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   43857   clinical trials with a EudraCT protocol, of which   7284   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 Single-Arm, Open-Label, Multicenter Clinical Trial with Nivolumab (BMS-936558) for Subjects with Histologically Confirmed Stage III (unresectable) or stage IV Melanoma progressing after prior treatment Containing an Anti-CTLA-4 Monoclonal Antibody.

    Summary
    EudraCT number
    		 2014-001286-28
    Trial protocol
    		 BE   IT   DE   GB   ES   NL   AT   DK   PT   IE   SE   FI   HU   CZ   GR   PL  
    Global end of trial date
    18 Jan 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    02 Feb 2020
    First version publication date
    02 Feb 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CA209-172
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bristol-Myers Squibb
    Sponsor organisation address
    Chaussée de la Hulpe 185, Brussels, Belgium, 1170
    Public contact
    EU Study Start-Up Unit, Bristol-Myers Squibb International Corporation, Clinical.Trials@bms.com
    Scientific contact
    Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, Clinical.Trials@bms.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
    18 Jan 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Jan 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main study objective is to determine the incidence of high-grade, treatment-related, select adverse events (AEs) in patients with histologically confirmed stage III (unresectable) or stage IV melanoma and progression after prior treatment containing an anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) monoclonal antibody.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Oct 2014
    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
    Austria: 37
    Country: Number of subjects enrolled
    Belgium: 53
    Country: Number of subjects enrolled
    Czech Republic: 5
    Country: Number of subjects enrolled
    Finland: 8
    Country: Number of subjects enrolled
    Germany: 196
    Country: Number of subjects enrolled
    Greece: 37
    Country: Number of subjects enrolled
    Hungary: 5
    Country: Number of subjects enrolled
    Ireland: 11
    Country: Number of subjects enrolled
    Italy: 259
    Country: Number of subjects enrolled
    Luxembourg: 1
    Country: Number of subjects enrolled
    Netherlands: 40
    Country: Number of subjects enrolled
    Norway: 14
    Country: Number of subjects enrolled
    Poland: 16
    Country: Number of subjects enrolled
    Portugal: 13
    Country: Number of subjects enrolled
    Romania: 5
    Country: Number of subjects enrolled
    Russian Federation: 48
    Country: Number of subjects enrolled
    Spain: 92
    Country: Number of subjects enrolled
    Sweden: 13
    Country: Number of subjects enrolled
    Switzerland: 24
    Country: Number of subjects enrolled
    United Kingdom: 132
    Worldwide total number of subjects
    1009
    EEA total number of subjects
    937
    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)
    583
    From 65 to 84 years
    418
    85 years and over
    8

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 1009 participants were enrolled into the study , 1008 wrere treated, 1 participants was not treated due to withdrew consent

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Nivolumab 3mg/kg
    Arm description
    		 Nivolumab 3 mg/kg as a 60-minute IV infusion every 2 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    BMS-936558-01
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    3 mg/kg

    Number of subjects in period 1 [1]
    		Nivolumab 3mg/kg
    Started
    1008
    Completed
    1008
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 1009 participants were enrolled into the study , 1008 wrere treated, 1 participants was not treated due to withdrew consent.

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Nivolumab 3mg/kg
    Reporting group description
    		 Nivolumab 3 mg/kg as a 60-minute IV infusion every 2 weeks

    Reporting group values
    		 Nivolumab 3mg/kg Total
    Number of subjects
    		 1008 1008
    Age categorical
    Units: Subjects
        Adult < 65
    		 583 583
        Adult >= 65 and <85
    		 417 417
        Adult >=85
    		 8 8
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 60.1 ( 13.84 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 451 451
        Male
    		 557 557
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0
        Asian
    		 3 3
        Native Hawaiian or Other Pacific Islander
    		 0 0
        Black or African American
    		 3 3
        White
    		 987 987
        More than one race
    		 6 6
        Unknown or Not Reported
    		 9 9
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 27 27
        Not Hispanic or Latino
    		 972 972
        Unknown or Not Reported
    		 9 9

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Nivolumab 3mg/kg
    Reporting group description
    		 Nivolumab 3 mg/kg as a 60-minute IV infusion every 2 weeks

    Primary: the Incidence of highgrade (CTCAE v4.0 Grade 3 or higher), treatment related,select adverse events.

