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    Clinical Trial Results:
    Randomized study with a run-in feasibility phase to assess the added value of Clofarabine in combination with standard remission-induction chemotherapy in patients aged 18-65 years with previously untreated acute myeloid leukemia (AML) or myelodysplasia (MDS) (RAEB with IPSS ≥ 1.5)

    Summary
    EudraCT number
    		 2009-011613-24
    Trial protocol
    		 NL   BE   SE  
    Global end of trial date
    07 May 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 Apr 2025
    First version publication date
    05 Apr 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    HOVON102AML/SAKK30/09
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    HOVON
    Sponsor organisation address
    Dr. Molewaterplein 40, Rotterdam, Netherlands,
    Public contact
    HOVON , HOVON, +31 107041560, hovon@erasmusmc.nl
    Scientific contact
    HOVON , HOVON, +31 107041560, hovon@erasmusmc.nl
    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
    01 Jan 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Oct 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    07 May 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    For part A of the study: ¨ To determine the feasibility of Clofarabine when given at three possible dose levels together with standard induction cycles I and II in patients with AML/ RAEB with IPSS>=1.5 in a prospective comparison to standard induction cycles I and II without Clofarabine. For part B of the study: ¨ To evaluate the effect of Clofarabine at the selected feasible dose level when combined with remission induction chemotherapy cycles I and II as regards clinical outcome (“event-free survival”) in comparison to remission induction cycles I and II with no addition of Clofarabine in a phase III study.
    Protection of trial subjects
    Monitoring and Insurance
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 Feb 2010
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Switzerland: 225
    Country: Number of subjects enrolled
    Netherlands: 483
    Country: Number of subjects enrolled
    Norway: 14
    Country: Number of subjects enrolled
    Sweden: 1
    Country: Number of subjects enrolled
    Belgium: 167
    Worldwide total number of subjects
    890
    EEA total number of subjects
    665
    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)
    831
    From 65 to 84 years
    59
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 All subjects gave written informed consent and were screened according to the inclusion- and exclusion criteria

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Control group
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Idarubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Infusion
    Dosage and administration details
    12 mg/m2 3 hr infusion Days 1, 2, 3

    Arm title
    		 Experimental 10 mg
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Clofarabine 10mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Infusion
    Dosage and administration details
    10 mg/m2, 1 hr infusion Days 1 thru 5

    Arm title
    		 Experimental 15 mg
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Clofarabine 15mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Infusion
    Dosage and administration details
    15 mg/m2, 1 hr infusion Days 1 thru 5

    Number of subjects in period 1
    		Control group Experimental 10 mg Experimental 15 mg
    Started
    445
    413
    32
    Completed
    313
    257
    15
    Not completed
    132
    156
    17
         Adverse events, all combined
    5
    28
    2
         Other
    35
    38
    2
         Unknown
    1
    3
    -
         Lack of efficacy
    91
    87
    13

    Baseline characteristics

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

    Reporting group values
    		 Overall period Total
    Number of subjects
    		 890 890
    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)
    		 890 890
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Gender categorical
    Units: Subjects
        Female
    		 387 387
        Male
    		 503 503

    End points

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    End points reporting groups
    Reporting group title
    Control group
    Reporting group description
    		 -

    Reporting group title
    Experimental 10 mg
    Reporting group description
    		 -

    Reporting group title
    Experimental 15 mg
    Reporting group description
    		 -

    Primary: Primary endpoint

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    End point title
    		 Primary endpoint [1]
    End point description
    End point type
    Primary
    End point timeframe
    See publication
    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: See HO102 statistical data section from publication 23-03-20217
    End point values
    		 Control group Experimental 10 mg Experimental 15 mg
    Number of subjects analysed
    445
    413
    32
    Units: Whole
    445
    413
    32
    Attachments
    		 Untitled (Filename: HO102_Statistical data section from publication_23-03-2017 (1).pdf)
    Untitled (Filename: HO102 List of reported non-Sae's (1).pdf)
    Untitled (Filename: HO102 List of reported SAE's (1).pdf)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All AEs of CTCAE grade 2 or higher, with the exception of alopecia, nausea/vomiting and progression of the disease under study, have to be reported on the Adverse Events CRF.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4
    Reporting groups
    Reporting group title
    Control group
    Reporting group description
    		 -

