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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial to Evaluate the Protective Efficacy and Safety of a Therapeutic Vaccine, ASP0113, in Cytomegalovirus (CMV)-Seropositive Recipients Undergoing Allogeneic, Hematopoietic Cell Transplant (HCT)

    Summary
    EudraCT number
    2013-000903-18
    Trial protocol
    SE   DE   BE   ES  
    Global end of trial date

    Results information
    Results version number
    v1(current)
    This version publication date
    03 Oct 2018
    First version publication date
    03 Oct 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    0113-CL-1004
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01877655
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Astellas Pharma Global Development US
    Sponsor organisation address
    1 Astellas Way, Northbrook, United States,
    Public contact
    Clinical Trial Disclosure, Astellas Pharma Global Development US, 001 800-888-7704 ex 5473, astellas.resultsdisclosure@astellas.com
    Scientific contact
    Clinical Trial Disclosure, Astellas Pharma Global Development US, 001 800-888-7704 ex 5473, astellas.resultsdisclosure@astellas.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
    Interim
    Date of interim/final analysis
    28 Sep 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Sep 2017
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate efficacy of ASP0113 compared with placebo as measured by a primary composite endpoint of overall mortality and cytomegalovirus end organ disease (CMV EOD) through 1 year posttransplant and to evaluate safety of ASP0113 in participants undergoing allogeneic hematopoietic cell transplant (HCT).
    Protection of trial subjects
    This clinical study was written, conducted and reported in accordance with the protocol, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) Guidelines, and applicable local regulations, including the European Directive 2001/20/EC, on the protection of human rights, and with the ethical principles that have their origin in the Declaration of Helsinki. Astellas ensures that the use and disclosure of protected health information (PHI) obtained during a research study complies with the federal, national and/or regional legislation related to the privacy and protection of personal information.
    Background therapy
    All concomitant medications and therapies administered from 30 days prior to transplant through 30 days after the last dose of study drug were recorded on the eCRF. From 31 days after the last dose of study drug through 1 year posttransplant, concomitant medications and therapies associated with all events required adjudication.
    Evidence for comparator
    -
    Actual start date of recruitment
    11 Sep 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    5 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 5
    Country: Number of subjects enrolled
    Belgium: 47
    Country: Number of subjects enrolled
    Canada: 15
    Country: Number of subjects enrolled
    France: 30
    Country: Number of subjects enrolled
    Germany: 54
    Country: Number of subjects enrolled
    Japan: 47
    Country: Number of subjects enrolled
    Korea, Republic of: 23
    Country: Number of subjects enrolled
    Spain: 75
    Country: Number of subjects enrolled
    Sweden: 31
    Country: Number of subjects enrolled
    Taiwan: 17
    Country: Number of subjects enrolled
    United States: 170
    Worldwide total number of subjects
    514
    EEA total number of subjects
    237
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    431
    From 65 to 84 years
    83
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    A total of 514 participants were enrolled across 11 countries. At least 30% of enrolled participants had cytomegalovirus (CMV) seronegative donor and underwent allogeneic hematopoietic cell transplant (HCT). After the primary study period (day 365) participants were monitored for 5.5 years post-transplant for long-term safety.

    Pre-assignment
    Screening details
    Screening assessment occurred from 30 to 5 days before transplant. Participants who met the inclusion and none of the exclusion criteria were randomly assigned in a 1:1 ratio to receive either ASP0113 or placebo. The randomization to treatment was stratified by donor-recipient relatedness and by donor CMV serostatus.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Carer, Assessor
    Blinding implementation details
    Study drug assignment was blinded to all site staff except the pharmacist, designated staff and the unblinded administrator.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Participants received 1 mL of 5 mg/mL of matching placebo via intramuscular injection in the deltoid muscle alternating sides with each dose on days -14 to -3 pretransplant, 14 to 40, 60, 90 and 180 in relation to the day of transplant (Day 0).
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Participants received matching placebo in 2-mL vials containing phosphate-buffered saline.

    Arm title
    ASP0113 5mg
    Arm description
    Participants received 1 mL of 5 mg/mL of ASP0113 via intramuscular injection in the deltoid muscle alternating sides with each dose on days -14 to -3 pretransplant, 14 to 40, 60, 90 and 180 in relation to the day of transplant (Day 0).
    Arm type
    Experimental

    Investigational medicinal product name
    ASP0113
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Participants received ASP0113 in single-dose 2-mL vials containing 1.3 mL of 5 mg/mL ASP0113.

    Number of subjects in period 1
    Placebo ASP0113 5mg
    Started
    263
    251
    Received Treatment
    255
    246
    Completed
    165
    154
    Not completed
    98
    97
         Death
    57
    52
         Miscellaneous
    4
    4
         Physician decision
    11
    10
         Randomized but Never Received Drug
    8
    5
         Consent withdrawn by subject
    18
    26

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Participants received 1 mL of 5 mg/mL of matching placebo via intramuscular injection in the deltoid muscle alternating sides with each dose on days -14 to -3 pretransplant, 14 to 40, 60, 90 and 180 in relation to the day of transplant (Day 0).

    Reporting group title
    ASP0113 5mg
    Reporting group description
    Participants received 1 mL of 5 mg/mL of ASP0113 via intramuscular injection in the deltoid muscle alternating sides with each dose on days -14 to -3 pretransplant, 14 to 40, 60, 90 and 180 in relation to the day of transplant (Day 0).

    Reporting group values
    Placebo ASP0113 5mg Total
    Number of subjects
    263 251
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    52.0 ± 13.15 51.8 ± 12.41 -
    Gender categorical
    Units: Subjects
        Female
    105 110 215
        Male
    158 141 299
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    0 0 0
        Asian
    47 50 97
        Native Hawaiian or Other Pacific Islander
    0 0 0
        Black or African American
    6 7 13
        White
    189 177 366
        More than one race
    0 0 0
        Unknown or Not Reported
    21 17 38
    Strata
    Units: Subjects
        Related Seropositive Donor
    65 73 138
        Related Seronegative Donor
    30 26 56
        Non-related Seropositive Donor
    96 73 169
        Non-related Seronegative Donor
    72 79 151
    Primary Diagnosis
    Units: Subjects
        Acute Myeloid Leukemia (AML)
    126 97 223
        Acute Lymphoblastic Leukemia (ALL)
    34 34 68
        Acute Undifferentiated Leukemia (AUL)
    1 2 3
        Acute Biphenotypic Leukemia (ABL)
    2 2 4
        Chronic Myelogenous Leukemia (CML)
    6 12 18
        Chronic Lymphocytic Leukemia (CLL)
    7 10 17
        Myelodysplastic Syndrome
    46 51 97
        Primary or Secondary Myelofibrosis
    8 11 19
        Lymphoma
    33 31 64
        Missing
    0 1 1
    Conditioning Regimen
    Units: Subjects
        Myeloablative
    122 120 242
        Non-Myeloablative
    131 124 255
        Missing
    10 7 17
    Antithymocyte Globulin (ATG) Use
    Units: Subjects
        Yes
    45 43 88
        No
    218 208 426
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    11 19 30
        Not Hispanic or Latino
    252 232 484
    Height
    Units: Centimeteres
        arithmetic mean (standard deviation)
    170.6 ± 9.91 169.7 ± 9.88 -
    Body Mass Index (BMI)
    Units: kg/m^2
        arithmetic mean (standard deviation)
    27.0 ± 5.02 26.0 ± 5.05 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Participants received 1 mL of 5 mg/mL of matching placebo via intramuscular injection in the deltoid muscle alternating sides with each dose on days -14 to -3 pretransplant, 14 to 40, 60, 90 and 180 in relation to the day of transplant (Day 0).