    		 Close Top of page
    End point title
    		 the Incidence of highgrade (CTCAE v4.0 Grade 3 or higher), treatment related,select adverse events. [1]
    End point description
    The number of participants who reported high-grade (CTCAE v4.0 Grade 3 or higher), treatment-related, select AEs (pulmonary,gastrointestinal, skin, renal, hepatic, endocrine) were summarized using the all treated analysis set by system organ class and Medical Dictionary for Regulatory (MedDRA) preferred term.
    End point type
    Primary
    End point timeframe
    Up to 2 years
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only summary statistics were planned for this endpoint.
    End point values
    		 Nivolumab 3mg/kg
    Number of subjects analysed
    1008
    Units: Number
        Gastrointestinal Adverse events (Grade 3-4)
    17
        Gastrointestinal adverse events (Grade 5)
    0
        Hepatic adverse events (Grade 3-4)
    31
        Hepatic adverse events (Grade 5)
    0
        Pulmonary adverse events(Grade 3-4)
    6
        Pulmonary adverse events(Grade 5)
    0
        Renal adverse events (Grade 3-4)
    4
        Renal adverse events (Grade 5)
    0
        Skin adverse events ( Grade 3-4)
    14
        Skin adverse events ( Grade 5)
    0
        Hypersensitivity adverse event( Grade 3-4)
    0
        Hypersensitivity adverse event( Grade 5)
    0
        Endocrine adverse events(Grade 3-4)
    18
        Endocrine adverse events(Grade 5)
    0
    No statistical analyses for this end point

    Secondary: The Incidence of all high-grade (Grades 3 and higher), select adverse events

    		 Close Top of page
    End point title
    		 The Incidence of all high-grade (Grades 3 and higher), select adverse events
    End point description
    The number of Participants who reported high-grade (CTCAE v4.0 Grade 3 or higher), select AEs were summarized using the all treated analysis set by system organ class and MedDRA preferred term.
    End point type
    Secondary
    End point timeframe
    Up to 2 years
    End point values
    		 Nivolumab 3mg/kg
    Number of subjects analysed
    1008
    Units: Number
        Gastrointestinal Adverse events (Grade 3-4)
    24
        Gastrointestinal adverse events (Grade 5)
    0
        Hepatic adverse events (Grade 3-4)
    52
        Hepatic adverse events (Grade 5)
    1
        Pulmonary adverse events(Grade 3-4)
    7
        Pulmonary adverse events(Grade 5)
    1
        Renal adverse events (Grade 3-4)
    12
        Renal adverse events (Grade 5)
    1
        Skin adverse events ( Grade 3-4)
    20
        Skin adverse events ( Grade 5)
    0
        Hypersensitivity adverse event( Grade 3-4)
    1
        Hypersensitivity adverse event( Grade 5)
    0
        Endocrine adverse events(Grade 3-4)
    23
        Endocrine adverse events(Grade 5)
    0
    No statistical analyses for this end point

    Secondary: Median time to onset (Grades 3-4) of select adverse events

    		 Close Top of page
    End point title
    		 Median time to onset (Grades 3-4) of select adverse events
    End point description
    Select AEs were summarized according to their incidence as well as their time to onset.
    End point type
    Secondary
    End point timeframe
    Up to 2 years.
    End point values
    		 Nivolumab 3mg/kg
    Number of subjects analysed
    1008
    Units: Weeks
    number (not applicable)
        Endocrine Adverse Event
    12
        Gastrointestinal Adverse Event
    23.50
        Hepatic Adverse Event
    10.14
        Pulmonary Adverse Event
    14.86
        Renal Adverse Event
    11.71
        Skin Adverse Event
    34.36
        Hypersensitivity/infusion reaction
    29.57
    No statistical analyses for this end point