    Reporting group title
    Clofa 10mg
    Reporting group description
    		 -

    Reporting group title
    Clofa 15mg
    Reporting group description
    		 -

    Serious adverse events
    		 Control group Clofa 10mg Clofa 15mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    161 / 440 (36.59%)
    197 / 407 (48.40%)
    18 / 32 (56.25%)
         number of deaths (all causes)
    281
    243
    18
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma in lung
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diffuse large B-cell lymphoma
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteosarcoma
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Solitary fibrous tumour
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Acute vascular leak syndrome
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    1 / 440 (0.23%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hemorrhage
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hemorrhagic shock
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombolic event
         subjects affected / exposed
    2 / 440 (0.45%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Capillary leak
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Shock
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Reversal of colostomy right and jejunostomy left
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Constipation
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 440 (0.23%)
    4 / 407 (0.98%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fever
         subjects affected / exposed
    4 / 440 (0.91%)
    5 / 407 (1.23%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    2 / 4
    2 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fever (in the absence of neutropenia)
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fever eci
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fever no focus
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gall bladder necrosis
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mucositis
         subjects affected / exposed
    1 / 440 (0.23%)
    2 / 407 (0.49%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multi organ failure
         subjects affected / exposed
    2 / 440 (0.45%)
    1 / 407 (0.25%)
    2 / 32 (6.25%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    1 / 2
    0 / 1
    1 / 1
    Malaise
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SIRS
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fever (with cough)
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Allergic reaction
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cutaneous GvHD grade 3
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    GvHD
         subjects affected / exposed
    1 / 440 (0.23%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    ARDS
         subjects affected / exposed
    2 / 440 (0.45%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atelectasis right lung
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    6 / 440 (1.36%)
    1 / 407 (0.25%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
    Hemopthysis
         subjects affected / exposed
    1 / 440 (0.23%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Interstitial pneumonia
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    2 / 440 (0.45%)
    1 / 407 (0.25%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    7 / 440 (1.59%)
    4 / 407 (0.98%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    4 / 7
    3 / 4
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    2 / 2
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 440 (0.23%)
    2 / 407 (0.49%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    Respiratory insufficiency
         subjects affected / exposed
    6 / 440 (1.36%)
    19 / 407 (4.67%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    4 / 5
    16 / 19
    0 / 0
         deaths causally related to treatment / all
    2 / 2
    3 / 4
    0 / 0
    Bronchopulmonary hemorrhage
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung embolism
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary infiltrates
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Embolism with ARDS
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute dyspnoe due to pulmonary oedema
         subjects affected / exposed
    0 / 440 (0.00%)
    0 / 407 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute psychosis
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    C-difficile toxin intoxication
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    ECG QT time corrected prolonged
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    GGT elevated
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Low potassium
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prolonged QT time
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Increased liver values
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical procedure: biopsy vertebral body
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Weight loss
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    AST, ALT increased
         subjects affected / exposed
    0 / 440 (0.00%)
    0 / 407 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Elevated liverenzymes
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    GGT increased
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic rupture
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Neoral toxicity
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Splenic rupture
         subjects affected / exposed
    2 / 440 (0.45%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tacrolimus intoxication
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Drug toxicity
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip facture
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Prolonged aplasia
         subjects affected / exposed
    2 / 440 (0.45%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    2 / 440 (0.45%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial febrillation
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 440 (0.23%)
    2 / 407 (0.49%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Heart failure
         subjects affected / exposed
    3 / 440 (0.68%)
    4 / 407 (0.98%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    Left ventricular systolic dysfunction
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infection (non SCT elevated)