    Reporting group title
    ASP0113 5mg
    Reporting group description
    Participants received 1 mL of 5 mg/mL of ASP0113 via intramuscular injection in the deltoid muscle alternating sides with each dose on days -14 to -3 pretransplant, 14 to 40, 60, 90 and 180 in relation to the day of transplant (Day 0).

    Primary: Percentage of Participants With Composite of All-Cause Mortality and Adjudicated Cytomegalovirus End Organ Disease (CMV EOD) Through 1 Year Post Transplant

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    End point title
    Percentage of Participants With Composite of All-Cause Mortality and Adjudicated Cytomegalovirus End Organ Disease (CMV EOD) Through 1 Year Post Transplant
    End point description
    This was the composite of all-cause mortality and adjudicated CMV EOD through 1 year posttransplant, The CMV EOD was assessed by the independent and blinded adjudication committee, which counted events that were observed up to day 380 from transplantation. Deaths that occurred up to day 365 from transplant were also counted.
    End point type
    Primary
    End point timeframe
    From first study dose injection (Day -14 to -3 prior to transplant) up to one year post study drug injection (Day 365)
    End point values
    Placebo ASP0113 5mg
    Number of subjects analysed
    255
    246
    Units: Percentage of Participants
    number (not applicable)
        Participants With Composite Endpoint
    30.20
    35.37
        All-Cause Mortality
    28.24
    31.71
        Adjudicated CMV EOD
    3.53
    6.10
    Statistical analysis title
    All-Cause Mortality and Adjudicated CMV EOD
    Statistical analysis description
    Analysis was completed using the Cochran-Mantel-Haenszel (CMH) test at the 1-sided 5% level stratified by use of antithymocyte globulin (ATG) and by receipt of a kidney from a living or deceased donor.
    Comparison groups
    Placebo v ASP0113 5mg
    Number of subjects included in analysis
    501
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.205 [1]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.27
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.87
         upper limit
    1.85
    Notes
    [1] - P-value based on CMH general association test stratified by donor-recipient relatedness and donor CMV serostatus.

    Secondary: Percentage of Participants With Protocol-Defined CMV Viremia Through 1 Year Posttransplant

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    End point title
    Percentage of Participants With Protocol-Defined CMV Viremia Through 1 Year Posttransplant
    End point description
    Protocol-defined CMV viremia was defined as a CMV plasma viral load ≥1000 IU/mL as assessed by the central laboratory. Rate was based on cumulative incidence function estimated at 1 year. The central laboratory had the lower limit of quantification [LLOQ] for CMV viral load assessment, so when the viral load was below the LLOQ the actual viral load reading was not possible and was denoted as ≤LLOQ. If participant had any CMV viral load assessments greater than the LLOQ it was classified as viremic.
    End point type
    Secondary
    End point timeframe
    From first study dose injection (Day -14 to -3 prior to transplant) up to one year post study drug injection (Day 365)
    End point values
    Placebo ASP0113 5mg
    Number of subjects analysed
    255
    246
    Units: Percentage of Participants
    number (confidence interval 95%)
        Participants
    58.6 (52.0 to 64.6)
    56.7 (50.1 to 62.8)
    Statistical analysis title
    CMV Viremia Through 1 Yr Posttransplant
    Statistical analysis description
    CMV viremia was defined by the protocol as CMV plasma viral load ≥ 1000 IU/mL as assessed by the central laboratory. The 95% CI was based on cumulative incidence function CMV viremia rate at 1 year.
    Comparison groups
    Placebo v ASP0113 5mg
    Number of subjects included in analysis
    501
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.748 [2]
    Method
    Cox Proportional Hazard Model
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.96
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.76
         upper limit
    1.22
    Notes
    [2] - P-value based on cox proportional hazard model (ASP0113 v placebo) with treatment & randomization strata adjusted for death as a competing risk.

    Secondary: Percentage of Participants With Adjudicated CMV-Specific Antiviral Therapy (AVT) Through 1 Year Posttransplant

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    End point title
    Percentage of Participants With Adjudicated CMV-Specific Antiviral Therapy (AVT) Through 1 Year Posttransplant
    End point description
    The CMV-specific AVT use was adjudicated by the independent and blinded committee. When the CMV-specific AVT was initiated, a central CMV viral load was obtained weekly until it was discontinued. Participants without any CMV-specific AVT events were censored on the last study evaluation.
    End point type
    Secondary
    End point timeframe
    From first study dose injection (Day -14 to -3 prior to transplant) up to one year post study drug injection (Day 365)
    End point values
    Placebo ASP0113 5mg
    Number of subjects analysed
    255
    246
    Units: Percentage of Participants
        number (confidence interval 95%)
    53.2 (46.8 to 59.1)
    54.6 (48.1 to 60.6)
    Statistical analysis title
    CMV-Specific Antiviral Therapy (AVT) Through 1 Yr
    Statistical analysis description
    Time to first adjudicated CMV-specific therapy was defined as time to the start of AVT for CMV viremia. CMV-specific AVT was determined by the adjudication committee.
    Comparison groups
    Placebo v ASP0113 5mg
    Number of subjects included in analysis
    501
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.888 [3]
    Method
    Cox Proportional Hazard Model
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.8
         upper limit
    1.29
    Notes
    [3] - P-value based on cox proportional hazard model (ASP0113 v placebo) with treatment & randomization strata adjusted for death as a competing risk.

    Secondary: Percentage of Participants With a Composite Endpoint of Protocol-defined CMV Viremia and Adjudicated CMV-Specific AVT Use

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    End point title
    Percentage of Participants With a Composite Endpoint of Protocol-defined CMV Viremia and Adjudicated CMV-Specific AVT Use
    End point description
    Protocol-defined CMV Viremia was as CMV plasma viral load ≥ 1000 IU/mL as assessed by the central laboratory. The CMV-specific AVT was determined by the adjudication committee. Participants with no posttransplant viral load data were excluded from the analysis.
    End point type
    Secondary
    End point timeframe
    From first study dose injection (Day -14 to -3 prior to transplant) up to one year post study drug injection (Day 365)
    End point values
    Placebo ASP0113 5mg
    Number of subjects analysed
    255
    246
    Units: Percentage of Participants
    number (not applicable)
        Percentage of Participants
    60.78
    60.98
    Statistical analysis title
    Composite of CMV Viremia and Adjudicated CMV-AVT
    Statistical analysis description
    CMV viremia was defined by the protocol as CMV plasma viral load ≥ 1000 IU/mL as assessed by the central laboratory. CMV-specific AVT was determined by the adjudication committee. Patients with no posttransplant viral load data were excluded from the analysis.
    Comparison groups
    Placebo v ASP0113 5mg
    Number of subjects included in analysis
    501
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.802 [4]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.05
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.73
         upper limit
    1.51
    Notes
    [4] - P-value based on CMH general association test stratified by donor-recipient relatedness and donor CMV serostatus.