    Secondary: Median time to resolution (Grades 3-4) of select adverse events

    		 Close Top of page
    End point title
    		 Median time to resolution (Grades 3-4) of select adverse events
    End point description
    Select AEs were summarized according to their incidence as well as their time to resolution
    End point type
    Secondary
    End point timeframe
    Up to 2 years
    End point values
    		 Nivolumab 3mg/kg
    Number of subjects analysed
    1008
    Units: Weeks
    number (not applicable)
        Endocrine Adverse Event
    2.43
        Gastrointestinal Adverse Event
    3.71
        Hepatic Adverse Event
    9.43
        Pulmonary Adverse Event
    2.57
        Renal Adverse Event
    1.93
        Skin Adverse Event
    5.07
        Hypersensitivity/Infusion Adverse Event
    0.29
    No statistical analyses for this end point

    Secondary: Overall Survival

    		 Close Top of page
    End point title
    		 Overall Survival
    End point description
    The time from first dosing date to the date of death.
    End point type
    Secondary
    End point timeframe
    Up to 2 years
    End point values
    		 Nivolumab 3mg/kg
    Number of subjects analysed
    1008
    Units: Months
    median (confidence interval 95%)
        Overall survival
    21.2 (18.2 to 24.4)
    No statistical analyses for this end point

    Adverse events

    		 Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    Between first dose and 100 days after last dose ( up to 2 years)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    NIVOLUMAB 3 MG/KG IV
    Reporting group description
    		 Nivolumab 3 mg/kg as a 60-minute IV infusion every 2 weeks.

