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    Clinical Trial Results:
    Prospective, Open-label, Comparative, Multicenter Study of Voriconazole Compared to Itraconazole for the Primary Prophylaxis of Invasive Fungal Infections (IFI) in Subjects with Allogeneic Hematopoietic Stem Cell Transplants (HSCT)

    Summary
    EudraCT number
    		 2005-002800-40
    Trial protocol
    		 GB   CZ   ES   PT   GR  
    Global end of trial date
    10 Feb 2009

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 May 2016
    First version publication date
    25 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    A1501073
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00289991
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pfizer Inc.
    Sponsor organisation address
    235 E 42nd Street, New York, United States, NY 10017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc. , 001 800-718-1021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc. , 001 800-718-1021, ClinicalTrials.gov_Inquiries@pfizer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    16 Sep 2011
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Feb 2009
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to compare the “Success” of antifungal prophylaxis with voriconazole versus itraconazole at 180 days post transplant. Success was measured using a composite endpoint of: survival to Day 180 with no breakthrough invasive fungal infection and no discontinuation of study drug for more than 14 days during the 100-day prophylaxis period.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    08 Mar 2006
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 12 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Portugal: 26
    Country: Number of subjects enrolled
    Spain: 107
    Country: Number of subjects enrolled
    United Kingdom: 115
    Country: Number of subjects enrolled
    Czech Republic: 27
    Country: Number of subjects enrolled
    France: 88
    Country: Number of subjects enrolled
    Greece: 14
    Country: Number of subjects enrolled
    Jordan: 1
    Country: Number of subjects enrolled
    Egypt: 18
    Country: Number of subjects enrolled
    Canada: 61
    Country: Number of subjects enrolled
    Switzerland: 21
    Country: Number of subjects enrolled
    Russian Federation: 6
    Country: Number of subjects enrolled
    Turkey: 5
    Worldwide total number of subjects
    489
    EEA total number of subjects
    377
    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)
    20
    Adults (18-64 years)
    444
    From 65 to 84 years
    25
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Subjects were stratified at the time of randomization by the following factors: conditioning regimen (myeloablative or non-myeloablative); relatedness of donor (matched/related or mismatched/unrelated).

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Voriconazole
    Arm description
    		 Voriconazole loading dose regimen for first 24 hours and maintenance dose after first 24 hours.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Voriconazole IV
    Investigational medicinal product code
    Other name
    VFEND
    Pharmaceutical forms
    Tablet, Powder for oral suspension
    Routes of administration
    Intravenous use
    Dosage and administration details
    Voriconazole (tablet or powder for oral suspension) loading dose regimen intravenous (IV) for first 24 hours: 6 milligrams per kilogram (mg/kg) of body weight every 12 hours; maintenance dose (after first 24 hours) 4 mg/kg of body weight IV twice daily (BID).

    Investigational medicinal product name
    Voriconazole Oral
    Investigational medicinal product code
    Other name
    VFEND
    Pharmaceutical forms
    Powder for oral solution, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Voriconazole 200 mg tablet or powder for oral suspension by mouth (PO) BID (subjects greater than or equal to [≥] 40 kg body weight) or 100 mg tablet or powder for oral suspension twice daily (subjects less than [<] 40 kg body weight).

    Arm title
    		 Itraconazole
    Arm description
    		 Itraconazole (Sporanox™ Liquid) loading dose on Days 0 and 1.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Itraconazole Oral
    Investigational medicinal product code
    Other name
    Sporanox
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Itraconazole (Sporanox™ Liquid) oral solution 200 mg PO BID.

    Investigational medicinal product name
    Itraconazole IV
    Investigational medicinal product code
    Other name
    Sporanox
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Itraconazole (Sporanox™ Liquid) 200 mg BID as loading dose on Days 0 and 1 then 200 mg once daily.

    Number of subjects in period 1
    		Voriconazole Itraconazole
    Started
    234
    255
    Completed
    176
    175
    Not completed
    58
    80
         'Failure of prophylaxis '
    1
    1
         Consent withdrawn by subject
    2
    12
         Adverse Event
    15
    13
         Death
    35
    38
         Unspecified
    5
    14
         Lost to follow-up
    -
    1
         'Fungal breakthrough infection '
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Voriconazole
    Reporting group description
    		 Voriconazole loading dose regimen for first 24 hours and maintenance dose after first 24 hours.

    Reporting group title
    Itraconazole
    Reporting group description
    		 Itraconazole (Sporanox™ Liquid) loading dose on Days 0 and 1.

    Reporting group values
    		 Voriconazole Itraconazole Total
    Number of subjects
    		 234 255 489
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 43.3 ( 14.4 ) 42.7 ( 14.6 ) -
    Gender categorical
    Units: Subjects
        Female
    		 96 100 196
        Male
    		 138 155 293

    End points

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    End points reporting groups
    Reporting group title
    Voriconazole
    Reporting group description
    		 Voriconazole loading dose regimen for first 24 hours and maintenance dose after first 24 hours.

