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    Clinical Trial Results:
    A Phase II Safety Trial of Nivolumab in Patients with Metastatic Renal Cell Carcinoma Who Have Progressed During or After Prior Systemic Anti-Angiogenic Regimen.

    Summary
    EudraCT number
    		 2015-004117-24
    Trial protocol
    		 FR  
    Global end of trial date
    30 Jun 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 May 2025
    First version publication date
    21 May 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GETUG-AFU26
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03013335
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    UNICANCER
    Sponsor organisation address
    101 rue de Tolbiac, Paris, France,
    Public contact
    Nourredine AIT RAHMOUNE, UNICANCER, +33 0171936704, n.ait-rahmoune@unicancer.fr
    Scientific contact
    Nourredine AIT RAHMOUNE, UNICANCER, +33 0171936704, n.ait-rahmoune@unicancer.fr
    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
    14 Apr 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Jun 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Jun 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the incidence of high-grade (i.e. Grade 3-4 and Grade 5 of CTCAE v4.0) adverse reactions of interest in patients with metastatic RCC who have progressed during or after receiving at least one prior systemic anti-angiogenic treatment and who are eligible for nivolumab monotherapy.
    Protection of trial subjects
    This study was conducted in compliance with the protocol and in accordance with the French national regulatory requirements and the Declaration of Helsinki (1964) and subsequent amendments, ICH Good Clinical Practice (GCP) Guidelines (CPMP/ICH/135/95), the European Directive (2001/20/CE) and the applicable local regulatory requirements and laws.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Dec 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 5 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 720
    Worldwide total number of subjects
    720
    EEA total number of subjects
    720
    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)
    353
    From 65 to 84 years
    360
    85 years and over
    7

    Subject disposition

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    Recruitment
    Recruitment details
    		 From 01-Feb-2016 to 27-Jul-2017, 729 patients were enrolled in the NIVOREN study across 26 centers in France. The 720 patients who received at least 1 dose of nivolumab were included and analyzed.

    Pre-assignment
    Screening details
    		 Patients were included in the study with mRCC with clear cell component; at least one prior systemic anti-angiogenic treatment; ECOG ≤2.Patients will be treated with nivolumab every 2 weeks until disease progression without clinical benefit, unacceptable toxicity, or withdrawal of informed consent, follow-up is planned to last up to 5 years.

    Period 1
    Period 1 title
    Overall periode
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    NA

    Arms
    Arm title
    		 NIVOLUMAB
    Arm description
    		 Only one arm in this trial Treatment: Nivolumab
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    The dose and schedule of nivolumab in this study was 3 mg/kg every 2 weeks. Infusion of nivolumab were performed in 30 minutes (± 5 minutes). Nivolumab was administered until death, disease progression, unacceptable toxicity or withdrawal of the informed consent.

    Number of subjects in period 1
    		NIVOLUMAB
    Started
    720
    Completed
    0
    Not completed
    720
         Physician decision
    22
         Patient decision
    23
         End of study/ Progressive disease
    495
         Response observed by physician/patient/other (Comp
    24
         Death
    41
         Other
    1
         Toxicity/adverse event
    114

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall periode
    Reporting group description
    		 -

    Reporting group values
    		 Overall periode Total
    Number of subjects
    		 720 720
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 353 353
        From 65-84 years
    		 360 360
        85 years and over
    		 7 7
    Age continuous
    Units: years
        median (full range (min-max))
    		 64 (22 to 90) -
    Gender categorical
    Units: Subjects
        Female
    		 164 164
        Male
    		 556 556
    ECOG
    Units: Subjects
        Missing data
    		 36 36
        ECOG 0
    		 229 229
        ECOG 1
    		 352 352
        ECOG 2
    		 100 100
        ECOG 3
    		 3 3
    Menopausal status
    Units: Subjects
        Missing data
    		 2 2
        Non-menopause
    		 17 17
        Pre-menopause
    		 4 4
        Menopause
    		 131 131
        Unknown
    		 10 10
        Non applicable
    		 556 556
    Hemoglobin ≤LLN
    Units: Subjects
        NO
    		 324 324
        YES
    		 396 396
    Calcium (corrected) ≥ULN
    Units: Subjects
        Missing data
    		 2 2
        No
    		 553 553
        Yes
    		 165 165
    Neutrophils ≥ULN
    Units: Subjects
        No
    		 645 645
        Yes
    		 75 75
    Platelets >ULN
    Units: Subjects
        No
    		 623 623
        Yes
    		 97 97
    IMDC prognostic/ Score
    Units: Subjects
        Missing data
    		 2 2
        Score = 0
    		 132 132
        Score =1
    		 234 234
        Score =2
    		 171 171
        Score =3
    		 94 94
        Score =4
    		 54 54
        Score =5
    		 25 25
        Score =6
    		 8 8
    IMDC Prognostic
    Units: Subjects
        Missing data
    		 2 2
        Favorable
    		 132 132
        Intermediate
    		 405 405
        Poor
    		 181 181
    Favorable/intermediate versus poor IMDC prognostic
    Units: Subjects
        Missing data
    		 2 2
        Favorable/intermediate prognostic
    		 537 537
        Poor prognostic
    		 181 181