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocarditis
         subjects affected / exposed
    1 / 440 (0.23%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    1 / 440 (0.23%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Symptomatic bradycardia with possible circulation arrest
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tachycardic atrial fibrillation
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Torsade
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Asystole
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    0 / 440 (0.00%)
    2 / 407 (0.49%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardial ischemia
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiomyopathie
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrhythmia grade 4
         subjects affected / exposed
    0 / 440 (0.00%)
    0 / 407 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Ataxia
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CVA
         subjects affected / exposed
    1 / 440 (0.23%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Carbonarcosis
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Cognitive disturbance
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    1 / 440 (0.23%)
    2 / 407 (0.49%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epilepsy crisis
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Plexitis right thigh
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stroke
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    CNS hemorrhage
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral bleeding
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Cerebral edema
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Cerebral hemorrhage
         subjects affected / exposed
    0 / 440 (0.00%)
    2 / 407 (0.49%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Dysarthria
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epileptic insult
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Intercranial hemorrhage
         subjects affected / exposed
    4 / 440 (0.91%)
    3 / 407 (0.74%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    3 / 4
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    Neurologic toxicity
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral motor neuropathy
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Encehalopathy
         subjects affected / exposed
    0 / 440 (0.00%)
    0 / 407 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Bone marrow hypocellular
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 440 (0.23%)
    3 / 407 (0.74%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fever in aplasia
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenic fever
         subjects affected / exposed
    2 / 440 (0.45%)
    2 / 407 (0.49%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Thrombopenia
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Agranulocytosis
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    3 / 440 (0.68%)
    0 / 407 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 440 (0.00%)
    0 / 407 (0.00%)
    2 / 32 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Monocular diplopia
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    3 / 440 (0.68%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Colonic perforation
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhea
         subjects affected / exposed
    2 / 440 (0.45%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Digestive hemorrhage
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 440 (0.23%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    1 / 440 (0.23%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Gastric hemorrhage
         subjects affected / exposed
    1 / 440 (0.23%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Gastric perforation
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    3 / 440 (0.68%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
    Ileus grade 4
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenic colitis
         subjects affected / exposed
    2 / 440 (0.45%)
    1 / 407 (0.25%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    Neutropenic enterocolitis
         subjects affected / exposed
    1 / 440 (0.23%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Obstipation
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Esophagal hemorrhage
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastro intestinal disorders
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Jejunal hemorrhage
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mallory Weiss syndrome
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Paralytic Ileus
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Typhlitis
         subjects affected / exposed
    0 / 440 (0.00%)
    4 / 407 (0.98%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    3 / 440 (0.68%)
    2 / 407 (0.49%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Toxic hepatic cytolysis
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gall bladder inflammation
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepathotoxicity
         subjects affected / exposed
    0 / 440 (0.00%)
    2 / 407 (0.49%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Hepactic toxicity
         subjects affected / exposed
    0 / 440 (0.00%)
    2 / 407 (0.49%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyper bilirubinemia
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Liver dysfunction
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Intestinal obstruction
         subjects affected / exposed
    1 / 440 (0.23%)
    1 / 407 (0.25%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bullous dermatitis
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Erythroderma
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Leucocytoclastic vasculitis
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Palmar erythema
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    0 / 440 (0.00%)
    2 / 407 (0.49%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin toxicity
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Acute renal insufficiency
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Kidney insufficiency
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hematuria
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 440 (0.00%)
    0 / 407 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    SIADH