    Reporting group title
    Itraconazole
    Reporting group description
    		 Itraconazole (Sporanox™ Liquid) loading dose on Days 0 and 1.

    Primary: Success at Day 180: Percent of Responders (Randomization Strata)

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    End point title
    		 Success at Day 180: Percent of Responders (Randomization Strata)
    End point description
    Percent of responders (by randomization strata) with success of antifungal prophylaxis at 180 days after allogeneic HSCT. Success: alive at Day 180 (Visit 9), had not developed a breakthrough proven or probable IFI by Visit 9, and received full course of study drug prophylaxis without interruption of greater than 14 days in total during the prophylaxis period; defined as failure if these criteria were not met. Additionally, if subject withdrew from study completely before Visit 9, imputed as failure at Visit 9 (programmatically). Modified Intent to Treat (MITT): primary analysis population; all randomized subjects received at least 1 dose of randomized study drug and had allogeneic HSCT; data from 1 site excluded due to Good Clinical Practice (GCP) deviations, (n)=number of subjects with analyzable data at observation for voriconazole and itraconazole, respectively.
    End point type
    Primary
    End point timeframe
    Day 180 (Visit 9)
    End point values
    		 Voriconazole Itraconazole
    Number of subjects analysed
    224
    241
    Units: percent of subjects
    number (not applicable)
        Myeloablative/matched related (n=66, 85)
    59.1
    44.7
        Myeloablative/mismatched unrelated (n=59, 58)
    52.5
    25.9
        Non-myeloablative/matched related (n=58, 57)
    34.5
    28.1
        Non-myeloablative/mismatched unrelated (n=41, 41)
    46.3
    26.8
    Statistical analysis title
    		 Success at Day 180: Percent of Responders
    Statistical analysis description
    Non-inferiority inferred if lower limit of 2-sided 95 percent (%) confidence interval (CI) for difference between treatment groups in proportion of subjects classified as "Success" at Day 180 after transplant is above -10%. If testing for non-inferiority was successful, then an assessment of superiority of voriconazole over itraconazole was carried out. Overall treatment difference adjusted randomization strata calculated using Fleiss method. 
    Comparison groups
    Voriconazole v Itraconazole
    Number of subjects included in analysis
    465
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    Parameter type
    		 Difference in adjusted responder rates
    Point estimate
    16.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 7.7
         upper limit
    		 25.1
    Notes
    [1] - Assuming a true success rate of 50% in voriconazole (Vori) treatment (Tx) group and 45% in itraconazole (Itra) Tx group, sample size of 232 subjects per group=90% power to demonstrate non-inferiority of Vori to Itra using pre-specified non-inferiority margin of -10%. Sample has at least 80% power to demonstrate superiority of Vori over Itra if true success rates for Vori and Itra are 57% and 44% respectively. Based on this, up to 500 subjects were to be enrolled to obtain 464 eligible subjects.

    Secondary: Success at Day 100: Percent of Responders (Randomization Strata)

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    End point title
    		 Success at Day 100: Percent of Responders (Randomization Strata)
    End point description
    Percent of responders (by randomization strata) with success of antifungal prophylaxis at 100 days after allogeneic HSCT. Success defined as: alive at Day 100 (Visit 7), had not developed a breakthrough proven or probable IFI by Visit 7, and received full course of study drug prophylaxis without an interruption of >14 days in total during the prophylaxis period; defined as failure if these criteria were not met. Additionally, if subject withdrew from study completely before Visit 7, imputed as failure at Visit 7 (programmatically). MITT, data from 1 site excluded due to GCP deviations, (n)=number of subjects with analyzable data at observation for voriconazole and itraconazole, respectively.
    End point type
    Secondary
    End point timeframe
    Day 100 (Visit 7)
    End point values
    		 Voriconazole Itraconazole
    Number of subjects analysed
    224
    241
    Units: percent of subjects
    number (not applicable)
        Myeloablative/matched related (n=66, 85)
    65.2
    50.6
        Myeloablative/mismatched unrelated (n=59, 58)
    55.9
    27.6
        Non-myeloablative/matched related (n=58, 57)
    43.1
    38.6
        Non-myeloablative/mismatched unrelated (n=41, 41)
    48.8
    36.6
    Statistical analysis title
    		 Success at Day 100: Percent of Responders
    Statistical analysis description
    Non-inferiority inferred if lower limit of 2-sided 95 percent (%) confidence interval (CI) for difference between treatment groups in proportion of subjects classified as "Success" at Day 100 after transplant is above -10%. If testing for non-inferiority was successful, then an assessment of superiority of voriconazole over itraconazole was carried out. Overall treatment difference adjusted randomization strata calculated using Fleiss method. 
    Comparison groups
    Voriconazole v Itraconazole
    Number of subjects included in analysis
    465
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Difference in adjusted responder rates
    Point estimate
    15.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 6.6
         upper limit
    		 24.2