    Secondary: Percentage of Participants With First Occurrence of Adjudicated CMV-specific AVT or Adjudicated Diagnosis of CMV EOD After Study Drug First Injection Through 1 Year Posttransplant

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    End point title
    Percentage of Participants With First Occurrence of Adjudicated CMV-specific AVT or Adjudicated Diagnosis of CMV EOD After Study Drug First Injection Through 1 Year Posttransplant
    End point description
    Rate was based on cumulative incidence function estimate at 1 year. Time to first CMV-specific AVT was defined as time to the start of AVT for CMV viremia or CMV EOD. CMV-specific AVT and EOD were determined by the adjudication committee. This endpoint was a composite endpoint based on the independent adjudication committee assessments of CMV-specific AVT and CMV EOD.
    End point type
    Secondary
    End point timeframe
    From first study dose injection (Day -14 to -3 prior to transplant) up to one year post study drug injection (Day 365)
    End point values
    Placebo ASP0113 5mg
    Number of subjects analysed
    255
    246
    Units: Percentage of Participants
        number (confidence interval 95%)
    54.4 (48.0 to 60.3)
    55.4 (48.9 to 61.5)
    Statistical analysis title
    Rate of Adjudicated CMV AVT or CMV EOD
    Statistical analysis description
    Time to first CMV-specific AVT defined as time to the start of AVT for CMV viremia or CMV EOD. CMV-specific AVT and EOD were determined by the adjudication committee. Rate based on cumulative incidence function estimate at 1 year.
    Comparison groups
    Placebo v ASP0113 5mg
    Number of subjects included in analysis
    501
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.928 [5]
    Method
    Cox Proportional Hazard Model
    Parameter type
    Hazard ratio (HR)
    Point estimate
    -0.01
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.28
         upper limit
    0.2
    Notes
    [5] - P-value based on cox proportional hazard model (ASP0113 v placebo) with treatment & randomization strata adjusted for death as a competing risk.

    Secondary: All-Cause Mortality at 1 Year Posttransplant

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    End point title
    All-Cause Mortality at 1 Year Posttransplant
    End point description
    All-cause mortality through 1-year post-transplantation summary included all deaths and unknown survival status. For the known deaths, the adjudication committee assessed results and summarized them according to the following category: Mortality due to the participant’s primary disease, and Mortality due to causes unrelated to the participant’s primary disease. Participants with unknown survival status at 1 year were considered dead for this analysis.
    End point type
    Secondary
    End point timeframe
    From first study dose injection (Day -14 to -3 prior to transplant) up to one year post study drug injection (Day 365)
    End point values
    Placebo ASP0113 5mg
    Number of subjects analysed
    255
    246
    Units: Percentage of Participants
    number (not applicable)
        Percentage of Participants
    28.24
    31.71
    Statistical analysis title
    All-Cause Mortality at 1 Year
    Statistical analysis description
    Participants with unknown survival status at 1 year were considered dead for this analysis.
    Comparison groups
    Placebo v ASP0113 5mg
    Number of subjects included in analysis
    501
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.393 [6]
    Method
    Cox Proportional Hazards Model
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.18
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.81
         upper limit
    1.73
    Notes
    [6] - P-value based on cox proportional hazards model parameter estimate for the treatment effect.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug up to 30 days after last dose of study drug (Day 365)
    Adverse event reporting additional description
    Treatment Emergent Adverse Event (TEAE) was defined as an adverse event observed after the first dose of study drug injection through Day 365 and within 30 days of the last dose of study drug. Drug-related TEAE was defined as any TEAE with possible relationship to study treatment as assessed by the investigator.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16
    Reporting groups
    Reporting group title
    ASP0113 5mg
    Reporting group description
    Participants received 1 mL of 5 mg/mL of ASP0113 via intramuscular injection in the deltoid muscle alternating sides with each dose on days -14 to -3 pretransplant, 14 to 40, 60, 90 and 180 in relation to the day of transplant (Day 0).

    Reporting group title
    Placebo
    Reporting group description
    Participants received 1 mL of 5 mg/mL of matching placebo via intramuscular injection in the deltoid muscle alternating sides with each dose on days -14 to -3 pretransplant, 14 to 40, 60, 90 and 180 in relation to the day of transplant (Day 0).