    End points

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    End points reporting groups
    Reporting group title
    NIVOLUMAB
    Reporting group description
    		 Only one arm in this trial Treatment: Nivolumab

    Primary: Incidence of Grade 3, 4, or 5 ADR

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    End point title
    		 Incidence of Grade 3, 4, or 5 ADR [1]
    End point description
    The primary endpoint of this study was the incidence for high-grade (Grade 3-4 and Grade 5) adverse reactions of interest [i.e. adverse event related to the study treatment (TRAE)]. The adverse reactions of interest were skin, endocrinopathy, gastrointestinal, hepatic, renal, pulmonary, and hypersensitivity adverse events. Due to the frequency of TRAEs observed during the study, safety analyses were done on all TRAEs of grade 3 or more observed by the investigator during the study.
    End point type
    Primary
    End point timeframe
    5 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: The primary endpoint of this study was the incidence for high-grade (Grade 3-4 and Grade 5) adverse reactions of interest (i.e. adverse event related to the study treatment). The forms AE from the CRF was used and correspond to the adverse event related to the study treatment judged from investigator. The number of patients with at least one AE of grade ≥3 related to nivolumab were presented with count, % and 95% confidence interval. Only one arm in this study ,there were no statistical analyses
    End point values
    		 NIVOLUMAB
    Number of subjects analysed
    720
    Units: percent of patients
    number (not applicable)
        Patient with at least 1 ADR ≥ grade 3
    19.9
    No statistical analyses for this end point

    Secondary: Overall survival (OS)

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    End point title
    		 Overall survival (OS)
    End point description
    OS is defined as the time from first dosing date to the date of death. A patient who has not died will be censored at last known date alive. OS will be followed continuously while patients are on the treatment and every 3 months via in-person or phone contact after patients discontinue the study drug.
    End point type
    Secondary
    End point timeframe
    5 years
    End point values
    		 NIVOLUMAB
    Number of subjects analysed
    720
    Units: Months
        median (confidence interval 95%)
    55.9 (54.4 to 57.3)
    No statistical analyses for this end point

    Secondary: Objective response rate (ORR)

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    End point title
    		 Objective response rate (ORR)
    End point description
    Objective response rate (ORR) is defined as the number and percentage of patients with a Best Overall Response (BOR) of confirmed complete response (CR) or partial response (PR). Best overall response (BOR) is defined as the best response designation, recorded between the date of first dose and the date of the initial objectively documented tumor progression per RECIST v1.1 or the date of subsequent therapy, whichever occurs first. For Patients without documented progression or subsequent therapy, all available response designations will contribute to the BOR determination.
    End point type
    Secondary
    End point timeframe
    5 years
    End point values
    		 NIVOLUMAB
    Number of subjects analysed
    720
    Units: percent
        median (confidence interval 95%)
    21.3 (18.3 to 24.5)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From inclusion until 30 days after end of treatment (up to 5 years).
    Adverse event reporting additional description
    For non serious adverse events only treatment-related adverse events (TRAEs) were available.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.1
    Reporting groups
    Reporting group title
    NIVOLUMAB
    Reporting group description
    		 Of the 729 patients included in the study, 720 patients received at least one dose of nivolumab and were evaluable for the safety analysis. Nine patients did not received the study treatment and were excluded of the safety analysis.