    Secondary: Time to Breakthrough Invasive Fungal Infection (IFI)

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    End point title
    		 Time to Breakthrough Invasive Fungal Infection (IFI)
    End point description
    Summary of time (in days) from start of prophylaxis to first recorded occurrence of breakthrough proven or probable IFI. MITT, data from 1 site excluded due to GCP deviations. Analysis excludes additional data on IFIs that were only captured on European Organization for Research and Treatment of Cancer or Mycoses Study Group (EORTC or MSG) worksheets (not on Case Report Forms or in the database). Times were summarized only for subjects who experienced a breakthrough IFI.
    End point type
    Secondary
    End point timeframe
    Day 1 up to Day 180 (Visit 9)
    End point values
    		 Voriconazole Itraconazole
    Number of subjects analysed
    3
    4
    Units: days
        arithmetic mean (confidence interval 95%)
    119 (48 to 190)
    77 (0 to 199.6)
    No statistical analyses for this end point

    Secondary: Percent of Subjects With Occurrence of Breakthrough IFI

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    End point title
    		 Percent of Subjects With Occurrence of Breakthrough IFI
    End point description
    Percent of subjects with occurrence of breakthrough IFI (proven or probable). Included all subjects in the MITT population. MITT, data from 1 site excluded due to GCP deviations. Analysis excludes additional data on IFIs that were only captured on EORTC or MSG worksheets (not on Case Report Forms or in the database).
    End point type
    Secondary
    End point timeframe
    Day 1 up to Day 100 (Visit 7) and Day 180 (Visit 9)
    End point values
    		 Voriconazole Itraconazole
    Number of subjects analysed
    224
    241
    Units: percent of subjects
    number (not applicable)
        Day 100
    0.9
    1.2
        Day 180
    1.3
    1.7
    Statistical analysis title
    		 Statistical Analysis for Day 100
    Statistical analysis description
    Statistical analysis for percent of subjects with occurrence of breakthrough IFI for Day 100; difference in proportions (expressed as percentages) of voriconazole relative to itraconazole was analyzed. Difference in proportions (approximate result) was calculated.
    Comparison groups
    Voriconazole v Itraconazole
    Number of subjects included in analysis
    465
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.7114 [2]
    Method
    		 difference in proportions
    Parameter type
    		 difference in proportions: percent
    Point estimate
    -0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.2
         upper limit
    		 1.5
    Notes
    [2] - The p-value was used to test the null hypothesis of no difference between the proportions.
    Statistical analysis title
    		 Statistical Analysis for Day 180
    Statistical analysis description
    Statistical analysis for percent of subjects with occurrence of breakthrough IFI for Day 180; difference in proportions (expressed as percentages) of voriconazole relative to itraconazole was analyzed. Difference in proportions (approximate result) was calculated.
    Comparison groups
    Voriconazole v Itraconazole
    Number of subjects included in analysis
    465
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.7759 [3]
    Method
    		 difference in proportions
    Parameter type
    		 difference in proportions: percent
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.5
         upper limit
    		 1.9
    Notes
    [3] - The p-value was used to test the null hypothesis of no difference between the proportions.

    Secondary: Survival: Percent of Subjects Who Died at or Before Day 180

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    End point title
    		 Survival: Percent of Subjects Who Died at or Before Day 180
    End point description
    Percent of subjects who died at or before Day 180, derived from the crude death rate. All subjects in the MITT population included in this proportion. MITT, data from 1 site excluded due to GCP deviations. Analysis does not include any deaths recorded in the long-term follow-up data (not available at time of analysis).
    End point type
    Secondary
    End point timeframe
    Day 1 up to Day 180 (Visit 9)
    End point values
    		 Voriconazole Itraconazole
    Number of subjects analysed
    224
    241
    Units: percent of subjects
        number (not applicable)
    17.85
    18.25
    Statistical analysis title
    		 Statistical Analysis on Day 180
    Statistical analysis description
    Difference in proportions (expressed as a percentage) of voriconazole relative to itraconazole (approximate result) was calculated.
    Comparison groups
    Voriconazole v Itraconazole
    Number of subjects included in analysis
    465
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 Logistic regression (logit model)
    Parameter type
    		 difference in proportions: percent
    Point estimate
    0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.3
         upper limit
    		 6.9