    Serious adverse events
    ASP0113 5mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    221 / 246 (89.84%)
    221 / 255 (86.67%)
         number of deaths (all causes)
    67
    68
         number of deaths resulting from adverse events
    61
    63
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 246 (0.00%)
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    2 / 246 (0.81%)
    3 / 255 (1.18%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Microangiopathy
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venoocclusive disease
         subjects affected / exposed
    1 / 246 (0.41%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Venous thrombosis
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Appendicectomy
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Central venous catheter removal
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colectomy
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Donor leukocyte infusion
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug therapy
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stem cell transplant
         subjects affected / exposed
    2 / 246 (0.81%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transurethral prostatectomy
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute lymphocytic leukaemia
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute lymphocytic leukaemia recurrent
         subjects affected / exposed
    5 / 246 (2.03%)
    6 / 255 (2.35%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myeloid leukaemia
         subjects affected / exposed
    6 / 246 (2.44%)
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Acute myeloid leukaemia recurrent
         subjects affected / exposed
    17 / 246 (6.91%)
    18 / 255 (7.06%)
         occurrences causally related to treatment / all
    2 / 22
    0 / 21
         deaths causally related to treatment / all
    1 / 10
    0 / 8
    Adult T-cell lymphoma/leukaemia recurrent
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    2 / 246 (0.81%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Central nervous system lymphoma
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chloroma
         subjects affected / exposed
    1 / 246 (0.41%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Chronic lymphocytic leukaemia
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic lymphocytic leukaemia recurrent
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic myeloid leukaemia
         subjects affected / exposed
    2 / 246 (0.81%)
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Chronic myelomonocytic leukaemia
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diffuse large B-cell lymphoma
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hepatic cancer metastatic
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hodgkin's disease
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Kaposi's sarcoma
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukaemia recurrent
         subjects affected / exposed
    3 / 246 (1.22%)
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Leukaemic infiltration brain
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphoma
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    2 / 246 (0.81%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    2 / 246 (0.81%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Monoclonal gammopathy
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mycosis fungoides recurrent
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myelodysplastic syndrome
         subjects affected / exposed
    5 / 246 (2.03%)
    3 / 255 (1.18%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Myelofibrosis
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-Hodgkin's lymphoma recurrent
         subjects affected / exposed
    0 / 246 (0.00%)
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral T-cell lymphoma unspecified recurrent
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post transplant lymphoproliferative disorder
         subjects affected / exposed
    2 / 246 (0.81%)
    3 / 255 (1.18%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Small cell lung cancer
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    T-cell lymphoma
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    T-cell lymphoma recurrent
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    T-cell type acute leukaemia
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Acute graft versus host disease
         subjects affected / exposed
    7 / 246 (2.85%)
    9 / 255 (3.53%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute graft versus host disease in intestine
         subjects affected / exposed
    76 / 246 (30.89%)
    76 / 255 (29.80%)
         occurrences causally related to treatment / all
    1 / 123
    0 / 120
         deaths causally related to treatment / all
    1 / 3
    0 / 8
    Acute graft versus host disease in liver
         subjects affected / exposed
    18 / 246 (7.32%)
    24 / 255 (9.41%)
         occurrences causally related to treatment / all
    1 / 23
    0 / 30
         deaths causally related to treatment / all
    1 / 2
    0 / 3
    Acute graft versus host disease in skin
         subjects affected / exposed
    118 / 246 (47.97%)
    122 / 255 (47.84%)
         occurrences causally related to treatment / all
    3 / 165
    1 / 171
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Alloimmunisation
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic graft versus host disease
         subjects affected / exposed
    2 / 246 (0.81%)
    4 / 255 (1.57%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic graft versus host disease in intestine
         subjects affected / exposed
    3 / 246 (1.22%)
    6 / 255 (2.35%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Chronic graft versus host disease in liver
         subjects affected / exposed
    3 / 246 (1.22%)
    7 / 255 (2.75%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Chronic graft versus host disease in skin
         subjects affected / exposed
    1 / 246 (0.41%)
    5 / 255 (1.96%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    4 / 246 (1.63%)
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    3 / 246 (1.22%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug resistance
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    2 / 246 (0.81%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion site extravasation
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    1 / 246 (0.41%)
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    6 / 246 (2.44%)
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 5
    0 / 2
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 246 (0.41%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema due to cardiac disease
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    26 / 246 (10.57%)
    23 / 255 (9.02%)
         occurrences causally related to treatment / all
    2 / 27
    0 / 29
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Serositis
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 246 (0.41%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Systemic inflammatory response syndrome
         subjects affected / exposed
    2 / 246 (0.81%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    1 / 246 (0.41%)
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    1 / 246 (0.41%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disorientation
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mania
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental disorder
         subjects affected / exposed
    1 / 246 (0.41%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    3 / 246 (1.22%)
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (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
    Blood stem cell transplant failure
         subjects affected / exposed
    3 / 246 (1.22%)
    4 / 255 (1.57%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Drug dose omission
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 246 (0.41%)
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle strain
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Spinal compression fracture
         subjects affected / exposed
    1 / 246 (0.41%)
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transfusion microchimerism
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transplant failure
         subjects affected / exposed
    0 / 246 (0.00%)
    3 / 255 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Computerised tomogram thorax abnormal
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immunosuppressant drug level increased
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    1 / 246 (0.41%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Angina pectoris
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    4 / 246 (1.63%)
    3 / 255 (1.18%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure
         subjects affected / exposed
    1 / 246 (0.41%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac tamponade
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (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
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiogenic shock
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pericardial effusion
         subjects affected / exposed
    2 / 246 (0.81%)
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    1 / 246 (0.41%)
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulseless electrical activity
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 246 (0.41%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    1 / 246 (0.41%)
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 246 (0.00%)
    6 / 255 (2.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    1 / 5
    Acute respiratory failure
         subjects affected / exposed
    2 / 246 (0.81%)
    4 / 255 (1.57%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Atelectasis
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    3 / 246 (1.22%)
    4 / 255 (1.57%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    3 / 246 (1.22%)
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Idiopathic pneumonia syndrome
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    3 / 246 (1.22%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Mediastinal mass
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obliterative bronchiolitis
         subjects affected / exposed
    1 / 246 (0.41%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstructive airways disorder
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Organising pneumonia
         subjects affected / exposed
    2 / 246 (0.81%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 246 (0.41%)
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 246 (0.41%)
    7 / 255 (2.75%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary alveolar haemorrhage
         subjects affected / exposed
    1 / 246 (0.41%)
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Pulmonary embolism
         subjects affected / exposed
    1 / 246 (0.41%)
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    1 / 246 (0.41%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Pulmonary oedema
         subjects affected / exposed
    1 / 246 (0.41%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary thrombosis
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 246 (0.41%)
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    8 / 246 (3.25%)
    11 / 255 (4.31%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 13
         deaths causally related to treatment / all
    0 / 5
    0 / 5
    Wheezing
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Agranulocytosis
         subjects affected / exposed