    Serious adverse events
    		 NIVOLUMAB
    Total subjects affected by serious adverse events
         subjects affected / exposed
    330 / 720 (45.83%)
         number of deaths (all causes)
    518
         number of deaths resulting from adverse events
    8
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloblastic leukemia
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    4 / 720 (0.56%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    Bone metastases
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Brain metastases
         subjects affected / exposed
    4 / 720 (0.56%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Breast cancer
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cancer pain
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intestinal metastasis
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lentigo maligna melanoma
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lobular breast carcinoma (in situ)
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lymphangitis carcinomatosis
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Malignant neoplasm progression
         subjects affected / exposed
    4 / 720 (0.56%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 4
    Metastases to pituitary gland
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metastatic pain
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Myeloid leukaemia
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Myeloma
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neoplasm progression
         subjects affected / exposed
    10 / 720 (1.39%)
         occurrences causally related to treatment / all
    0 / 10
         deaths causally related to treatment / all
    0 / 7
    Osteolytic bone metastases
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pancreatic cancer
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Prostate cancer
         subjects affected / exposed
    3 / 720 (0.42%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Spinocellular carcinom
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Squamous cell carcinoma of the cervix
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Superficial basal cell carcinoma
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tumor compression
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tumor progression
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Aortic thrombosis
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Cerebral hemorrhage
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Ischemic stroke
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Pregnancy
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Anasarca
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Asthenia
         subjects affected / exposed
    4 / 720 (0.56%)
         occurrences causally related to treatment / all
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    Chest pain
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Chronic pain
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Death
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Disease progression
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Drug side effect
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Face edema
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Face oedema
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Fatigue
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Fever
         subjects affected / exposed
    7 / 720 (0.97%)
         occurrences causally related to treatment / all
    2 / 7
         deaths causally related to treatment / all
    0 / 0
    Fever malignant
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    32 / 720 (4.44%)
         occurrences causally related to treatment / all
    2 / 33
         deaths causally related to treatment / all
    0 / 14
    Hyperthermia
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pain
         subjects affected / exposed
    5 / 720 (0.69%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Thoracic pain
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Unknown cause of death
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Immune system disorders
    Allergic reaction
         subjects affected / exposed
    4 / 720 (0.56%)
         occurrences causally related to treatment / all
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hypertrophy
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Asthmatoid bronchitis
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Atelectasis
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bronchial hemorrhage
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bronchial obstruction
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Chronic obstructive pulmonary disease exacerbation
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Distress respiratory
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Dyspnea
         subjects affected / exposed
    11 / 720 (1.53%)
         occurrences causally related to treatment / all
    1 / 11
         deaths causally related to treatment / all
    0 / 3
    Interstitial lung disease
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Interstitial pneumonitis
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia interstitial
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonitis allergic
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumopathy
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Toxic pneumonitis
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Clinomania
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Confusion
         subjects affected / exposed
    4 / 720 (0.56%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    Depressive symptom
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychomotor retardation
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Suicide
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Investigations
    Lost weight
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Arm fracture
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cerebral edema
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Drug overdose
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Fall
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Femur fracture
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Humerus fracture
         subjects affected / exposed
    3 / 720 (0.42%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Pathological fracture
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Radiation proctitis
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Scalp injury NOS
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Trauma
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Wrist fracture
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    3 / 720 (0.42%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Cardiomyopathy
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Decompensation cardiac
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Heart failure
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    1 / 1
    Myocardial infarction
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Myocarditis
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pericardial tamponade
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pericarditis
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pleuropericarditis
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Sinus bradycardia
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Thoracic pain
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Cervical myelopathy
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Encephalopathy
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Epileptic seizure
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Generalized tonic-clonic seizure
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hemiparesis (right)
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Ischemic stroke
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Myasthenia gravis
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Neurologic disorder NOS
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Paresthesia lower limb
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Quadriparesis
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sciatica
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Seizures
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    7 / 720 (0.97%)
         occurrences causally related to treatment / all
    0 / 7
         deaths causally related to treatment / all
    0 / 1
    Blood and lymphatic system disorders
    Acute anemia
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Anemia
         subjects affected / exposed
    7 / 720 (0.97%)
         occurrences causally related to treatment / all
    3 / 8
         deaths causally related to treatment / all
    0 / 0
    Macrophage activation syndrome
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Ear and labyrinth disorders
    Vestibular disorder