    Secondary: Time to Discontinuation of Study Treatment

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    End point title
    		 Time to Discontinuation of Study Treatment
    End point description
    Time in days to discontinuation of study treatment defined as the number of days from first dose to last dose inclusive as recorded in the dosing log. MITT, data from 1 site excluded due to GCP deviations.
    End point type
    Secondary
    End point timeframe
    Day 1 up to Day 180 (Visit 9)
    End point values
    		 Voriconazole Itraconazole
    Number of subjects analysed
    224
    241
    Units: days
        arithmetic mean (confidence interval 95%)
    88.7 (80.6 to 96.8)
    71.5 (64.9 to 78.2)
    Statistical analysis title
    		 Statistical Analysis on Day 180
    Statistical analysis description
    Mann-Whitney test used to investigate the null hypothesis that the times to discontinuation of study medication in each treatment group come from the same distribution.
    Comparison groups
    Voriconazole v Itraconazole
    Number of subjects included in analysis
    465
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0026
    Method
    		 Non-parametric Mann-Whitney Test
    Confidence interval

    Secondary: Survival: Percent of Subjects Who Died Within 1 Year

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    End point title
    		 Survival: Percent of Subjects Who Died Within 1 Year
    End point description
    Percent of subjects who died within 1 year after transplant, derived from the crude death rate. All subjects in the MITT population included in this proportion. Only deaths up until and including 365 days after first dose of study medication included in the analysis. MITT, data from 1 site excluded due to GCP deviations. Typically, subjects received first dose study treatment on the day of their transplant; however, some subjects started treatment up to 48 hours after transplant. Data summarized with first day of study medication defined as Day 1.
    End point type
    Secondary
    End point timeframe
    Day 1 up to 1 year (Day 365)
    End point values
    		 Voriconazole Itraconazole
    Number of subjects analysed
    224
    241
    Units: percent of subjects
        number (not applicable)
    25.9
    31.1
    Statistical analysis title
    		 Statistical Analysis on Day 365
    Statistical analysis description
    On Day 365, difference in proportions (expressed as a percentage), voriconazole relative to itraconazole (approximate result) was calculated.
    Comparison groups
    Voriconazole v Itraconazole
    Number of subjects included in analysis
    465
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.2487 [4]
    Method
    		 Logistic regression (logit model)
    Parameter type
    		 difference in proportions
    Point estimate
    -4.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13
         upper limit
    		 3.4
    Notes
    [4] - The p-value was used to test the null hypothesis of no difference between the proportions.

    Secondary: Duration of Treatment

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    End point title
    		 Duration of Treatment
    End point description
    Median duration in days of treatment. Treatment is defined as the total number of days on which subjects took medication. MITT, data from 1 site excluded due to GCP deviations.
    End point type
    Secondary
    End point timeframe
    Day 1 up to Day 180
    End point values
    		 Voriconazole Itraconazole
    Number of subjects analysed
    224
    241
    Units: days
        median (full range (min-max))
    96 (1 to 258)
    68 (3 to 223)
    No statistical analyses for this end point

    Secondary: Percent of Subjects With Use of Other Systemic Antifungal Agents as Empirical or Therapeutic Treatment

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    End point title
    		 Percent of Subjects With Use of Other Systemic Antifungal Agents as Empirical or Therapeutic Treatment
    End point description
    Percent of subjects who used other systemic antifungal agents as empirical or therapeutic treatment, defined as either empirical: subject took a systemic antifungal agent at any time after the day of first dose of medication and did not develop a breakthrough proven or probable IFI during the study or therapeutic: subject developed a breakthrough proven or probable IFI. MITT, data from 1 site excluded due to GCP deviations. Subjects who developed a breakthrough proven or probable IFI were identified only from the study database, not the EORTC or MSG worksheet. In addition, all agents identified to be antifungals were considered to be systemic.
    End point type
    Secondary
    End point timeframe
    Day 1 up to Day 180
    End point values
    		 Voriconazole Itraconazole
    Number of subjects analysed
    224
    241
    Units: percent of subjects
        number (not applicable)
    40.6
    49.4
    Statistical analysis title
    		 Use of Other Systemic Antifungal Agents
    Statistical analysis description
    Statistical Analysis for percent of subjects with use of other systemic antifungal agents as empirical or therapeutic treatment. Difference in proportions (expressed as a percentage), voriconazole relative to itraconazole.
    Comparison groups
    Voriconazole v Itraconazole
    Number of subjects included in analysis
    465
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.057 [5]
    Method
    		 Difference in proportions
    Parameter type
    		 Difference in proportions: percent
    Point estimate
    -8.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -17.8
         upper limit
    		 0.3
    Notes
    [5] - The p-value was used to test the null hypothesis of no difference between the proportions.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline upto 7 days after last dose of investigational product
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Itraconazole
    Reporting group description
    		 Itraconazole (Sporanox™ Liquid) oral solution 200 mg PO BID. Loading dose as IV formulation on Days 0 and 1.