    0 / 246 (0.00%)
    3 / 255 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Anaemia
         subjects affected / exposed
    3 / 246 (1.22%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aplasia pure red cell
         subjects affected / exposed
    1 / 246 (0.41%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone marrow failure
         subjects affected / exposed
    3 / 246 (1.22%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coagulopathy
         subjects affected / exposed
    2 / 246 (0.81%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Eosinophilia
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile bone marrow aplasia
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    11 / 246 (4.47%)
    11 / 255 (4.31%)
         occurrences causally related to treatment / all
    0 / 14
    0 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemolytic anaemia
         subjects affected / exposed
    3 / 246 (1.22%)
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Haemolytic uraemic syndrome
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Neutropenia
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    5 / 246 (2.03%)
    5 / 255 (1.96%)
         occurrences causally related to treatment / all
    0 / 6
    1 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Thrombocytopenia
         subjects affected / exposed
    3 / 246 (1.22%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombotic microangiopathy
         subjects affected / exposed
    1 / 246 (0.41%)
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nervous system disorders
    Acute polyneuropathy
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Amnesia
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain oedema
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Central nervous system lesion
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coma
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    3 / 246 (1.22%)
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    2 / 246 (0.81%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalitis
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Encephalopathy
         subjects affected / exposed
    2 / 246 (0.81%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Facial paresis
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    2 / 246 (0.81%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Memory impairment
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neurological decompensation
         subjects affected / exposed
    1 / 246 (0.41%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Paraplegia
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 246 (0.81%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thalamus haemorrhage
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    2 / 246 (0.81%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VIIth nerve paralysis
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Mydriasis
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Aural polyp
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deafness neurosensory
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (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 discomfort
         subjects affected / exposed
    2 / 246 (0.81%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    2 / 246 (0.81%)
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain lower
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal fissure
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    10 / 246 (4.07%)
    11 / 255 (4.31%)
         occurrences causally related to treatment / all
    1 / 13
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 246 (0.81%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastrointestinal toxicity
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophagitis
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Impaired gastric emptying
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intra-abdominal haemorrhage
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestinal haemorrhage
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Megacolon
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nausea
         subjects affected / exposed
    10 / 246 (4.07%)
    8 / 255 (3.14%)
         occurrences causally related to treatment / all
    1 / 10
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral pain
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 246 (0.41%)
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 246 (0.41%)
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumatosis intestinalis
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctalgia
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    2 / 246 (0.81%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal perforation
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    11 / 246 (4.47%)
    7 / 255 (2.75%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    3 / 246 (1.22%)
    5 / 255 (1.96%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Renal failure acute
         subjects affected / exposed
    28 / 246 (11.38%)
    41 / 255 (16.08%)
         occurrences causally related to treatment / all
    0 / 38
    0 / 46
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure chronic
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 246 (0.00%)
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal injury
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal tubular necrosis
         subjects affected / exposed
    1 / 246 (0.41%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Acute hepatic failure
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 246 (0.00%)
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic vein occlusion
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    2 / 246 (0.81%)
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venoocclusive liver disease
         subjects affected / exposed
    5 / 246 (2.03%)
    4 / 255 (1.57%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Skin and subcutaneous tissue disorders
    Diabetic foot
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain of skin
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    1 / 246 (0.41%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin lesion
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stasis dermatitis
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxic epidermal necrolysis
         subjects affected / exposed
    1 / 246 (0.41%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Urticaria
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 246 (0.41%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chondrocalcinosis pyrophosphate
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myopathy
         subjects affected / exposed
    1 / 246 (0.41%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polyarthritis
         subjects affected / exposed
    1 / 246 (0.41%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Inappropriate antidiuretic hormone secretion
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Decreased appetite
         subjects affected / exposed
    2 / 246 (0.81%)
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    4 / 246 (1.63%)
    4 / 255 (1.57%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    0 / 246 (0.00%)
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    1 / 246 (0.41%)
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Fluid overload
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    2 / 246 (0.81%)
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    2 / 246 (0.81%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    2 / 246 (0.81%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal abscess
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess intestinal
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Acinetobacter bacteraemia
         subjects affected / exposed
    2 / 246 (0.81%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenovirus infection
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anorectal cellulitis
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspergillosis
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Atypical mycobacterial infection
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BK virus infection
         subjects affected / exposed
    2 / 246 (0.81%)
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    4 / 246 (1.63%)
    4 / 255 (1.57%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial infection
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    3 / 246 (1.22%)
    3 / 255 (1.18%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Brain abscess
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Bronchitis
         subjects affected / exposed
    2 / 246 (0.81%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    4 / 246 (1.63%)
    3 / 255 (1.18%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Campylobacter gastroenteritis
         subjects affected / exposed
    1 / 246 (0.41%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter site infection
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    3 / 246 (1.22%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral aspergillosis
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Citrobacter sepsis
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    2 / 246 (0.81%)
    5 / 255 (1.96%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    3 / 246 (1.22%)
    4 / 255 (1.57%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Corona virus infection
         subjects affected / exposed
    2 / 246 (0.81%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis bacterial
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus colitis
         subjects affected / exposed
    3 / 246 (1.22%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cytomegalovirus gastritis
         subjects affected / exposed
    2 / 246 (0.81%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus gastroenteritis
         subjects affected / exposed
    1 / 246 (0.41%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus infection
         subjects affected / exposed
    10 / 246 (4.07%)
    6 / 255 (2.35%)
         occurrences causally related to treatment / all
    0 / 10
    1 / 6
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Cytomegalovirus viraemia
         subjects affected / exposed
    11 / 246 (4.47%)
    9 / 255 (3.53%)
         occurrences causally related to treatment / all
    2 / 13
    1 / 11
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    Device related infection
         subjects affected / exposed
    2 / 246 (0.81%)
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    0 / 246 (0.00%)
    3 / 255 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea infectious
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalitis cytomegalovirus
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Encephalitis herpes
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalitis viral
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Enterococcal bacteraemia
         subjects affected / exposed
    1 / 246 (0.41%)
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterococcal sepsis
         subjects affected / exposed
    0 / 246 (0.00%)
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis bacterial
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis infectious
         subjects affected / exposed
    2 / 246 (0.81%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epstein-Barr viraemia
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epstein-Barr virus infection
         subjects affected / exposed
    1 / 246 (0.41%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Escherichia bacteraemia