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Eye disorders
    Posterior uveitis
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Uveitis
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Visual impairment
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    5 / 720 (0.69%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Acute hemorrhagic ulcerative colitis
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Acute pancreatitis
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Ascites
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Autoimmune colitis
         subjects affected / exposed
    3 / 720 (0.42%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Bleeding gastrointestinal
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bleeding rectal
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    C.difficile diarrhoea
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Colitis
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Colon perforation
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Colonic obstruction
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Diarrhea
         subjects affected / exposed
    8 / 720 (1.11%)
         occurrences causally related to treatment / all
    8 / 8
         deaths causally related to treatment / all
    0 / 0
    Duodenal stenosis
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastric hemorrhage
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastric ulcer hemorrhage
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal bleeding
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Hemorrhage gastric
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hemorrhage of digestive tract
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Inguinal hernia
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Lip oedema
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Melena
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Peritonitis biliary
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rectal bleeding
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rectal hemorrhage
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Small bowel obstruction
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Stomach hemorrhage
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Subocclusive syndrom
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Upper gastrointestinal bleeding
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Acute cholecystitis
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Cholangitis
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Cholecystitis
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatic cytolysis
         subjects affected / exposed
    5 / 720 (0.69%)
         occurrences causally related to treatment / all
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    Hepatitis
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Icterus
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Liver cholestasis
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Obstruction of bile duct
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Portal hypertension
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Bullous dermatitis
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Dermatosis bullous
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Lupus syndrome
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Maculo-papular rash
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Papular rash
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Acute prerenal failure
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Acute renal failure
         subjects affected / exposed
    9 / 720 (1.25%)
         occurrences causally related to treatment / all
    2 / 10
         deaths causally related to treatment / all
    0 / 0
    Acute renal insufficiency
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Hematuria
         subjects affected / exposed
    3 / 720 (0.42%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Proteinuria
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal failure
         subjects affected / exposed
    5 / 720 (0.69%)
         occurrences causally related to treatment / all
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    6 / 720 (0.83%)
         occurrences causally related to treatment / all
    5 / 6
         deaths causally related to treatment / all
    0 / 0
    Autoimmune thyroiditis
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Decompensated diabetes
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Goiter
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hyperthyroidism
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypophysitis
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Inappropriate antidiuretic hormone secretion
         subjects affected / exposed
    1 / 720 (0.14%)
         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 / 720 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Arthralgia multiple
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Bone pain
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Costal pain
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Inflammatory arthritis
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Leg pain
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lumbalgia
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lumbar pain
         subjects affected / exposed
    3 / 720 (0.42%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Osteolytic lesion
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pain in leg
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pain sacroiliac
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Polyarthritis
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Polymyalgia rheumatica
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Sacroiliac fracture
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Spinal pain
         subjects affected / exposed
    3 / 720 (0.42%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Vertebral pain
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Abscess periodontal
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Acute appendicitis
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Aspergillosis
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bacterial infection
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bronchial infection
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bronchiolitis
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Catheter infection
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Catheter related infection
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Enterococcus faecalis infection
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Epiduritis
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Foot infection
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haemophilus influenza infection
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatitis E
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infection NOS
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infection urinary tract
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infectious pneumonitis
         subjects affected / exposed
    7 / 720 (0.97%)
         occurrences causally related to treatment / all
    1 / 7
         deaths causally related to treatment / all
    0 / 1
    Lung infection
         subjects affected / exposed
    5 / 720 (0.69%)
         occurrences causally related to treatment / all
    2 / 5
         deaths causally related to treatment / all
    1 / 1
    Parvovirus B19 infection
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumocystis pneumonia
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    Pneumonia
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Prostatic abscess
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    3 / 720 (0.42%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Sepsis syndrome
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Septic cholangitis
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Septic encephalopathy
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Septic shock
         subjects affected / exposed
    3 / 720 (0.42%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    Septicemia
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Staphylococcus epidermidis infection
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Surgical site infection
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary infection
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    4 / 720 (0.56%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Diabetic metabolic decompensation
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Hypercalcemia
         subjects affected / exposed
    26 / 720 (3.61%)
         occurrences causally related to treatment / all
    1 / 29
         deaths causally related to treatment / all
    0 / 0
    Hyperglycemia
         subjects affected / exposed
    5 / 720 (0.69%)
         occurrences causally related to treatment / all