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Fasciitis
         subjects affected / exposed
    1 / 440 (0.23%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CPK increased
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Osteonecrosis of jaw
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    (Aspergilosis) pulmonary infection
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
    Spondylodiscitis
         subjects affected / exposed
    1 / 440 (0.23%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspergilloma
         subjects affected / exposed
    1 / 440 (0.23%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspergillosis
         subjects affected / exposed
    1 / 440 (0.23%)
    3 / 407 (0.74%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspiration pneumonia
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bilateral pneumonia
         subjects affected / exposed
    1 / 440 (0.23%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchial infection
         subjects affected / exposed
    2 / 440 (0.45%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Candida sepsis
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Catheter related infection
         subjects affected / exposed
    3 / 440 (0.68%)
    2 / 407 (0.49%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    E-coli - sepsis
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Gastro -enteritis
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infection Tyflitt
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infection billiary tract
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Infection upper way
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myositis
         subjects affected / exposed
    1 / 440 (0.23%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    10 / 440 (2.27%)
    2 / 407 (0.49%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    9 / 10
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    2 / 3
    0 / 0
    0 / 0
    Lung infection (abscess)
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mediastinal infection
         subjects affected / exposed
    1 / 440 (0.23%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Necrotizing fascilitis
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Neutropenic streptococcus sepsis
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumocystis carinii - pneumonia
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    9 / 440 (2.05%)
    11 / 407 (2.70%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    9 / 9
    11 / 12
    1 / 1
         deaths causally related to treatment / all
    5 / 5
    6 / 6
    0 / 0
    Pneumosepsis (coli +)
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Pulmonary infection
         subjects affected / exposed
    1 / 440 (0.23%)
    2 / 407 (0.49%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Pulmonary invasive aspergillosis
         subjects affected / exposed
    1 / 440 (0.23%)
    2 / 407 (0.49%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Sepsis
         subjects affected / exposed
    22 / 440 (5.00%)
    30 / 407 (7.37%)
    2 / 32 (6.25%)
         occurrences causally related to treatment / all
    18 / 24
    29 / 33
    3 / 3
         deaths causally related to treatment / all
    7 / 10
    10 / 12
    1 / 1
    Sepsis (septic pneumonia)
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis E-coli ESBL
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    4 / 440 (0.91%)
    10 / 407 (2.46%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    2 / 4
    6 / 10
    0 / 0
         deaths causally related to treatment / all
    1 / 2
    4 / 4
    0 / 0
    Septicemia
         subjects affected / exposed
    1 / 440 (0.23%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinusitis maxillaris both sides
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Adeno viremia
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Bacteremia
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Candidemia
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral aspergillosis
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    EBV reactivation
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Invasive infection cerebral
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meningo encephalitis
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Mucormycosis
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Mucosal infection
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CMV reactivation
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Para influenza type 3
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary fungal infection
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Soft tissue infection both tighs
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subacute cutaneous abcess
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Suspicion of pulmonary aspergillosis
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Zona
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Zygomycetes infection
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Iatrogenic pneumothorax
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Electrocardiogram QT interval prolonged
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 440 (0.00%)
    0 / 407 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infection other-blood
         subjects affected / exposed
    0 / 440 (0.00%)
    0 / 407 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Metabolism and nutrition disorders
    Diabetic ketoacidosis
         subjects affected / exposed
    1 / 440 (0.23%)
    0 / 407 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 440 (0.23%)
    2 / 407 (0.49%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anorexia
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tumor lysis syndrome
         subjects affected / exposed
    0 / 440 (0.00%)
    1 / 407 (0.25%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Control group Clofa 10mg Clofa 15mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    435 / 440 (98.86%)
    403 / 407 (99.02%)
    31 / 32 (96.88%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasms benign, malignant and unspecified
    Additional description: All combined
         subjects affected / exposed
    4 / 440 (0.91%)
    6 / 407 (1.47%)
    0 / 32 (0.00%)
         occurrences all number
    4
    7
    0
    Vascular disorders
    Vascular disorders