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    3 / 246 (1.22%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    2 / 246 (0.81%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gangrene
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 246 (0.41%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis adenovirus
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Genital herpes
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic candidiasis
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Herpes simplex
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    4 / 246 (1.63%)
    5 / 255 (1.96%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster ophthalmic
         subjects affected / exposed
    1 / 246 (0.41%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Human herpesvirus 6 infection
         subjects affected / exposed
    0 / 246 (0.00%)
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Human polyomavirus infection
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected skin ulcer
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    2 / 246 (0.81%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    3 / 246 (1.22%)
    3 / 255 (1.18%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Klebsiella bacteraemia
         subjects affected / exposed
    1 / 246 (0.41%)
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella sepsis
         subjects affected / exposed
    2 / 246 (0.81%)
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    1 / 246 (0.41%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Localised infection
         subjects affected / exposed
    1 / 246 (0.41%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection bacterial
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    4 / 246 (1.63%)
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Meningitis aseptic
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal candidiasis
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral candidiasis
         subjects affected / exposed
    0 / 246 (0.00%)
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral herpes
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis jiroveci pneumonia
         subjects affected / exposed
    2 / 246 (0.81%)
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    19 / 246 (7.72%)
    15 / 255 (5.88%)
         occurrences causally related to treatment / all
    0 / 20
    1 / 18
         deaths causally related to treatment / all
    0 / 5
    0 / 6
    Pneumonia adenoviral
         subjects affected / exposed
    1 / 246 (0.41%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia bacterial
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonia cytomegaloviral
         subjects affected / exposed
    3 / 246 (1.22%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonia escherichia
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia fungal
         subjects affected / exposed
    1 / 246 (0.41%)
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonia herpes viral
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia influenzal
         subjects affected / exposed
    1 / 246 (0.41%)
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia klebsiella
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia legionella
         subjects affected / exposed
    0 / 246 (0.00%)
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia respiratory syncytial viral
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia staphylococcal
         subjects affected / exposed
    0 / 246 (0.00%)
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia streptococcal
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomonal bacteraemia
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary mycosis
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed
    1 / 246 (0.41%)
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory tract infection
         subjects affected / exposed
    4 / 246 (1.63%)
    3 / 255 (1.18%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    14 / 246 (5.69%)
    20 / 255 (7.84%)
         occurrences causally related to treatment / all
    0 / 14
    1 / 23
         deaths causally related to treatment / all
    0 / 3
    0 / 8
    Septic shock
         subjects affected / exposed
    10 / 246 (4.07%)
    9 / 255 (3.53%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 10
         deaths causally related to treatment / all
    0 / 7
    0 / 3
    Sialoadenitis
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    1 / 246 (0.41%)
    3 / 255 (1.18%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis fungal
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Skin infection
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    5 / 246 (2.03%)
    4 / 255 (1.57%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal bacteraemia
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal sepsis
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic mycosis
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tubo-ovarian abscess
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 246 (1.63%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 246 (0.81%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection bacterial
         subjects affected / exposed
    3 / 246 (1.22%)
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection enterococcal
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection fungal
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral haemorrhagic cystitis
         subjects affected / exposed
    2 / 246 (0.81%)
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 255 (0.39%)
         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
    ASP0113 5mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    244 / 246 (99.19%)
    254 / 255 (99.61%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    66 / 246 (26.83%)
    83 / 255 (32.55%)
         occurrences all number
    78
    96
    Hypotension
         subjects affected / exposed
    39 / 246 (15.85%)
    36 / 255 (14.12%)
         occurrences all number
    50
    37
    Immune system disorders
    Chronic graft versus host disease
         subjects affected / exposed
    62 / 246 (25.20%)
    60 / 255 (23.53%)
         occurrences all number
    110
    109
    Chronic graft versus host disease in intestine
         subjects affected / exposed
    20 / 246 (8.13%)
    21 / 255 (8.24%)
         occurrences all number
    22
    28
    Chronic graft versus host disease in skin
         subjects affected / exposed
    37 / 246 (15.04%)
    46 / 255 (18.04%)
         occurrences all number
    40
    51
    Chronic graft versus host disease in liver
         subjects affected / exposed
    30 / 246 (12.20%)
    35 / 255 (13.73%)
         occurrences all number
    43
    45
    Engraftment syndrome
         subjects affected / exposed
    13 / 246 (5.28%)
    9 / 255 (3.53%)
         occurrences all number
    15
    9
    Hypogammaglobulinaemia
         subjects affected / exposed
    20 / 246 (8.13%)
    19 / 255 (7.45%)
         occurrences all number
    20
    20
    General disorders and administration site conditions
    Catheter site pain
         subjects affected / exposed
    22 / 246 (8.94%)
    21 / 255 (8.24%)
         occurrences all number
    29
    23
    Asthenia
         subjects affected / exposed
    30 / 246 (12.20%)
    34 / 255 (13.33%)
         occurrences all number
    39
    43
    Chills
         subjects affected / exposed
    36 / 246 (14.63%)
    44 / 255 (17.25%)
         occurrences all number
    46
    59
    Fatigue
         subjects affected / exposed
    58 / 246 (23.58%)
    69 / 255 (27.06%)
         occurrences all number
    65
    80
    Injection site erythema
         subjects affected / exposed
    49 / 246 (19.92%)
    5 / 255 (1.96%)
         occurrences all number
    72
    5
    Injection site induration
         subjects affected / exposed
    38 / 246 (15.45%)
    3 / 255 (1.18%)
         occurrences all number
    57
    3
    Injection site swelling
         subjects affected / exposed
    24 / 246 (9.76%)
    4 / 255 (1.57%)
         occurrences all number
    36
    4
    Injection site pain
         subjects affected / exposed
    193 / 246 (78.46%)
    47 / 255 (18.43%)
         occurrences all number
    1053
    83
    Malaise
         subjects affected / exposed
    15 / 246 (6.10%)
    10 / 255 (3.92%)
         occurrences all number
    15
    11
    Mucosal inflammation
         subjects affected / exposed
    75 / 246 (30.49%)
    101 / 255 (39.61%)
         occurrences all number
    94
    147
    Oedema
         subjects affected / exposed
    35 / 246 (14.23%)
    21 / 255 (8.24%)
         occurrences all number
    39
    24
    Oedema peripheral
         subjects affected / exposed
    66 / 246 (26.83%)
    69 / 255 (27.06%)
         occurrences all number
    88
    95
    Pain
         subjects affected / exposed
    27 / 246 (10.98%)
    32 / 255 (12.55%)
         occurrences all number
    34
    34
    Pyrexia
         subjects affected / exposed
    123 / 246 (50.00%)
    128 / 255 (50.20%)
         occurrences all number
    180
    195
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    40 / 246 (16.26%)
    44 / 255 (17.25%)
         occurrences all number
    42
    53
    Depression
         subjects affected / exposed
    11 / 246 (4.47%)
    18 / 255 (7.06%)
         occurrences all number
    11
    18
    Insomnia
         subjects affected / exposed
    72 / 246 (29.27%)
    76 / 255 (29.80%)
         occurrences all number
    86
    85
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    15 / 246 (6.10%)
    10 / 255 (3.92%)
         occurrences all number
    17
    12
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    30 / 246 (12.20%)
    30 / 255 (11.76%)
         occurrences all number
    49
    45
    Alanine aminotransferase increased
         subjects affected / exposed
    33 / 246 (13.41%)
    31 / 255 (12.16%)
         occurrences all number
    66
    47
    Blood alkaline phosphatase increased
         subjects affected / exposed
    18 / 246 (7.32%)
    17 / 255 (6.67%)
         occurrences all number
    23
    24
    Blood creatinine increased
         subjects affected / exposed
    22 / 246 (8.94%)
    29 / 255 (11.37%)
         occurrences all number
    27
    42
    Blood bilirubin increased
         subjects affected / exposed
    21 / 246 (8.54%)
    23 / 255 (9.02%)
         occurrences all number
    43
    48
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    15 / 246 (6.10%)
    13 / 255 (5.10%)
         occurrences all number
    26
    24
    Platelet count decreased
         subjects affected / exposed
    28 / 246 (11.38%)
    37 / 255 (14.51%)
         occurrences all number
    49
    83
    Neutrophil count decreased
         subjects affected / exposed
    28 / 246 (11.38%)
    33 / 255 (12.94%)
         occurrences all number
    62
    70
    Transaminases increased
         subjects affected / exposed
    18 / 246 (7.32%)
    10 / 255 (3.92%)
         occurrences all number
    19
    11
    Weight decreased
         subjects affected / exposed
    12 / 246 (4.88%)
    15 / 255 (5.88%)
         occurrences all number
    15
    15
    White blood cell count decreased
         subjects affected / exposed
    24 / 246 (9.76%)
    23 / 255 (9.02%)
         occurrences all number
    45
    65
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    22 / 246 (8.94%)
    22 / 255 (8.63%)
         occurrences all number
    28
    24
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    40 / 246 (16.26%)
    44 / 255 (17.25%)
         occurrences all number
    50
    53
    Cough
         subjects affected / exposed
    55 / 246 (22.36%)
    60 / 255 (23.53%)
         occurrences all number
    71
    71
    Epistaxis
         subjects affected / exposed