    Reporting group title
    Voriconazole
    Reporting group description
    		 Voriconazole (tablet or powder for oral suspension) loading dose regimen IV for first 24 hours: 6 mg/kg of body weight every 12 hours; maintenance dose (after first 24 hours) 4 mg/kg of body weight (IV) BID or 200 mg tablet or powder for oral suspension PO BID (subjects ≥40 kg body weight) or 100 mg tablet or powder for oral suspension twice daily (subjects < 40 kg body weight).

    Serious adverse events
    		 Itraconazole Voriconazole
    Total subjects affected by serious adverse events
         subjects affected / exposed
    95 / 255 (37.25%)
    111 / 234 (47.44%)
         number of deaths (all causes)
    47
    40
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lymphoma
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myelodysplastic syndrome
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Plasma cell myeloma
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute leukaemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myeloid leukaemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Acute myeloid leukaemia recurrent
    alternative assessment type: Non-systematic
         subjects affected / exposed
    4 / 255 (1.57%)
    2 / 234 (0.85%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Non-Hodgkin's lymphoma
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    2 / 234 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Leukaemia recurrent
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 255 (1.18%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Leukaemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Disseminated large cell lymphoma
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Vascular disorders
    Hypotension
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jugular vein thrombosis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Extremity necrosis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vena cava thrombosis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subclavian vein thrombosis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Subdural haematoma evacuation
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Drug intolerance
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chills
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperthermia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 255 (0.78%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug withdrawal syndrome
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multi-organ failure
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 255 (1.18%)
    3 / 234 (1.28%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 3
    0 / 3
    Disease progression
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Pyrexia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    11 / 255 (4.31%)
    19 / 234 (8.12%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 21
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Performance status decreased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 255 (0.78%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Acute graft versus host disease in intestine
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 255 (0.78%)
    3 / 234 (1.28%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Graft versus host disease
    alternative assessment type: Non-systematic
         subjects affected / exposed
    8 / 255 (3.14%)
    7 / 234 (2.99%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone marrow transplant rejection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute graft versus host disease in liver
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic graft versus host disease
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 255 (1.18%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transplant rejection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Graft versus host disease in skin
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    2 / 234 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Graft versus host disease in liver
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    4 / 234 (1.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Graft versus host disease in gastrointestinal tract
    alternative assessment type: Non-systematic
         subjects affected / exposed
    4 / 255 (1.57%)
    3 / 234 (1.28%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Acute graft versus host disease
    alternative assessment type: Non-systematic
         subjects affected / exposed
    7 / 255 (2.75%)
    2 / 234 (0.85%)
         occurrences causally related to treatment / all
    1 / 7
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    2 / 234 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchospasm
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute pulmonary oedema
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    2 / 234 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute lung injury
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung disorder
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 255 (1.18%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infiltration
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obliterative bronchiolitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Organising pneumonia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory disorder
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory arrest
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 255 (0.78%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
    alternative assessment type: Non-systematic
         subjects affected / exposed
    5 / 255 (1.96%)
    2 / 234 (0.85%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Psychiatric disorders
    Confusional state
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 255 (0.78%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hallucination, visual
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    2 / 234 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 255 (1.18%)
    2 / 234 (0.85%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 255 (0.78%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood alkaline phosphatase increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood bilirubin increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus test
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gram stain positive
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrocardiogram QT prolonged
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Serum ferritin increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory syncytial virus test positive
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test abnormal
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    4 / 234 (1.71%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoglobin decreased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematocrit decreased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus test positive
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 255 (1.18%)