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    Hyperkalemia
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hyponatremia
         subjects affected / exposed
    5 / 720 (0.69%)
         occurrences causally related to treatment / all
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 NIVOLUMAB
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    676 / 720 (93.89%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences all number
    8
    Seborrheic keratosis
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    2
    Vascular disorders
    Flushing
         subjects affected / exposed
    3 / 720 (0.42%)
         occurrences all number
    3
    Hot flush
         subjects affected / exposed
    4 / 720 (0.56%)
         occurrences all number
    6
    Hypertension
         subjects affected / exposed
    8 / 720 (1.11%)
         occurrences all number
    14
    Hypotension
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences all number
    2
    Varicose vein
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    1
    Pregnancy, puerperium and perinatal conditions
    Abortion missed
         subjects affected / exposed
    3 / 720 (0.42%)
         occurrences all number
    6
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    185 / 720 (25.69%)
         occurrences all number
    929
    Chest discomfort
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences all number
    2
    Chest pain
         subjects affected / exposed
    3 / 720 (0.42%)
         occurrences all number
    4
    Chills
         subjects affected / exposed
    9 / 720 (1.25%)
         occurrences all number
    12
    Exercise tolerance decreased
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    1
    Face edema
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    2
    Fatigue
         subjects affected / exposed
    52 / 720 (7.22%)
         occurrences all number
    234
    Feeling cold
         subjects affected / exposed
    3 / 720 (0.42%)
         occurrences all number
    3
    General physical health deterioration
         subjects affected / exposed
    3 / 720 (0.42%)
         occurrences all number
    4
    Generalized edema
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    2
    Influenza like illness
         subjects affected / exposed
    5 / 720 (0.69%)
         occurrences all number
    5
    Malaise
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    2
    Mucosal dryness
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences all number
    2
    Mucosal inflammation
         subjects affected / exposed
    15 / 720 (2.08%)
         occurrences all number
    48
    Edema
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    1
    Edema peripheral
         subjects affected / exposed
    11 / 720 (1.53%)
         occurrences all number
    29
    Pain
         subjects affected / exposed
    6 / 720 (0.83%)
         occurrences all number
    8
    Pyrexia
         subjects affected / exposed
    15 / 720 (2.08%)
         occurrences all number
    24
    Sense of oppression
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    1
    Xerosis
         subjects affected / exposed
    36 / 720 (5.00%)
         occurrences all number
    259
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    6 / 720 (0.83%)
         occurrences all number
    8
    Sarcoidosis
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences all number
    4
    Reproductive system and breast disorders
    Balanoposthitis
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences all number
    4
    Erectile dysfunction
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences all number
    13
    Genital erythema
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    2
    Genital rash
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences all number
    4
    Heavy menstrual bleeding
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    1
    Penile edema
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    2
    Pruritus genital
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    5
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    14 / 720 (1.94%)
         occurrences all number
    40
    Dysphonia
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences all number
    6
    Dyspnea
         subjects affected / exposed
    25 / 720 (3.47%)
         occurrences all number
    47
    Dyspnea exertional
         subjects affected / exposed
    6 / 720 (0.83%)
         occurrences all number
    20
    Epistaxis
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences all number
    12
    Hiccups
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    2
    Hypersensitivity pneumonitis
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences all number
    3
    Hypoxia
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    1
    Immune-mediated lung disease
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    3
    Interstitial lung disease
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences all number
    4
    Lung disorder
         subjects affected / exposed
    9 / 720 (1.25%)
         occurrences all number
    15
    Organizing pneumonia
         subjects affected / exposed
    4 / 720 (0.56%)
         occurrences all number
    14
    Oropharyngeal discomfort
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    19
    Pharyngeal paresthesia
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    1
    Pulmonary embolism
         subjects affected / exposed
    3 / 720 (0.42%)
         occurrences all number
    6
    Pulmonary interstitial emphysema syndrome
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences all number
    5
    Sneezing
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    4
    Psychiatric disorders
    Affective disorder
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    1
    Anxiety
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    1
    Confusional state
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences all number
    3
    Insomnia
         subjects affected / exposed
    3 / 720 (0.42%)
         occurrences all number
    5
    Psychomotor retardation
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences all number
    3
    Sleep disorder
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    2
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    11 / 720 (1.53%)
         occurrences all number
    36
    Aspartate aminotransferase increased
         subjects affected / exposed
    9 / 720 (1.25%)
         occurrences all number
    26
    Blood alkaline phosphatase increased
         subjects affected / exposed
    7 / 720 (0.97%)
         occurrences all number
    17
    Blood bilirubin increased
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    2
    Blood creatinine
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    1
    Blood creatinine increased
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences all number
    19
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    3 / 720 (0.42%)
         occurrences all number
    13
    Blood potassium increased
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    2
    Blood thyroid stimulating hormone decreased
         subjects affected / exposed
    3 / 720 (0.42%)
         occurrences all number
    11
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    6 / 720 (0.83%)
         occurrences all number
    28
    Blood urea increased
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    6
    Creatinine renal clearance decreased
         subjects affected / exposed
    4 / 720 (0.56%)
         occurrences all number
    8
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    9 / 720 (1.25%)
         occurrences all number
    28
    Lipase increased
         subjects affected / exposed
    4 / 720 (0.56%)
         occurrences all number
    16
    Lymphocyte count decreased
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences all number
    4
    Lymphocyte count increased
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    1
    Neutrophil count increased
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    1
    Thyroid hormones decreased
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    3
    Thyroid hormones increased
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    12
    Thyroxine free increased
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    1
    Transaminases increased
         subjects affected / exposed
    3 / 720 (0.42%)
         occurrences all number
    5
    Tri-iodothyronine free increased
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    1
    Weight decreased
         subjects affected / exposed
    6 / 720 (0.83%)
         occurrences all number
    8
    Weight increased
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences all number
    64
    White blood cell count increased
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    4
    Diabetes mellitus inadequate control