    Serious adverse events
    		 NIVOLUMAB 3 MG/KG IV
    Total subjects affected by serious adverse events
         subjects affected / exposed
    593 / 1008 (58.83%)
         number of deaths (all causes)
    527
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Adenocarcinoma of colon
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Anal neoplasm
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    4 / 1008 (0.40%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Bowen's disease
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Breast cancer
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cancer pain
         subjects affected / exposed
    5 / 1008 (0.50%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    Chronic lymphocytic leukaemia
         subjects affected / exposed
    2 / 1008 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Infected neoplasm
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intracranial tumour haemorrhage
         subjects affected / exposed
    2 / 1008 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Malignant ascites
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    3 / 1008 (0.30%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Malignant neoplasm of spinal cord
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    278 / 1008 (27.58%)
         occurrences causally related to treatment / all
    0 / 310
         deaths causally related to treatment / all
    0 / 239
    Melanoma recurrent
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Metastases to abdominal cavity
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metastases to adrenals
         subjects affected / exposed
    3 / 1008 (0.30%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Metastases to bladder
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metastases to bone
         subjects affected / exposed
    2 / 1008 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    16 / 1008 (1.59%)
         occurrences causally related to treatment / all
    0 / 16
         deaths causally related to treatment / all
    0 / 1
    Metastases to liver
         subjects affected / exposed
    3 / 1008 (0.30%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Metastases to lung
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metastases to meninges
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metastases to peritoneum
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    Metastases to skin
         subjects affected / exposed
    3 / 1008 (0.30%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Metastases to spine
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metastasis
         subjects affected / exposed
    5 / 1008 (0.50%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Metastatic malignant melanoma
         subjects affected / exposed
    15 / 1008 (1.49%)
         occurrences causally related to treatment / all
    0 / 18
         deaths causally related to treatment / all
    0 / 1
    Neoplasm
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pituitary tumour benign
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal cell carcinoma
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    2 / 1008 (0.20%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tonsil cancer
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Tumour associated fever
         subjects affected / exposed
    2 / 1008 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Tumour flare
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    1 / 1
    Tumour haemorrhage
         subjects affected / exposed
    8 / 1008 (0.79%)
         occurrences causally related to treatment / all
    0 / 8
         deaths causally related to treatment / all
    0 / 1
    Tumour necrosis
         subjects affected / exposed
    3 / 1008 (0.30%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Non-Hodgkin's lymphoma
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tumour pain
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Angiopathy
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Circulatory collapse
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Embolism
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Extremity necrosis
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypertension
         subjects affected / exposed
    2 / 1008 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    3 / 1008 (0.30%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Hypotension
         subjects affected / exposed
    4 / 1008 (0.40%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    Jugular vein thrombosis
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lymphoedema
         subjects affected / exposed
    3 / 1008 (0.30%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Peripheral venous disease
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Superior vena cava syndrome
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Thrombosis
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular occlusion
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lymphocele
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Pregnancy
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    5 / 1008 (0.50%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Chest pain
         subjects affected / exposed
    2 / 1008 (0.20%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Disease progression
         subjects affected / exposed
    2 / 1008 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Fatigue
         subjects affected / exposed
    7 / 1008 (0.69%)
         occurrences causally related to treatment / all
    4 / 7
         deaths causally related to treatment / all
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    22 / 1008 (2.18%)
         occurrences causally related to treatment / all
    0 / 25
         deaths causally related to treatment / all
    0 / 5
    Generalised oedema
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Malaise
         subjects affected / exposed
    3 / 1008 (0.30%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Nodule
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    4 / 1008 (0.40%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Pyrexia
         subjects affected / exposed
    9 / 1008 (0.89%)
         occurrences causally related to treatment / all
    2 / 9
         deaths causally related to treatment / all
    0 / 0
    Sudden death
         subjects affected / exposed
    3 / 1008 (0.30%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    1 / 3
    Treatment failure
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    2 / 1008 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    Pain
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Immune system disorders
    Anaphylactic shock
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Autoimmune disorder
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Contrast media allergy
         subjects affected / exposed
    2 / 1008 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Drug hypersensitivity
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Ovarian cyst ruptured
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pelvic pain
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Penile oedema
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Testicular oedema
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vaginal haemorrhage
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    2 / 1008 (0.20%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    Aspiration
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Atelectasis
         subjects affected / exposed
    3 / 1008 (0.30%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Cough
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dyspnoea
         subjects affected / exposed
    8 / 1008 (0.79%)
         occurrences causally related to treatment / all
    0 / 9
         deaths causally related to treatment / all
    0 / 1
    Haemoptysis
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    2 / 1008 (0.20%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Pleural effusion
         subjects affected / exposed
    9 / 1008 (0.89%)
         occurrences causally related to treatment / all
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    2 / 1008 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Pneumonitis
         subjects affected / exposed
    10 / 1008 (0.99%)
         occurrences causally related to treatment / all
    10 / 10
         deaths causally related to treatment / all