    4 / 234 (1.71%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight decreased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    2 / 234 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Lumbar vertebral fracture
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transplant failure
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    2 / 234 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiopulmonary failure
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Tachycardia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cognitive disorder
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Convulsion
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    2 / 234 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lethargy
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukoencephalopathy
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parkinsonism
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningorrhagia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Monoplegia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropathy peripheral
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss of consciousness
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 255 (0.78%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nervous system disorder
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Blood and lymphatic system disorders
    Anaemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone marrow failure
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemolysis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune thrombocytopenic purpura
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    4 / 255 (1.57%)
    2 / 234 (0.85%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 255 (0.78%)
    3 / 234 (1.28%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Optic ischaemic neuropathy
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Photopsia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vision blurred
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 255 (0.78%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal tenderness
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 255 (0.78%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    6 / 255 (2.35%)
    2 / 234 (0.85%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retching
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    9 / 255 (3.53%)
    8 / 234 (3.42%)
         occurrences causally related to treatment / all
    2 / 9
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysbacteriosis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
    alternative assessment type: Non-systematic
         subjects affected / exposed
    7 / 255 (2.75%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    3 / 8
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Biliary colic
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    2 / 234 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic hepatitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic function abnormal
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    2 / 234 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis toxic
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatotoxicity
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    4 / 234 (1.71%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatorenal syndrome
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatocellular injury
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperbilirubinaemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    2 / 234 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venoocclusive liver disease
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    2 / 234 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis bullous
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dry skin
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 255 (0.78%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Dysuria
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis haemorrhagic
    alternative assessment type: Non-systematic
         subjects affected / exposed
    6 / 255 (2.35%)
    3 / 234 (1.28%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 255 (0.78%)
    2 / 234 (0.85%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure acute
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    3 / 234 (1.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 255 (0.78%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle twitching
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthralgia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myopathy
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhabdomyolysis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Aspergillus infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BK virus infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchiolitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 255 (0.78%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus gastrointestinal infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 255 (0.78%)
    3 / 234 (1.28%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 255 (0.78%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia sepsis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fungal infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Human herpesvirus 6 infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    11 / 255 (4.31%)
    9 / 234 (3.85%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus viraemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomonal sepsis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomonal bacteraemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 255 (0.78%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral herpes
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metapneumovirus infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningoencephalitis herpetic
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella sepsis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stenotrophomonas infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 255 (0.78%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory syncytial virus infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 255 (0.78%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomonas infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Bacteraemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Neutropenic sepsis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 255 (1.18%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Sepsis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    4 / 255 (1.57%)
    3 / 234 (1.28%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia pseudomonal
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    4 / 255 (1.57%)
    4 / 234 (1.71%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Septic shock
    alternative assessment type: Non-systematic
         subjects affected / exposed