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences all number
    25
    Gout
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    1
    Hypercalcemia
         subjects affected / exposed
    3 / 720 (0.42%)
         occurrences all number
    11
    Hypercholesterolemia
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    1
    Lip injury
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    1
    Muscle rupture
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    1
    Cardiac disorders
    trial fibrillation
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences all number
    2
    Atrioventricular block
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    2
    Cardiac arrest
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    1
    Cardiac failure
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    1
    Cyanosis
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences all number
    6
    Myocarditis
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    2
    Pleuropericarditis
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    3
    Tachycardia
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    1
    Nervous system disorders
    Anosmia
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    10
    Burning sensation
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    1
    Cerebrovascular accident
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    1
    Dizziness
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences all number
    2
    Dysarthria
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    1
    Dysgeusia
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences all number
    8
    Epilepsy
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    2
    Headache
         subjects affected / exposed
    10 / 720 (1.39%)
         occurrences all number
    29
    Hypoesthesia
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    2
    Ischemic stroke
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    1
    Migraine
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    2
    Motor dysfunction
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences all number
    18
    Myasthenia gravis
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    3
    Nervous system disorder
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    1
    Neuralgia
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    2
    Neuropathy peripheral
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences all number
    10
    Paresthesia
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences all number
    6
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    10
    Sciatica
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    1
    Seizure
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    4
    Sensorimotor disorder
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    8
    Somnolence
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    1
    Tremor
         subjects affected / exposed
    3 / 720 (0.42%)
         occurrences all number
    3
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    22 / 720 (3.06%)
         occurrences all number
    87
    Autoimmune hemolytic anemia
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    2
    Eosinophilia
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences all number
    15
    Leukopenia
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    1
    Lymphopenia
         subjects affected / exposed
    12 / 720 (1.67%)
         occurrences all number
    36
    Neutropenia
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences all number
    17
    Thrombocytopenia
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences all number
    40
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    2
    Vertigo
         subjects affected / exposed
    4 / 720 (0.56%)
         occurrences all number
    7
    Vertigo positional
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    2
    Eye disorders
    Abnormal sensation in eye
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    1
    Blepharitis
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences all number
    4
    Diplopia
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    7
    Dry eye
         subjects affected / exposed
    8 / 720 (1.11%)
         occurrences all number
    27
    Episcleritis
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    3
    Eyelid edema
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    7
    Eyelids pruritus
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    2
    Keratitis
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    2
    Ocular hyperemia
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    2
    Uveitis
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences all number
    8
    Vision blurred
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences all number
    2
    Xerophthalmia
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences all number
    55
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    3 / 720 (0.42%)
         occurrences all number
    5
    Abdominal pain
         subjects affected / exposed
    10 / 720 (1.39%)
         occurrences all number
    32
    Abdominal pain upper
         subjects affected / exposed
    8 / 720 (1.11%)
         occurrences all number
    22
    Aphthous ulcer
         subjects affected / exposed
    4 / 720 (0.56%)
         occurrences all number
    10
    Aptyalism
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    4
    Autoimmune colitis
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences all number
    3
    Colitis
         subjects affected / exposed
    4 / 720 (0.56%)
         occurrences all number
    7
    Constipation
         subjects affected / exposed
    25 / 720 (3.47%)
         occurrences all number
    56
    Diarrhea
         subjects affected / exposed
    76 / 720 (10.56%)
         occurrences all number
    209
    Dry mouth
         subjects affected / exposed
    14 / 720 (1.94%)
         occurrences all number
    110
    Dyspepsia
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences all number
    2
    Frequent bowel movements
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    2
    Gastric disorder
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    1
    Gastrointestinal hemorrhage
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    1
    Hemorrhoids
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    2
    Large intestine polyp
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    1
    Mouth hemorrhage
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    3
    Nausea
         subjects affected / exposed
    35 / 720 (4.86%)
         occurrences all number
    60
    Oral discomfort
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    2
    Oral lichen planus
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    5
    Rectal hemorrhage
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    5
    Stomatitis
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    2
    Vomiting
         subjects affected / exposed
    17 / 720 (2.36%)
         occurrences all number
    32
    Hepatobiliary disorders
    Autoimmune hepatitis
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    2
    Cholangitis
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    2
    Cholecystitis
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    1
    Cholestasis
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences all number
    7
    Hepatic cytolysis
         subjects affected / exposed
    7 / 720 (0.97%)
         occurrences all number
    16
    Hepatitis
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    1
    Portal hypertension
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    2
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences all number
    10
    Alopecia
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences all number
    5
    Dermatitis acneiform
         subjects affected / exposed
    4 / 720 (0.56%)
         occurrences all number
    9
    Dermatitis bullous
         subjects affected / exposed
    4 / 720 (0.56%)
         occurrences all number
    17
    Dermatitis diaper
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    1
    Dry skin
         subjects affected / exposed
    13 / 720 (1.81%)
         occurrences all number
    35
    Dyshidrotic eczema
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    3
    Eczema
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences all number
    19
    Erythema
         subjects affected / exposed
    11 / 720 (1.53%)
         occurrences all number
    25
    Erythrosis
         subjects affected / exposed
    3 / 720 (0.42%)
         occurrences all number
    7
    Hyperhidrosis
         subjects affected / exposed
    3 / 720 (0.42%)
         occurrences all number
    4
    Hyperkeratosis
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    3
    Lichen planus
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    1