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    14 / 1008 (1.39%)
         occurrences causally related to treatment / all
    0 / 14
         deaths causally related to treatment / all
    0 / 3
    Pulmonary toxicity
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory failure
         subjects affected / exposed
    2 / 1008 (0.20%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Respiratory muscle weakness
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    4 / 1008 (0.40%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    Depression
         subjects affected / exposed
    3 / 1008 (0.30%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Personality change
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Schizophrenia
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 1008 (0.30%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 1008 (0.20%)
         occurrences causally related to treatment / all
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General physical condition abnormal
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    International normalised ratio increased
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Lipase increased
         subjects affected / exposed
    2 / 1008 (0.20%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Pancreatic enzymes increased
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Transaminases increased
         subjects affected / exposed
    2 / 1008 (0.20%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Csf test abnormal
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gamma-Glutamyltransferase increased
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Troponin t increased
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ankle fracture
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dose calculation error
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 13
         deaths causally related to treatment / all
    0 / 0
    Fall
         subjects affected / exposed
    4 / 1008 (0.40%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Femur fracture
         subjects affected / exposed
    2 / 1008 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Fractured sacrum
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Joint dislocation
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Overdose
         subjects affected / exposed
    5 / 1008 (0.50%)
         occurrences causally related to treatment / all
    4 / 20
         deaths causally related to treatment / all
    0 / 0
    Procedural headache
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Radiation necrosis
         subjects affected / exposed
    2 / 1008 (0.20%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Radius fracture
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Spinal fracture
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ulna fracture
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pubis fracture
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    2 / 1008 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Angina pectoris
         subjects affected / exposed
    2 / 1008 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    3 / 1008 (0.30%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Coronary artery occlusion
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ischaemic cardiomyopathy
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    2 / 1008 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Myocarditis
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Coronary artery insufficiency
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardio-Respiratory arrest
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Nervous system disorders
    Altered state of consciousness
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Aphasia
         subjects affected / exposed
    3 / 1008 (0.30%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Brachial plexopathy
         subjects affected / exposed
    2 / 1008 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Brain injury
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Brain oedema
         subjects affected / exposed
    3 / 1008 (0.30%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Brain stem haemorrhage
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Central nervous system lesion
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cerebral haematoma
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Cerebrovascular accident
         subjects affected / exposed
    7 / 1008 (0.69%)
         occurrences causally related to treatment / all
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    Encephalopathy
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Epilepsy
         subjects affected / exposed
    3 / 1008 (0.30%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Facial paralysis
         subjects affected / exposed
    2 / 1008 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Facial paresis
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    2 / 1008 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    Headache
         subjects affected / exposed
    3 / 1008 (0.30%)
         occurrences causally related to treatment / all
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    Hemiparesis
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatic encephalopathy
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypertensive encephalopathy
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lumbar radiculopathy
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Myasthenia gravis
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Narcolepsy
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorder
         subjects affected / exposed
    3 / 1008 (0.30%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Peripheral nerve lesion
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Peripheral sensorimotor neuropathy
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Polyneuropathy
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Seizure
         subjects affected / exposed
    6 / 1008 (0.60%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    Sensorimotor disorder
         subjects affected / exposed
    2 / 1008 (0.20%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    4 / 1008 (0.40%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    Status epilepticus
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Syncope
         subjects affected / exposed
    3 / 1008 (0.30%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Diabetic hyperosmolar coma
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lethargy
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Neurological decompensation
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sciatica
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Miller fisher syndrome
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    10 / 1008 (0.99%)
         occurrences causally related to treatment / all
    1 / 12
         deaths causally related to treatment / all
    0 / 0
    Haemorrhagic anaemia
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    2 / 1008 (0.20%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Eye disorders
    Ectropion
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Iridocyclitis
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Iritis
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Macular hole
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ulcerative keratitis
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Uveitis
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Vision blurred
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Retinal detachment
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Vitreous haemorrhage
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    13 / 1008 (1.29%)
         occurrences causally related to treatment / all
    0 / 13
         deaths causally related to treatment / all
    0 / 0
    Ascites
         subjects affected / exposed
    5 / 1008 (0.50%)
         occurrences causally related to treatment / all
    1 / 7
         deaths causally related to treatment / all
    0 / 0
    Autoimmune colitis
         subjects affected / exposed
    3 / 1008 (0.30%)
         occurrences causally related to treatment / all
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    Autoimmune pancreatitis
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Colitis
         subjects affected / exposed
    7 / 1008 (0.69%)