    Additional description: All combined
         subjects affected / exposed
    111 / 440 (25.23%)
    111 / 407 (27.27%)
    7 / 32 (21.88%)
         occurrences all number
    145
    170
    9
    Surgical and medical procedures
    Surgical and medical procedures
    Additional description: All combined
         subjects affected / exposed
    3 / 440 (0.68%)
    4 / 407 (0.98%)
    1 / 32 (3.13%)
         occurrences all number
    4
    4
    1
    General disorders and administration site conditions
    General disorders and administration site conditions
    Additional description: All combined
         subjects affected / exposed
    154 / 440 (35.00%)
    156 / 407 (38.33%)
    9 / 32 (28.13%)
         occurrences all number
    268
    296
    17
    Immune system disorders
    Immune system disorders
    Additional description: All combined
         subjects affected / exposed
    32 / 440 (7.27%)
    42 / 407 (10.32%)
    2 / 32 (6.25%)
         occurrences all number
    38
    58
    2
    Reproductive system and breast disorders
    Reproductive system and breast disorders
    Additional description: All combined
         subjects affected / exposed
    20 / 440 (4.55%)
    15 / 407 (3.69%)
    2 / 32 (6.25%)
         occurrences all number
    25
    17
    2
    Respiratory, thoracic and mediastinal disorders
    Respiratory, thoracic and mediastinal disorders
    Additional description: All combined
         subjects affected / exposed
    136 / 440 (30.91%)
    141 / 407 (34.64%)
    8 / 32 (25.00%)
         occurrences all number
    203
    243
    18
    Psychiatric disorders
    Psychiatric disorders
    Additional description: All combined
         subjects affected / exposed
    57 / 440 (12.95%)
    80 / 407 (19.66%)
    3 / 32 (9.38%)
         occurrences all number
    74
    111
    4
    Investigations
    Investigations
    Additional description: All combined
         subjects affected / exposed
    178 / 440 (40.45%)
    203 / 407 (49.88%)
    16 / 32 (50.00%)
         occurrences all number
    607
    786
    45
    Injury, poisoning and procedural complications
    Injury, poisoning and procedural complications
    Additional description: All combined
         subjects affected / exposed
    16 / 440 (3.64%)
    11 / 407 (2.70%)
    2 / 32 (6.25%)
         occurrences all number
    19
    12
    5
    Congenital, familial and genetic disorders
    Congenital, familial and genetic disorders
    Additional description: All combined
         subjects affected / exposed
    1 / 440 (0.23%)
    2 / 407 (0.49%)
    0 / 32 (0.00%)
         occurrences all number
    1
    2
    0
    Cardiac disorders
    Cardiac disorders
    Additional description: All combined
         subjects affected / exposed
    60 / 440 (13.64%)
    71 / 407 (17.44%)
    7 / 32 (21.88%)
         occurrences all number
    70
    91
    10
    Nervous system disorders
    Nervous system disorders
    Additional description: All combined
         subjects affected / exposed
    93 / 440 (21.14%)
    98 / 407 (24.08%)
    3 / 32 (9.38%)
         occurrences all number
    126
    150
    3
    Blood and lymphatic system disorders
    Blood and lymphatic system disorders
    Additional description: All combined
         subjects affected / exposed
    318 / 440 (72.27%)
    276 / 407 (67.81%)
    20 / 32 (62.50%)
         occurrences all number
    721
    704
    42
    Ear and labyrinth disorders
    Ear and labyrinth disorders
    Additional description: All combined
         subjects affected / exposed
    8 / 440 (1.82%)
    12 / 407 (2.95%)
    0 / 32 (0.00%)
         occurrences all number
    8
    13
    0
    Eye disorders
    Eye disorders
    Additional description: All combined
         subjects affected / exposed
    60 / 440 (13.64%)
    56 / 407 (13.76%)
    3 / 32 (9.38%)
         occurrences all number
    62
    61
    3
    Gastrointestinal disorders
    Gastrointestinal disorders
    Additional description: All combined
         subjects affected / exposed
    357 / 440 (81.14%)
    338 / 407 (83.05%)
    25 / 32 (78.13%)
         occurrences all number
    945
    990
    55
    Hepatobiliary disorders
    Hepatobiliary disorders
    Additional description: All combined
         subjects affected / exposed
    30 / 440 (6.82%)
    28 / 407 (6.88%)
    1 / 32 (3.13%)
         occurrences all number
    36
    31
    1
    Skin and subcutaneous tissue disorders
    Skin and subcutaneous tissue disorders
    Additional description: All combined
         subjects affected / exposed
    280 / 440 (63.64%)
    268 / 407 (65.85%)
    22 / 32 (68.75%)
         occurrences all number
    461
    521
    52
    Renal and urinary disorders
    Renal and urinary disorders
    Additional description: All combined
         subjects affected / exposed
    52 / 440 (11.82%)
    64 / 407 (15.72%)
    2 / 32 (6.25%)
         occurrences all number
    60
    78
    2
    Endocrine disorders
    Endocrine disorders
    Additional description: All combined
         subjects affected / exposed
    4 / 440 (0.91%)
    4 / 407 (0.98%)
    1 / 32 (3.13%)
         occurrences all number
    4
    4
    1
    Musculoskeletal and connective tissue disorders
    Musculoskeletal and connective tissue dis
    Additional description: All combined
         subjects affected / exposed
    55 / 440 (12.50%)
    56 / 407 (13.76%)
    2 / 32 (6.25%)
         occurrences all number
    67
    78
    2
    Infections and infestations
    Infections and infestations
    Additional description: All combined
         subjects affected / exposed
    326 / 440 (74.09%)
    303 / 407 (74.45%)
    22 / 32 (68.75%)
         occurrences all number
    778
    812
    58
    Metabolism and nutrition disorders
    Metabolism and nutrition disorders
    Additional description: All combined
         subjects affected / exposed
    187 / 440 (42.50%)
    210 / 407 (51.60%)
    11 / 32 (34.38%)
         occurrences all number
    536
    701
    31

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Jan 2010
    Addition of Maxima MC as participating site
    09 Mar 2010
    Addition of Reinier de Graaf Gasthuis as participating site
    27 Apr 2010
    Addition of GZA hospitals as participating site
    14 Sep 2010
    Changes in protocol (statistician, number of patients part A)

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/34953042
    For support, Contact us.
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