    4 / 255 (1.57%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Metabolism and nutrition disorders
    Diabetic ketoacidosis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decreased appetite
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 255 (0.78%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fluid retention
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperferritinaemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic acidosis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Itraconazole Voriconazole
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    252 / 255 (98.82%)
    228 / 234 (97.44%)
    Vascular disorders
    Hypertension
    alternative assessment type: Non-systematic
         subjects affected / exposed
    49 / 255 (19.22%)
    44 / 234 (18.80%)
         occurrences all number
    58
    50
    Hypotension
    alternative assessment type: Non-systematic
         subjects affected / exposed
    18 / 255 (7.06%)
    16 / 234 (6.84%)
         occurrences all number
    24
    23
    General disorders and administration site conditions
    Asthenia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    31 / 255 (12.16%)
    19 / 234 (8.12%)
         occurrences all number
    38
    26
    Catheter site erythema
    alternative assessment type: Non-systematic
         subjects affected / exposed
    10 / 255 (3.92%)
    16 / 234 (6.84%)
         occurrences all number
    11
    18
    Chest pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    11 / 255 (4.31%)
    12 / 234 (5.13%)
         occurrences all number
    12
    14
    Chills
    alternative assessment type: Non-systematic
         subjects affected / exposed
    23 / 255 (9.02%)
    17 / 234 (7.26%)
         occurrences all number
    25
    22
    Fatigue
    alternative assessment type: Non-systematic
         subjects affected / exposed
    19 / 255 (7.45%)
    35 / 234 (14.96%)
         occurrences all number
    23
    41
    Oedema
    alternative assessment type: Non-systematic
         subjects affected / exposed
    13 / 255 (5.10%)
    12 / 234 (5.13%)
         occurrences all number
    15
    13
    Oedema peripheral
    alternative assessment type: Non-systematic
         subjects affected / exposed
    40 / 255 (15.69%)
    35 / 234 (14.96%)
         occurrences all number
    53
    48
    Pyrexia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    101 / 255 (39.61%)
    105 / 234 (44.87%)
         occurrences all number
    134
    146
    Mucosal inflammation
    alternative assessment type: Non-systematic
         subjects affected / exposed
    142 / 255 (55.69%)
    115 / 234 (49.15%)
         occurrences all number
    165
    129
    Immune system disorders
    Acute graft versus host disease
    alternative assessment type: Non-systematic
         subjects affected / exposed
    16 / 255 (6.27%)
    15 / 234 (6.41%)
         occurrences all number
    16
    16
    Graft versus host disease
    alternative assessment type: Non-systematic
         subjects affected / exposed
    27 / 255 (10.59%)
    26 / 234 (11.11%)
         occurrences all number
    30
    30
    Graft versus host disease in skin
    alternative assessment type: Non-systematic
         subjects affected / exposed
    18 / 255 (7.06%)
    12 / 234 (5.13%)
         occurrences all number
    20
    16
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    30 / 255 (11.76%)
    20 / 234 (8.55%)
         occurrences all number
    37
    28
    Dyspnoea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    14 / 255 (5.49%)
    17 / 234 (7.26%)
         occurrences all number
    14
    18
    Cough
    alternative assessment type: Non-systematic
         subjects affected / exposed
    42 / 255 (16.47%)
    45 / 234 (19.23%)
         occurrences all number
    52
    55
    Oropharyngeal pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    22 / 255 (8.63%)
    20 / 234 (8.55%)
         occurrences all number
    24
    22
    Rhinorrhoea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    16 / 255 (6.27%)
    16 / 234 (6.84%)
         occurrences all number
    18
    16
    Psychiatric disorders
    Insomnia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    17 / 255 (6.67%)
    22 / 234 (9.40%)
         occurrences all number
    17
    24
    Anxiety
    alternative assessment type: Non-systematic
         subjects affected / exposed
    18 / 255 (7.06%)
    15 / 234 (6.41%)
         occurrences all number
    19
    18
    Investigations
    Alanine aminotransferase increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    4 / 255 (1.57%)
    12 / 234 (5.13%)
         occurrences all number
    4
    15
    Haemoglobin decreased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    8 / 255 (3.14%)
    13 / 234 (5.56%)
         occurrences all number
    10
    41
    Liver function test abnormal
    alternative assessment type: Non-systematic
         subjects affected / exposed
    10 / 255 (3.92%)
    18 / 234 (7.69%)
         occurrences all number
    12
    18
    Weight increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    13 / 255 (5.10%)
    10 / 234 (4.27%)
         occurrences all number
    13
    10
    Cardiac disorders
    Tachycardia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    6 / 255 (2.35%)
    13 / 234 (5.56%)
         occurrences all number
    8
    13
    Nervous system disorders
    Headache
    alternative assessment type: Non-systematic
         subjects affected / exposed
    69 / 255 (27.06%)
    63 / 234 (26.92%)
         occurrences all number
    83
    84
    Dizziness
    alternative assessment type: Non-systematic
         subjects affected / exposed
    10 / 255 (3.92%)
    13 / 234 (5.56%)
         occurrences all number
    12
    15
    Paraesthesia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    5 / 255 (1.96%)
    14 / 234 (5.98%)
         occurrences all number
    5
    18
    Tremor
    alternative assessment type: Non-systematic
         subjects affected / exposed
    19 / 255 (7.45%)
    10 / 234 (4.27%)
         occurrences all number
    27
    10
    Blood and lymphatic system disorders
    Neutropenia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    30 / 255 (11.76%)
    21 / 234 (8.97%)
         occurrences all number
    30
    23
    Febrile neutropenia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    68 / 255 (26.67%)
    51 / 234 (21.79%)
         occurrences all number
    76
    57
    Anaemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    30 / 255 (11.76%)
    30 / 234 (12.82%)
         occurrences all number
    40
    32
    Thrombocytopenia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    41 / 255 (16.08%)
    35 / 234 (14.96%)
         occurrences all number
    54
    51
    Eye disorders
    Visual impairment
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 255 (0.78%)
    15 / 234 (6.41%)
         occurrences all number
    3
    16
    Gastrointestinal disorders
    Dyspepsia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    22 / 255 (8.63%)