         occurrences causally related to treatment / all
    6 / 7
         deaths causally related to treatment / all
    0 / 0
    Colitis ischaemic
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Constipation
         subjects affected / exposed
    2 / 1008 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea
         subjects affected / exposed
    14 / 1008 (1.39%)
         occurrences causally related to treatment / all
    12 / 16
         deaths causally related to treatment / all
    0 / 0
    Dyspepsia
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Food poisoning
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastritis
         subjects affected / exposed
    3 / 1008 (0.30%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 1008 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Ileal perforation
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    2 / 1008 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Intestinal fistula
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    4 / 1008 (0.40%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Intussusception
         subjects affected / exposed
    2 / 1008 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Melaena
         subjects affected / exposed
    3 / 1008 (0.30%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Nausea
         subjects affected / exposed
    8 / 1008 (0.79%)
         occurrences causally related to treatment / all
    4 / 9
         deaths causally related to treatment / all
    0 / 0
    Oesophagitis
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    2 / 1008 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Small intestinal perforation
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vomiting
         subjects affected / exposed
    10 / 1008 (0.99%)
         occurrences causally related to treatment / all
    3 / 12
         deaths causally related to treatment / all
    0 / 0
    Anal haemorrhage
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorder
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Subileus
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Autoimmune hepatitis
         subjects affected / exposed
    8 / 1008 (0.79%)
         occurrences causally related to treatment / all
    8 / 8
         deaths causally related to treatment / all
    1 / 1
    Cholecystitis
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    2 / 1008 (0.20%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Hepatic failure
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Hepatic function abnormal
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatic pain
         subjects affected / exposed
    3 / 1008 (0.30%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Hepatomegaly
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypertransaminasaemia
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Jaundice
         subjects affected / exposed
    2 / 1008 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Liver disorder
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Immune-Mediated hepatitis
         subjects affected / exposed
    4 / 1008 (0.40%)
         occurrences causally related to treatment / all
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dermatitis exfoliative
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Drug eruption
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Erythema
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Generalised erythema
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pemphigoid
         subjects affected / exposed
    2 / 1008 (0.20%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Pruritus generalised
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Rash generalised
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    2 / 1008 (0.20%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Skin ulcer
         subjects affected / exposed
    3 / 1008 (0.30%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Erythema multiforme
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rash macular
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    9 / 1008 (0.89%)
         occurrences causally related to treatment / all
    3 / 9
         deaths causally related to treatment / all
    0 / 0
    Autoimmune nephritis
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Bladder pain
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    2 / 1008 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Nephrolithiasis
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Postrenal failure
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal failure
         subjects affected / exposed
    4 / 1008 (0.40%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    0 / 3
    Renal impairment
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tubulointerstitial nephritis
         subjects affected / exposed
    2 / 1008 (0.20%)
         occurrences causally related to treatment / all
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    Ureteric stenosis
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    2 / 1008 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Endocrine disorders
    Addison's disease
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Adrenal insufficiency
         subjects affected / exposed
    5 / 1008 (0.50%)
         occurrences causally related to treatment / all
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    Autoimmune thyroiditis
         subjects affected / exposed
    2 / 1008 (0.20%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Hyperthyroidism
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypophysitis
         subjects affected / exposed
    4 / 1008 (0.40%)
         occurrences causally related to treatment / all
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    Hypopituitarism
         subjects affected / exposed
    3 / 1008 (0.30%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Hypothyroidism
         subjects affected / exposed
    3 / 1008 (0.30%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Lymphocytic hypophysitis
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Secondary adrenocortical insufficiency
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Steroid withdrawal syndrome
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Adrenal haemorrhage
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Arthritis
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Back pain
         subjects affected / exposed
    8 / 1008 (0.79%)
         occurrences causally related to treatment / all
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    Bone pain
         subjects affected / exposed
    2 / 1008 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Fistula
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Flank pain
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Groin pain
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Mobility decreased
         subjects affected / exposed
    2 / 1008 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Muscular weakness
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    2 / 1008 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Myositis
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Osteochondrosis
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tendonitis
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Abdominal infection
         subjects affected / exposed
    4 / 1008 (0.40%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Abdominal sepsis
         subjects affected / exposed
    2 / 1008 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Anal abscess
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Appendiceal abscess
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Appendicitis
         subjects affected / exposed
    2 / 1008 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bronchitis
         subjects affected / exposed
    2 / 1008 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Bronchopulmonary aspergillosis allergic
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cellulitis
         subjects affected / exposed
    6 / 1008 (0.60%)
         occurrences causally related to treatment / all
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    Conjunctivitis
         subjects affected / exposed
    2 / 1008 (0.20%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Device related infection
         subjects affected / exposed
    3 / 1008 (0.30%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Device related sepsis