    34 / 246 (13.82%)
    23 / 255 (9.02%)
         occurrences all number
    37
    28
    Hiccups
         subjects affected / exposed
    22 / 246 (8.94%)
    20 / 255 (7.84%)
         occurrences all number
    24
    21
    Hypoxia
         subjects affected / exposed
    17 / 246 (6.91%)
    10 / 255 (3.92%)
         occurrences all number
    21
    12
    Nasal congestion
         subjects affected / exposed
    8 / 246 (3.25%)
    18 / 255 (7.06%)
         occurrences all number
    8
    20
    Oropharyngeal pain
         subjects affected / exposed
    30 / 246 (12.20%)
    41 / 255 (16.08%)
         occurrences all number
    33
    42
    Rhinorrhoea
         subjects affected / exposed
    18 / 246 (7.32%)
    16 / 255 (6.27%)
         occurrences all number
    19
    17
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    66 / 246 (26.83%)
    75 / 255 (29.41%)
         occurrences all number
    146
    160
    Febrile neutropenia
         subjects affected / exposed
    91 / 246 (36.99%)
    92 / 255 (36.08%)
         occurrences all number
    101
    98
    Leukopenia
         subjects affected / exposed
    20 / 246 (8.13%)
    23 / 255 (9.02%)
         occurrences all number
    51
    56
    Neutropenia
         subjects affected / exposed
    65 / 246 (26.42%)
    65 / 255 (25.49%)
         occurrences all number
    99
    98
    Pancytopenia
         subjects affected / exposed
    21 / 246 (8.54%)
    18 / 255 (7.06%)
         occurrences all number
    21
    19
    Thrombocytopenia
         subjects affected / exposed
    49 / 246 (19.92%)
    48 / 255 (18.82%)
         occurrences all number
    131
    111
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    33 / 246 (13.41%)
    33 / 255 (12.94%)
         occurrences all number
    44
    38
    Dysgeusia
         subjects affected / exposed
    23 / 246 (9.35%)
    22 / 255 (8.63%)
         occurrences all number
    24
    22
    Headache
         subjects affected / exposed
    103 / 246 (41.87%)
    103 / 255 (40.39%)
         occurrences all number
    150
    153
    Neuropathy peripheral
         subjects affected / exposed
    14 / 246 (5.69%)
    17 / 255 (6.67%)
         occurrences all number
    17
    17
    Tremor
         subjects affected / exposed
    23 / 246 (9.35%)
    46 / 255 (18.04%)
         occurrences all number
    24
    49
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    12 / 246 (4.88%)
    17 / 255 (6.67%)
         occurrences all number
    12
    18
    Dry eye
         subjects affected / exposed
    42 / 246 (17.07%)
    37 / 255 (14.51%)
         occurrences all number
    45
    39
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    13 / 246 (5.28%)
    8 / 255 (3.14%)
         occurrences all number
    15
    11
    Abdominal distension
         subjects affected / exposed
    15 / 246 (6.10%)
    22 / 255 (8.63%)
         occurrences all number
    18
    22
    Abdominal pain
         subjects affected / exposed
    62 / 246 (25.20%)
    60 / 255 (23.53%)
         occurrences all number
    84
    83
    Abdominal pain upper
         subjects affected / exposed
    26 / 246 (10.57%)
    33 / 255 (12.94%)
         occurrences all number
    32
    37
    Constipation
         subjects affected / exposed
    90 / 246 (36.59%)
    103 / 255 (40.39%)
         occurrences all number
    119
    128
    Diarrhoea
         subjects affected / exposed
    166 / 246 (67.48%)
    167 / 255 (65.49%)
         occurrences all number
    242
    244
    Dyspepsia
         subjects affected / exposed
    31 / 246 (12.60%)
    25 / 255 (9.80%)
         occurrences all number
    35
    27
    Dry mouth
         subjects affected / exposed
    30 / 246 (12.20%)
    25 / 255 (9.80%)
         occurrences all number
    35
    31
    Gastritis
         subjects affected / exposed
    19 / 246 (7.72%)
    19 / 255 (7.45%)
         occurrences all number
    20
    19
    Gastrooesophageal reflux disease
         subjects affected / exposed
    24 / 246 (9.76%)
    16 / 255 (6.27%)
         occurrences all number
    25
    17
    Nausea
         subjects affected / exposed
    178 / 246 (72.36%)
    177 / 255 (69.41%)
         occurrences all number
    273
    261
    Haemorrhoids
         subjects affected / exposed
    27 / 246 (10.98%)
    23 / 255 (9.02%)
         occurrences all number
    28
    26
    Oral pain
         subjects affected / exposed
    19 / 246 (7.72%)
    16 / 255 (6.27%)
         occurrences all number
    20
    17
    Proctalgia
         subjects affected / exposed
    20 / 246 (8.13%)
    20 / 255 (7.84%)
         occurrences all number
    23
    20
    Stomatitis
         subjects affected / exposed
    79 / 246 (32.11%)
    69 / 255 (27.06%)
         occurrences all number
    105
    96
    Vomiting
         subjects affected / exposed
    125 / 246 (50.81%)
    122 / 255 (47.84%)
         occurrences all number
    195
    178
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    20 / 246 (8.13%)
    29 / 255 (11.37%)
         occurrences all number
    25
    33
    Haematuria
         subjects affected / exposed
    7 / 246 (2.85%)
    15 / 255 (5.88%)
         occurrences all number
    8
    15
    Pollakiuria
         subjects affected / exposed
    8 / 246 (3.25%)
    14 / 255 (5.49%)
         occurrences all number
    9
    16
    Renal failure
         subjects affected / exposed
    17 / 246 (6.91%)
    16 / 255 (6.27%)
         occurrences all number
    19
    17
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    13 / 246 (5.28%)
    16 / 255 (6.27%)
         occurrences all number
    17
    23
    Skin and subcutaneous tissue disorders
    Drug eruption
         subjects affected / exposed
    29 / 246 (11.79%)
    30 / 255 (11.76%)
         occurrences all number
    31
    32
    Dry skin
         subjects affected / exposed
    25 / 246 (10.16%)
    20 / 255 (7.84%)
         occurrences all number
    26
    20
    Erythema
         subjects affected / exposed
    34 / 246 (13.82%)
    28 / 255 (10.98%)
         occurrences all number
    50
    37
    Pruritus
         subjects affected / exposed
    59 / 246 (23.98%)
    67 / 255 (26.27%)
         occurrences all number
    67
    85
    Rash
         subjects affected / exposed
    51 / 246 (20.73%)
    52 / 255 (20.39%)
         occurrences all number
    67
    61
    Rash maculo-papular
         subjects affected / exposed
    12 / 246 (4.88%)
    13 / 255 (5.10%)
         occurrences all number
    15
    17
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    30 / 246 (12.20%)
    27 / 255 (10.59%)
         occurrences all number
    42
    30
    Bone pain
         subjects affected / exposed
    10 / 246 (4.07%)
    13 / 255 (5.10%)
         occurrences all number
    12
    14
    Back pain
         subjects affected / exposed
    44 / 246 (17.89%)
    39 / 255 (15.29%)
         occurrences all number
    52
    39
    Muscle spasms
         subjects affected / exposed
    14 / 246 (5.69%)
    19 / 255 (7.45%)
         occurrences all number
    15
    25
    Muscular weakness
         subjects affected / exposed
    10 / 246 (4.07%)
    14 / 255 (5.49%)
         occurrences all number
    10
    15
    Musculoskeletal pain
         subjects affected / exposed
    19 / 246 (7.72%)
    14 / 255 (5.49%)
         occurrences all number
    21
    14
    Myalgia
         subjects affected / exposed
    19 / 246 (7.72%)
    19 / 255 (7.45%)
         occurrences all number
    23
    22
    Neck pain
         subjects affected / exposed
    16 / 246 (6.50%)
    10 / 255 (3.92%)
         occurrences all number
    18
    10
    Pain in extremity
         subjects affected / exposed
    32 / 246 (13.01%)
    30 / 255 (11.76%)
         occurrences all number
    37
    31
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    72 / 246 (29.27%)
    91 / 255 (35.69%)
         occurrences all number
    89
    109
    Dehydration
         subjects affected / exposed
    13 / 246 (5.28%)
    13 / 255 (5.10%)
         occurrences all number
    31
    16
    Diabetes mellitus
         subjects affected / exposed
    17 / 246 (6.91%)
    8 / 255 (3.14%)
         occurrences all number
    19
    8
    Fluid overload
         subjects affected / exposed
    11 / 246 (4.47%)
    14 / 255 (5.49%)
         occurrences all number
    16
    14
    Hyperglycaemia
         subjects affected / exposed
    54 / 246 (21.95%)
    66 / 255 (25.88%)
         occurrences all number
    81
    90
    Hyperuricaemia
         subjects affected / exposed
    15 / 246 (6.10%)
    10 / 255 (3.92%)
         occurrences all number
    17
    14
    Hyperkalaemia
         subjects affected / exposed
    30 / 246 (12.20%)
    23 / 255 (9.02%)
         occurrences all number
    43
    40
    Hypoalbuminaemia
         subjects affected / exposed
    24 / 246 (9.76%)
    30 / 255 (11.76%)
         occurrences all number
    53
    43
    Hypocalcaemia
         subjects affected / exposed
    28 / 246 (11.38%)
    37 / 255 (14.51%)
         occurrences all number
    51
    58
    Hypokalaemia
         subjects affected / exposed
    92 / 246 (37.40%)
    83 / 255 (32.55%)
         occurrences all number
    140
    120
    Hypomagnesaemia
         subjects affected / exposed
    113 / 246 (45.93%)
    113 / 255 (44.31%)
         occurrences all number
    168
    157
    Hypophosphataemia
         subjects affected / exposed
    24 / 246 (9.76%)
    27 / 255 (10.59%)
         occurrences all number
    28
    30
    Hyponatraemia
         subjects affected / exposed
    26 / 246 (10.57%)
    25 / 255 (9.80%)
         occurrences all number
    32
    42
    Infections and infestations
    BK virus infection
         subjects affected / exposed
    13 / 246 (5.28%)
    13 / 255 (5.10%)
         occurrences all number
    15
    13
    Clostridium difficile infection
         subjects affected / exposed
    17 / 246 (6.91%)
    16 / 255 (6.27%)
         occurrences all number
    18
    16
    Cytomegalovirus infection
         subjects affected / exposed
    45 / 246 (18.29%)
    51 / 255 (20.00%)
         occurrences all number
    68
    64
    Cytomegalovirus viraemia
         subjects affected / exposed
    87 / 246 (35.37%)
    96 / 255 (37.65%)
         occurrences all number
    132
    141
    Device related infection
         subjects affected / exposed
    16 / 246 (6.50%)
    16 / 255 (6.27%)
         occurrences all number
    18
    16
    Epstein-Barr virus infection
         subjects affected / exposed
    15 / 246 (6.10%)
    13 / 255 (5.10%)
         occurrences all number
    16
    15
    Escherichia urinary tract infection
         subjects affected / exposed
    13 / 246 (5.28%)
    11 / 255 (4.31%)
         occurrences all number
    20
    11
    Folliculitis
         subjects affected / exposed
    8 / 246 (3.25%)
    14 / 255 (5.49%)
         occurrences all number
    8
    18
    Nasopharyngitis
         subjects affected / exposed
    15 / 246 (6.10%)
    12 / 255 (4.71%)
         occurrences all number
    15
    14
    Oral candidiasis
         subjects affected / exposed
    17 / 246 (6.91%)
    27 / 255 (10.59%)
         occurrences all number
    18
    31
    Oral herpes
         subjects affected / exposed
    8 / 246 (3.25%)
    17 / 255 (6.67%)
         occurrences all number
    13
    18
    Pneumonia
         subjects affected / exposed
    13 / 246 (5.28%)
    13 / 255 (5.10%)
         occurrences all number
    13
    13
    Staphylococcal bacteraemia
         subjects affected / exposed
    20 / 246 (8.13%)
    17 / 255 (6.67%)
         occurrences all number
    23
    20
    Upper respiratory tract infection
         subjects affected / exposed
    22 / 246 (8.94%)
    27 / 255 (10.59%)
         occurrences all number
    24
    36

