayed because Outcome Measure has zero total analyzed
    [12] - No data displayed because Outcome Measure has zero total analyzed
    No statistical analyses for this end point

    Adverse events

    		 Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    up to 27 months.
    Adverse event reporting additional description
    All Subjects as Treated (ASaT): All participants who were enrolled and took at least 1 dose of study medication.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Pembrolizumab + Epacadostat
    Reporting group description
    		 Pembrolizumab will be administered intravenously every 3 weeks starting at Day 1 (Week 1). Epacadostat will be administered orally daily starting at Day 1 (Week 1).

    Reporting group title
    Pembrolizumab + Placebo
    Reporting group description
    		 Pembrolizumab will be administered intravenously every 3 weeks starting at Day 1 (Week 1). Placebo will be administered orally daily starting at Day 1 (Week 1).

    Serious adverse events
    		 Pembrolizumab + Epacadostat Pembrolizumab + Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    99 / 353 (28.05%)
    100 / 352 (28.41%)
         number of deaths (all causes)
    147
    136
         number of deaths resulting from adverse events
    1
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    2 / 353 (0.57%)
    4 / 352 (1.14%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cancer pain
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma in situ
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cell carcinoma
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    3 / 353 (0.85%)
    3 / 352 (0.85%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    T-cell lymphoma
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    0 / 353 (0.00%)
    2 / 352 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour flare
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carcinoid tumour of the gastrointestinal
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Follicular thyroid cancer
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal adenocarcinoma
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 353 (0.28%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Essential hypertension
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 353 (0.00%)
    2 / 352 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphoedema
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 353 (0.28%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    2 / 353 (0.57%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 353 (0.28%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 353 (0.28%)
    2 / 352 (0.57%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    4 / 353 (1.13%)
    3 / 352 (0.85%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytokine release syndrome
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug hypersensitivity
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchial obstruction
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis chronic
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    2 / 353 (0.57%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    2 / 353 (0.57%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Pneumonitis
         subjects affected / exposed
    5 / 353 (1.42%)
    3 / 352 (0.85%)
         occurrences causally related to treatment / all
    5 / 5
    3 / 3
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 353 (0.57%)
    2 / 352 (0.57%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary infarction
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Emphysema
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paranoia
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 353 (0.28%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    2 / 353 (0.57%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood potassium increased
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pubis fracture
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiation necrosis
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound complication
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congestive cardiomyopathy
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Extrasystoles
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocarditis
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Chronic inflammatory demyelinating polyradiculoneuropathy
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 353 (0.28%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 353 (0.00%)
    5 / 352 (1.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiplegia
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic cerebral infarction
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuralgia
         subjects affected / exposed
    1 / 353 (0.28%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 353 (0.00%)
    2 / 352 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 353 (0.28%)
    2 / 352 (0.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tension headache
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Optic neuritis
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 353 (0.28%)
    4 / 352 (1.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo positional
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Retinopathy
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 353 (0.57%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Autoimmune colitis
         subjects affected / exposed
    1 / 353 (0.28%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    4 / 353 (1.13%)
    5 / 352 (1.42%)
         occurrences causally related to treatment / all
    3 / 4
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    9 / 353 (2.55%)
    4 / 352 (1.14%)
         occurrences causally related to treatment / all
    3 / 11
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intussusception
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 353 (0.28%)
    2 / 352 (0.57%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 353 (0.28%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 353 (0.28%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis chronic
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 353 (0.00%)
    2 / 352 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 353 (0.85%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ischaemic
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Autoimmune hepatitis
         subjects affected / exposed
    2 / 353 (0.57%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bile duct obstruction
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 353 (0.28%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis acute
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune-mediated hepatitis
         subjects affected / exposed
    1 / 353 (0.28%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis exfoliative
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug reaction with eosinophilia and systemic symptoms
         subjects affected / exposed
    1 / 353 (0.28%)
    2 / 352 (0.57%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erythema multiforme
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lichen planus
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    2 / 353 (0.57%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatitis allergic
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 353 (0.57%)
    3 / 352 (0.85%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder outlet obstruction
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephritis
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal injury
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder perforation
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrotic syndrome
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tubulointerstitial nephritis
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    4 / 353 (1.13%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    4 / 5
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypophysitis
         subjects affected / exposed
    1 / 353 (0.28%)
    3 / 352 (0.85%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypothyroidism
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 353 (0.57%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dupuytren's contracture
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myositis
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    1 / 353 (0.28%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polymyalgia rheumatica
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Scleroderma
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemarthrosis
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    1 / 353 (0.28%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dacryocanaliculitis
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected skin ulcer
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 353 (0.28%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonia
         subjects affected / exposed
    5 / 353 (1.42%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomonas infection
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhinitis
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 353 (0.57%)
    2 / 352 (0.57%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Septic shock
         subjects affected / exposed
    0 / 353 (0.00%)
    2 / 352 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Urinary tract infection
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 353 (0.28%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    1 / 353 (0.28%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 353 (0.00%)
    2 / 352 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Type 1 diabetes mellitus
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 352 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Steroid diabetes
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 352 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Pembrolizumab + Epacadostat Pembrolizumab + Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    327 / 353 (92.63%)
    325 / 352 (92.33%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    27 / 353 (7.65%)
    21 / 352 (5.97%)
         occurrences all number
    38
    29
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    68 / 353 (19.26%)
    46 / 352 (13.07%)
         occurrences all number
    99
    67
    Fatigue
         subjects affected / exposed
    100 / 353 (28.33%)
    94 / 352 (26.70%)
         occurrences all number
    124
    126
    Oedema peripheral
         subjects affected / exposed
    27 / 353 (7.65%)
    27 / 352 (7.67%)
         occurrences all number
    36
    30
    Pyrexia
         subjects affected / exposed
    46 / 353 (13.03%)
    38 / 352 (10.80%)
         occurrences all number
    60
    53
    Influenza like Illness
         subjects affected / exposed
    17 / 353 (4.82%)
    22 / 352 (6.25%)
         occurrences all number
    21
    33
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    73 / 353 (20.68%)
    63 / 352 (17.90%)
         occurrences all number
    93
    86
    Dyspnoea
         subjects affected / exposed
    22 / 353 (6.23%)
    29 / 352 (8.24%)
         occurrences all number
    28
    31
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    19 / 353 (5.38%)
    14 / 352 (3.98%)
         occurrences all number
    21
    15
    Insomnia
         subjects affected / exposed
    35 / 353 (9.92%)
    31 / 352 (8.81%)
         occurrences all number
    39
    33
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    39 / 353 (11.05%)
    25 / 352 (7.10%)
         occurrences all number
    43
    30
    Amylase increased
         subjects affected / exposed
    27 / 353 (7.65%)
    34 / 352 (9.66%)
         occurrences all number
    38
    42
    Aspartate aminotransferase increased
         subjects affected / exposed
    36 / 353 (10.20%)
    33 / 352 (9.38%)
         occurrences all number
    44
    37
    Lipase increased
         subjects affected / exposed
    36 / 353 (10.20%)
    39 / 352 (11.08%)
         occurrences all number
    62
    59
    Weight decreased
         subjects affected / exposed
    22 / 353 (6.23%)
    17 / 352 (4.83%)
         occurrences all number
    22
    18
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    33 / 353 (9.35%)
    32 / 352 (9.09%)
         occurrences all number
    38
    45
    Headache
         subjects affected / exposed
    66 / 353 (18.70%)
    74 / 352 (21.02%)
         occurrences all number
    121
    114
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    35 / 353 (9.92%)
    36 / 352 (10.23%)
         occurrences all number
    43
    40
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    37 / 353 (10.48%)
    37 / 352 (10.51%)
         occurrences all number
    47
    43
    Abdominal pain upper
         subjects affected / exposed
    24 / 353 (6.80%)
    16 / 352 (4.55%)
         occurrences all number
    24
    19
    Constipation
         subjects affected / exposed
    58 / 353 (16.43%)
    62 / 352 (17.61%)
         occurrences all number
    78
    68
    Diarrhoea
         subjects affected / exposed
    90 / 353 (25.50%)
    100 / 352 (28.41%)
         occurrences all number
    146
    158
    Dry mouth
         subjects affected / exposed
    19 / 353 (5.38%)
    30 / 352 (8.52%)
         occurrences all number
    20
    36
    Nausea
         subjects affected / exposed
    103 / 353 (29.18%)
    86 / 352 (24.43%)
         occurrences all number
    161
    119
    Vomiting
         subjects affected / exposed
    51 / 353 (14.45%)
    44 / 352 (12.50%)
         occurrences all number
    81
    65
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    23 / 353 (6.52%)
    23 / 352 (6.53%)
         occurrences all number
    26
    23
    Pruritus
         subjects affected / exposed
    83 / 353 (23.51%)
    101 / 352 (28.69%)
         occurrences all number
    104
    134
    Rash
         subjects affected / exposed
    77 / 353 (21.81%)
    81 / 352 (23.01%)
         occurrences all number
    105
    97
    Rash maculo-papular
         subjects affected / exposed
    21 / 353 (5.95%)
    18 / 352 (5.11%)
         occurrences all number
    25
    22
    Vitiligo
         subjects affected / exposed
    51 / 353 (14.45%)
    48 / 352 (13.64%)
         occurrences all number
    66
    50
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    22 / 353 (6.23%)
    27 / 352 (7.67%)
         occurrences all number
    23
    27
    Hypothyroidism
         subjects affected / exposed
    44 / 353 (12.46%)
    35 / 352 (9.94%)
         occurrences all number
    50
    37
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    63 / 353 (17.85%)
    63 / 352 (17.90%)
         occurrences all number
    95
    96
    Back pain
         subjects affected / exposed
    47 / 353 (13.31%)
    52 / 352 (14.77%)
         occurrences all number
    54
    67
    Myalgia
         subjects affected / exposed
    26 / 353 (7.37%)
    32 / 352 (9.09%)
         occurrences all number
    29
    38
    Pain in extremity
         subjects affected / exposed
    32 / 353 (9.07%)
    28 / 352 (7.95%)
         occurrences all number
    46
    34
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    50 / 353 (14.16%)
    50 / 352 (14.20%)
         occurrences all number
    74
    61
    Upper respiratory tract infection
         subjects affected / exposed
    19 / 353 (5.38%)
    33 / 352 (9.38%)
         occurrences all number
    21
    45
    Urinary tract infection
         subjects affected / exposed
    20 / 353 (5.67%)
    32 / 352 (9.09%)
         occurrences all number
    28
    41
    Influenza
         subjects affected / exposed
    19 / 353 (5.38%)
    17 / 352 (4.83%)
         occurrences all number
    22
    20
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    55 / 353 (15.58%)
    44 / 352 (12.50%)
         occurrences all number
    57
    57
    Hyperglycaemia
         subjects affected / exposed
    23 / 353 (6.52%)
    17 / 352 (4.83%)
         occurrences all number
    42
    27

    More information

    		 Close Top of page

    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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-Sun Apr 28 11:40:19 CEST 2024 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    EMA HMA