    Macule
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    1
    Nail disorder
         subjects affected / exposed
    3 / 720 (0.42%)
         occurrences all number
    29
    Nail toxicity
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    3
    Night sweats
         subjects affected / exposed
    4 / 720 (0.56%)
         occurrences all number
    11
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences all number
    2
    Pemphigoid
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    1
    Photosensitivity reaction
         subjects affected / exposed
    3 / 720 (0.42%)
         occurrences all number
    4
    Plantar erythema
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    1
    Prurigo
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    4
    Pruritus
         subjects affected / exposed
    66 / 720 (9.17%)
         occurrences all number
    450
    Psoriasis
         subjects affected / exposed
    6 / 720 (0.83%)
         occurrences all number
    52
    Purpura
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    4
    Rash
         subjects affected / exposed
    43 / 720 (5.97%)
         occurrences all number
    167
    Rash erythematous
         subjects affected / exposed
    7 / 720 (0.97%)
         occurrences all number
    17
    Rash macular
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    4
    Rash maculo-papular
         subjects affected / exposed
    11 / 720 (1.53%)
         occurrences all number
    17
    Rash papular
         subjects affected / exposed
    5 / 720 (0.69%)
         occurrences all number
    37
    Rash pruritic
         subjects affected / exposed
    3 / 720 (0.42%)
         occurrences all number
    4
    Skin exfoliation
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    2
    Skin lesion
         subjects affected / exposed
    7 / 720 (0.97%)
         occurrences all number
    26
    Skin reaction
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences all number
    2
    Skin toxicity
         subjects affected / exposed
    4 / 720 (0.56%)
         occurrences all number
    4
    Telangiectasia
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    4
    Toxic skin eruption
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences all number
    7
    Vitiligo
         subjects affected / exposed
    5 / 720 (0.69%)
         occurrences all number
    47
    Xeroderma
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    1
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    5 / 720 (0.69%)
         occurrences all number
    7
    Chronic kidney disease
         subjects affected / exposed
    3 / 720 (0.42%)
         occurrences all number
    14
    Proteinuria
         subjects affected / exposed
    4 / 720 (0.56%)
         occurrences all number
    16
    Renal failure
         subjects affected / exposed
    10 / 720 (1.39%)
         occurrences all number
    27
    Renal impairment
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    2
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    8 / 720 (1.11%)
         occurrences all number
    109
    Adrenocortical insufficiency acute
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences all number
    3
    Autoimmune thyroiditis
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences all number
    9
    Hyperthyroidism
         subjects affected / exposed
    12 / 720 (1.67%)
         occurrences all number
    39
    Hypophysitis
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    1
    Hypothyroidism
         subjects affected / exposed
    26 / 720 (3.61%)
         occurrences all number
    163
    Thyroid disorder
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences all number
    15
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    61 / 720 (8.47%)
         occurrences all number
    251
    Arthritis
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences all number
    8
    Back pain
         subjects affected / exposed
    12 / 720 (1.67%)
         occurrences all number
    31
    Bone pain
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    2
    Flank pain
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    1
    Muscle contracture
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    1
    Muscle spasms
         subjects affected / exposed
    7 / 720 (0.97%)
         occurrences all number
    16
    Muscular weakness
         subjects affected / exposed
    4 / 720 (0.56%)
         occurrences all number
    22
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    2
    Musculoskeletal pain
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    10
    Musculoskeletal stiffness
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences all number
    2
    Myalgia
         subjects affected / exposed
    28 / 720 (3.89%)
         occurrences all number
    82
    Pain in extremity
         subjects affected / exposed
    6 / 720 (0.83%)
         occurrences all number
    19
    Pain in jaw
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    2
    Plantar fasciitis
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    1
    Polyarthritis
         subjects affected / exposed
    4 / 720 (0.56%)
         occurrences all number
    19
    Polymyalgia rheumatica
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    2
    Rheumatoid arthritis
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    9
    Sjogren's syndrome
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    2
    Spinal pain
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences all number
    4
    Systemic lupus erythematosus
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    1
    Tendon disorder
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    2
    Infections and infestations
    Acute sinusitis
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    1
    Bronchitis
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences all number
    2
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    1
    Chorioretinitis
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    19
    Dermatitis infected
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    1
    Ecthyma
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    1
    Erysipelas
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    2
    Folliculitis
         subjects affected / exposed
    4 / 720 (0.56%)
         occurrences all number
    26
    Genital infection
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    2
    Herpes simplex
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    3
    Herpes zoster
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    1
    Infection
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    2
    Nasopharyngitis
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    1
    Onychomycosis
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    5
    Oral candidiasis
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences all number
    3
    Oral herpes
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    3
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    1
    Pneumonia
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    1
    Prostatic abscess
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    1
    Rhinitis
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    1
    Septic shock
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    2
    Skin infection
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences all number
    7
    Urinary tract infection
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    1
    Vulvovaginal mycotic infection
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    2
    Metabolism and nutrition disorders
    Cell death
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences all number
    3
    Decreased appetite
         subjects affected / exposed
    34 / 720 (4.72%)
         occurrences all number
    90
    Dehydration
         subjects affected / exposed
    3 / 720 (0.42%)
         occurrences all number
    6
    Diabetes mellitus
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences all number
    53
    Hyperglycemia
         subjects affected / exposed
    7 / 720 (0.97%)
         occurrences all number
    74
    Hyperkaliemia
         subjects affected / exposed
    9 / 720 (1.25%)
         occurrences all number
    22
    Hyperuricemia
         subjects affected / exposed
    2 / 720 (0.28%)
         occurrences all number
    2
    Hypochloremia
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    1
    Hypokalemia
         subjects affected / exposed
    3 / 720 (0.42%)
         occurrences all number
    5
    Hypomagnesaemia
         subjects affected / exposed
    1 / 720 (0.14%)
         occurrences all number
    8
    Hyponatremia
         subjects affected / exposed
    7 / 720 (0.97%)
         occurrences all number
    10
    Hypophosphatemia
         subjects affected / exposed
    5 / 720 (0.69%)
         occurrences all number
    18