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea infectious
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Enterocolitis infectious
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Erysipelas
         subjects affected / exposed
    7 / 1008 (0.69%)
         occurrences causally related to treatment / all
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    4 / 1008 (0.40%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Haematoma infection
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infected dermal cyst
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infected lymphocele
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infection
         subjects affected / exposed
    5 / 1008 (0.50%)
         occurrences causally related to treatment / all
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    Infective exacerbation of chronic obstructive airways disease
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Latent tuberculosis
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    9 / 1008 (0.89%)
         occurrences causally related to treatment / all
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Perirectal abscess
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumococcal sepsis
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    13 / 1008 (1.29%)
         occurrences causally related to treatment / all
    1 / 14
         deaths causally related to treatment / all
    0 / 2
    Pneumonia legionella
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pseudomembranous colitis
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    5 / 1008 (0.50%)
         occurrences causally related to treatment / all
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    8 / 1008 (0.79%)
         occurrences causally related to treatment / all
    0 / 8
         deaths causally related to treatment / all
    0 / 1
    Septic encephalopathy
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sinusitis
         subjects affected / exposed
    2 / 1008 (0.20%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tonsillitis
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tooth abscess
         subjects affected / exposed
    2 / 1008 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Tooth infection
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tracheobronchitis
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    11 / 1008 (1.09%)
         occurrences causally related to treatment / all
    0 / 13
         deaths causally related to treatment / all
    0 / 0
    Urosepsis
         subjects affected / exposed
    4 / 1008 (0.40%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Vascular device infection
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Viral diarrhoea
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Wound infection
         subjects affected / exposed
    2 / 1008 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Meningitis
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Tuberculosis
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dehydration
         subjects affected / exposed
    4 / 1008 (0.40%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    3 / 1008 (0.30%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    7 / 1008 (0.69%)
         occurrences causally related to treatment / all
    4 / 8
         deaths causally related to treatment / all
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    2 / 1008 (0.20%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Hypernatraemia
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    2 / 1008 (0.20%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    5 / 1008 (0.50%)
         occurrences causally related to treatment / all
    1 / 6
         deaths causally related to treatment / all
    1 / 1
    Hyponatraemia
         subjects affected / exposed
    6 / 1008 (0.60%)
         occurrences causally related to treatment / all
    4 / 8
         deaths causally related to treatment / all
    0 / 0
    Hypoproteinaemia
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ketoacidosis
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Type 1 diabetes mellitus
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Decreased appetite
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    1 / 1008 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 NIVOLUMAB 3 MG/KG IV
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    857 / 1008 (85.02%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    83 / 1008 (8.23%)
         occurrences all number
    115
    Aspartate aminotransferase increased
         subjects affected / exposed
    78 / 1008 (7.74%)
         occurrences all number
    90
    Blood alkaline phosphatase increased
         subjects affected / exposed
    52 / 1008 (5.16%)
         occurrences all number
    56
    Lipase increased
         subjects affected / exposed
    79 / 1008 (7.84%)
         occurrences all number
    155
    Weight decreased
         subjects affected / exposed
    63 / 1008 (6.25%)
         occurrences all number
    66
    Nervous system disorders
    Headache
         subjects affected / exposed
    122 / 1008 (12.10%)
         occurrences all number
    160
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    126 / 1008 (12.50%)
         occurrences all number
    157
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    168 / 1008 (16.67%)
         occurrences all number
    222
    Fatigue
         subjects affected / exposed
    295 / 1008 (29.27%)
         occurrences all number
    355
    Oedema peripheral
         subjects affected / exposed
    81 / 1008 (8.04%)
         occurrences all number
    94
    Pyrexia
         subjects affected / exposed
    130 / 1008 (12.90%)
         occurrences all number
    182
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    102 / 1008 (10.12%)
         occurrences all number
    113
    Abdominal pain upper
         subjects affected / exposed
    58 / 1008 (5.75%)
         occurrences all number
    81
    Constipation
         subjects affected / exposed
    132 / 1008 (13.10%)
         occurrences all number
    164
    Diarrhoea
         subjects affected / exposed
    210 / 1008 (20.83%)
         occurrences all number
    320
    Nausea
         subjects affected / exposed
    212 / 1008 (21.03%)
         occurrences all number
    299
    Vomiting
         subjects affected / exposed
    120 / 1008 (11.90%)
         occurrences all number
    169
    Dry mouth
         subjects affected / exposed
    51 / 1008 (5.06%)
         occurrences all number
    58
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    134 / 1008 (13.29%)
         occurrences all number
    160
    Dyspnoea
         subjects affected / exposed
    81 / 1008 (8.04%)
         occurrences all number
    94
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    54 / 1008 (5.36%)
         occurrences all number
    55
    Pruritus
         subjects affected / exposed
    115 / 1008 (11.41%)
         occurrences all number
    135
    Pruritus generalised
         subjects affected / exposed
    89 / 1008 (8.83%)
         occurrences all number
    107
    Rash
         subjects affected / exposed
    54 / 1008 (5.36%)
         occurrences all number
    72
    Vitiligo
         subjects affected / exposed
    77 / 1008 (7.64%)
         occurrences all number
    81
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    55 / 1008 (5.46%)
         occurrences all number
    56
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    114 / 1008 (11.31%)
         occurrences all number
    125
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    148 / 1008 (14.68%)
         occurrences all number
    199
    Back pain
         subjects affected / exposed
    116 / 1008 (11.51%)
         occurrences all number
    140
    Musculoskeletal pain
         subjects affected / exposed
    55 / 1008 (5.46%)
         occurrences all number
    60
    Myalgia
         subjects affected / exposed
    62 / 1008 (6.15%)
         occurrences all number
    80
    Pain in extremity
         subjects affected / exposed
    93 / 1008 (9.23%)
         occurrences all number
    108
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    88 / 1008 (8.73%)
         occurrences all number
    126
    Urinary tract infection
         subjects affected / exposed
    54 / 1008 (5.36%)
         occurrences all number
    68
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    143 / 1008 (14.19%)
         occurrences all number
    162