    25 / 234 (10.68%)
         occurrences all number
    30
    33
    Haemorrhoids
    alternative assessment type: Non-systematic
         subjects affected / exposed
    10 / 255 (3.92%)
    12 / 234 (5.13%)
         occurrences all number
    10
    12
    Nausea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    91 / 255 (35.69%)
    86 / 234 (36.75%)
         occurrences all number
    128
    129
    Diarrhoea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    132 / 255 (51.76%)
    97 / 234 (41.45%)
         occurrences all number
    188
    135
    Constipation
    alternative assessment type: Non-systematic
         subjects affected / exposed
    21 / 255 (8.24%)
    41 / 234 (17.52%)
         occurrences all number
    22
    45
    Abdominal pain upper
    alternative assessment type: Non-systematic
         subjects affected / exposed
    21 / 255 (8.24%)
    23 / 234 (9.83%)
         occurrences all number
    23
    27
    Abdominal pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    51 / 255 (20.00%)
    45 / 234 (19.23%)
         occurrences all number
    61
    56
    Oral pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    12 / 255 (4.71%)
    15 / 234 (6.41%)
         occurrences all number
    15
    15
    Vomiting
    alternative assessment type: Non-systematic
         subjects affected / exposed
    104 / 255 (40.78%)
    78 / 234 (33.33%)
         occurrences all number
    148
    107
    Stomatitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    15 / 255 (5.88%)
    12 / 234 (5.13%)
         occurrences all number
    15
    15
    Hepatobiliary disorders
    Hepatocellular injury
    alternative assessment type: Non-systematic
         subjects affected / exposed
    8 / 255 (3.14%)
    12 / 234 (5.13%)
         occurrences all number
    11
    13
    Cholestasis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    10 / 255 (3.92%)
    14 / 234 (5.98%)
         occurrences all number
    10
    15
    Hepatotoxicity
    alternative assessment type: Non-systematic
         subjects affected / exposed
    8 / 255 (3.14%)
    19 / 234 (8.12%)
         occurrences all number
    8
    23
    Hyperbilirubinaemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    13 / 255 (5.10%)
    5 / 234 (2.14%)
         occurrences all number
    14
    5
    Skin and subcutaneous tissue disorders
    Rash
    alternative assessment type: Non-systematic
         subjects affected / exposed
    45 / 255 (17.65%)
    48 / 234 (20.51%)
         occurrences all number
    67
    79
    Pruritus
    alternative assessment type: Non-systematic
         subjects affected / exposed
    24 / 255 (9.41%)
    25 / 234 (10.68%)
         occurrences all number
    29
    29
    Erythema
    alternative assessment type: Non-systematic
         subjects affected / exposed
    39 / 255 (15.29%)
    43 / 234 (18.38%)
         occurrences all number
    51
    63
    Dry skin
    alternative assessment type: Non-systematic
         subjects affected / exposed
    12 / 255 (4.71%)
    16 / 234 (6.84%)
         occurrences all number
    12
    18
    Petechiae
    alternative assessment type: Non-systematic
         subjects affected / exposed
    13 / 255 (5.10%)
    7 / 234 (2.99%)
         occurrences all number
    14
    8
    Renal and urinary disorders
    Renal failure
    alternative assessment type: Non-systematic
         subjects affected / exposed
    12 / 255 (4.71%)
    19 / 234 (8.12%)
         occurrences all number
    16
    19
    Dysuria
    alternative assessment type: Non-systematic
         subjects affected / exposed
    15 / 255 (5.88%)
    13 / 234 (5.56%)
         occurrences all number
    19
    15
    Musculoskeletal and connective tissue disorders
    Pain in extremity
    alternative assessment type: Non-systematic
         subjects affected / exposed
    24 / 255 (9.41%)
    21 / 234 (8.97%)
         occurrences all number
    29
    26
    Back pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    27 / 255 (10.59%)
    33 / 234 (14.10%)
         occurrences all number
    31
    38
    Arthralgia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    22 / 255 (8.63%)
    18 / 234 (7.69%)
         occurrences all number
    24
    24
    Infections and infestations
    Cytomegalovirus infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    17 / 255 (6.67%)
    22 / 234 (9.40%)
         occurrences all number
    19
    25
    Device related infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    9 / 255 (3.53%)
    12 / 234 (5.13%)
         occurrences all number
    12
    12
    Folliculitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    11 / 255 (4.31%)
    12 / 234 (5.13%)
         occurrences all number
    11
    12
    Upper respiratory tract infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    8 / 255 (3.14%)
    12 / 234 (5.13%)
         occurrences all number
    8
    13
    Metabolism and nutrition disorders
    Hyperglycaemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    9 / 255 (3.53%)
    12 / 234 (5.13%)
         occurrences all number
    9
    14
    Fluid retention
    alternative assessment type: Non-systematic
         subjects affected / exposed
    15 / 255 (5.88%)
    10 / 234 (4.27%)
         occurrences all number
    17
    12
    Fluid overload
    alternative assessment type: Non-systematic
         subjects affected / exposed
    20 / 255 (7.84%)
    8 / 234 (3.42%)
         occurrences all number
    22
    9
    Diabetes mellitus
    alternative assessment type: Non-systematic
         subjects affected / exposed
    12 / 255 (4.71%)
    13 / 234 (5.56%)
         occurrences all number
    13
    13
    Decreased appetite
    alternative assessment type: Non-systematic
         subjects affected / exposed
    41 / 255 (16.08%)
    27 / 234 (11.54%)
         occurrences all number
    47
    31
    Hypokalaemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    30 / 255 (11.76%)
    12 / 234 (5.13%)
         occurrences all number
    39
    13
    Hypomagnesaemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    30 / 255 (11.76%)
    21 / 234 (8.97%)
         occurrences all number
    36
    27

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 May 2006
    Approved SAE waiver for bone marrow suppression was added. The safety language in the protocol was revised to address new requirements related to Exposure In Utero.
    06 Dec 2007
    The reasons for this global amendment were to add the concomitant use of St. John’s Wort as an exclusion criterion to the study, in order to keep the protocol inline with the newly updated summary of product characteristics of voriconazole and to clarify the recording requirements of serious and non-serious adverse events on the case report form.

    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.
    Data was excluded from 1 site due to Good Clinical Practices deviations.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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