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Mar 2016
    - Modification of the investigators list
    25 Apr 2016
    - Modification of the document of reference for the tumor evaluation - Modification of inclusion and non-inclusion criteria - Modification of the study design scheme - Addition of optional ancillary study - Modification of the flowchart - Correction of typographic errors within the protocol and the synopsis - Modification of the informed consent form - Addition of the co-coordinating investigator - Addition of the statistician’s contact information - Modification of the project leader - Modification of the investigators list
    10 Jun 2016
    - Modification of the sample size - Redaction of a patient information letter to explain the rational for the new sample size - Modification of the investigators list
    05 Jul 2016
    - Modification of the inclusion criteria - Clarification of the statistical analysis plan - Modification of mode of declaration SAE related to disease progression - Modification of the informed consent form - Modification of the investigators list
    28 Oct 2016
    - Modification of the sample size - Harmonization of the protocol and inform consent form for treatment after disease progression - Declaration of new center involved in the ancillary study - Modification of the investigators list
    26 Jan 2017
    - Extension of the recruitment period - Modification of the investigators list
    11 May 2017
    - Modification of the investigators list
    03 May 2018
    - Update of the safety section (protocol and inform consent form) based on the new version of the investigator brochure - New version of investigator brochure - Modification of the investigators list
    15 Jul 2019
    - Modification of the informed consent form to inform patient that their personal data will be collected and processed in accordance with the new national data protection legislation: Regulation (EU) 2016/679 (General Data Protection Regulation). - Update of the safety section (inform consent form) based on the new version of the investigator brochure - New version of investigator brochure - Modification of the investigators list
    06 Nov 2020
    - Update of the safety section (inform consent form) based on the new version of the investigator brochure - Addition of a new ancillary study including collection of data for bone metastases - New version of investigator brochure - Modification of the investigators list
    11 May 2021
    - The follow up period was reduced for a new end of study plannified on June 2021 - New version of investigator brochure - Modification of the investigators list

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

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