    More information

    		 Close Top of page

    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Jan 2015
    The inclusion criteria have been expanded and the exclusion criteria have been minimized. The study rationale also offers greater support for the expanded subject population.  Treatment-naïve patients have been added.  The options for palliative local therapy have also been expanded to meet the needs of the current patient populations. The EORTC QLQ-C30 has been eliminated from the patients’ follow up.  The time points and frequency of assessments have been updated. The subjects in Cohort 2 will now be analyzed at the same frequency to Cohort 1, so the separate Time and Events Schedule for Cohort 2 was removed. The statistical section has been reformatted to aid understanding of the analyses to support the respective primary, secondary, and exploratory objectives. The timing and frequency of all assessments have been removed from sections of the protocol outside of the Time and Events tables. The endpoints are more representative of the data that will be collected in support of the objectives. The requirement for electrocardiograms has been removed.
    19 Mar 2015
    This Amendment removes the inclusion of the treatment-naïve patients, also referred to as the first-line cohort.
    02 Jun 2015
    Decreases sample size
    28 Oct 2015
    To provide further clarity on the requirements for lipase testing. To provide clarity on dose calculations. To allow the EQ-5D-3L to be completed without an office visit if one is not otherwise needed. The of expectations when lipase results are not available prior to dosing Aligning the footnotes of Table 5.1-2 and Section 5.3, Safety Assessments with the requirements for lipase described in Table 5.1-2. Assessments allowed to be done according to standard of care At what cycle assessments should start and assessment windows When RECIST 1.1 criteria must be used. NOTE: Administrative Letter 04 was not finalized because it was considered to not be needed. However, Administrative Letter 05 was created and finalized with the mistaken understanding that Administrative Letter 04 was finalized.
    08 Dec 2015
    Adds dosing windows to the time and events schedule.
    17 Nov 2017
    Changed the duration of follow-up from 5 years to 2 years after the first dose of study drug treatment due to a decision to close the study in 2018. This decision was based on adequate safety data obtained since the study’s opening in 2014, which are consistent with the known safety profiles of the study drugs. Changed MM Address.

    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-Tue Apr 23 14:46:27 CEST 2024 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    EMA HMA