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Oct 2013
    The changes include: Removal of all language referencing the donor sub-study. Added to Inclusion Criteria No. 10: clarification that male subjects and their female spouse/partners who are of child bearding potential must be using diaphragms or condoms starting at Screening and continue thought the treatment period and for 90 days after the final study drug administration. Added details to Exclusion Criteria No. 10: the components of the vaccine aminoglycoside antibiotics (kanamycin and the like used for the vaccine production). Added to Exclusion Criteria No. 13: Other subjects considered ineligible by the investigator/sub-investigator. Removal of all language referencing the Home Health Care (HHC) provider and procedures. Added a detailed table to show the time ranges of the specific examinations, observations, etc. Removal of specific language referencing portions of the PGx sub-study procedures that will not be followed in Japan. Removal of references that study drug should be returned to the sponsor or depot. Removed references to drug may be destroyed at the study center. Added that the head of the study drug store manager should take responsibility for the accountability, storage, inventory, reconciliation and returns. Removed the option to have others designated by the Sponsor perform subject unblinding. Revised SAE reporting contact information. Revised who is responsible for submitting expedited reports to the Japanese authorities. Revised that the investigator will report SAEs to the head of the study center and ensure reporting to JUTOKUNA YUUGAIJISHOU. Responsibilities of the investigator were added to judge when the follow up of an SAE is no longer necessary. Responsibilities of the study center head were added with regards to obtaining and reporting new information on serious and unexpected adverse reactions. Added in the always report as serious list to the study appendices.
    01 Oct 2013
    The changes include: Added additional actions for the investigator to take when they do not follow the protocol for medically inevitable reasons in order to avoid urgent risks for subjects. Deleted the rest of world confidentiality language and added Japan confidentiality language. Deleted the rest of world publication language and added Japan publication language. Deleted the rest of world insurance language and procedures and added Japan insurance language.
    28 Mar 2014
    The changes include: Added Multi Gated Acquisition Scan (MUGA) as an acceptable procedure to determine HCT-CI criteria. Revised language to indicate that the first dose of study drug can now be administered within 72 hours prior to the start of conditioning therapy.Added language to state that the platelet count must be greater than or equal to 50,000 mm3 within 3 days prior to all study drug injections, and added clarification that results must be converted to SI units. Added language for donating peripheral stem cells prior to the initiation of mobilization therapy (eg G-CSF) for the purpose of donor blood sample collection.Added criteria and methods language regarding the planned futility analyses.Added language to Inclusion Criteria 4 to state acceptable allelles crossmatch typing.Added language to Inclusion Criteria 6 (g)(i) to specify how refractory anemia is defined. Removed Wingard reference. Added language allowing serum pregnancy testing at Screening and subsequent testing days. Specified that the birth control requirement is for heterosexually active participants. Movedlanguage regarding acceptable forms of birth control to another inclusion criterion and increased the duration of birth control use while in the study. Added language regarding acceptable forms of birth control and male sterilization and increased duration of birth control use while in the study.Revised language to increase duration of birth control use while in the study. Revised the HCT-CI score to exclude subjects that have a comorbidity score of ≥ 4. Specified Polymerase Chain Reaction (PCR) as the type of hepatitis C RNA. Added a statement to clarify components used in manufacturing of the vaccine, kanamycin. Added that cord transplants and haploidentical transplant subjects are excluded because they are expected to have reduced response to ASP0113. Added that subjects with a platelet count of less than 50,000 mm3 within 3 days prior to randomization are excl
    28 Mar 2014
    The changes include: Added that subjects with aplastic anemia or multiple myeloma are excluded. In the Treatment and Study Discontinuation Section, added the criteria that subjects that fail to receive one or more doses of study drug after the first injection but are able to continue in the trial, should not be terminated. Also, included the criteria to allow the PI to use their medical discretion in determining whether a subject should continue with study drug treatment and/or the study. In the Treatment Only Discontinuation Section, added criteria regarding anaphylaxis, seizure, and participation in other interventional trials. Also revised language to clarify follow-up visit requirements for safety reporting purposes. Added instructions of the process for subjects that receive at least one dose of study drug, but do not complete the vaccination regimen. Added language stating that intravenous dose of Aciclovir may be rounded up to the nearest 100 mg. Revised value for the protocol-defined CMV viral load to 1000 IU/mL. a) Revised and added language to allow the Screening visit and Visit 2 to occur on the same day, b) allow the use of local laboratory results to determine eligibility at the Screening Visit,and c) to outline the rescreen/repeat lab parameters during the Screening Period. Added language to state that Screening safety laboratory assessments are to be completed by the local laboratory and beginning at Visit 2, all laboratory assessment are to be completed by the central laboratory. Added row to Table 1 for Karnofsky Performance scale and text to clearly state this will be assessed at Visits 2, 5, 7, 9, 11, 13, and 14. Increased the window to ± 4 days for the CMV & GVHD assessments on Day 7/Week 1(A1). Added a window of ± 10 minutes for vital signs and reactogenicity evaluations done 60 minutes after injection. Revised language regarding length of time concomitant medication information will be captured after the last administration of study drug.
    28 Mar 2014
    The changes include: Removed the optional Abbott whole blood sub-study. Added additional data points to be collected regarding transplant information, such as volume infused, donor race and ethnicity. Added language regarding SAE reporting requirements during the long-term follow-up period. Added language regarding non-clinical data. Clarify by what method the vaccine schedule was determined. Removed first bullet regarding an exploratory analysis and revised language in appendix. Added language to indicate current regulatory status of the Abbott device being used for CMV viral load testing. Removed language related to how to record the grade of GVHD and added a bullet to indicate how to assess chronic GVHD. Added language to indicate how to capture the day of engraftment. Revised language to indicate the information that will be collected by the site on the HEA. Total blood volume to be collected for the study is increased. Added language to include the Data Monitoring Committee’s responsibilities and planned futility analysis. Revised language for the potential of additional components to be incorporated into the composite endpoint. Added reference and include table of protocol defined definitions of comorbidities for the HCT-Comorbidity Index. Revised definition of CMV Retinitis diagnosis to include in vitreous fluid by culture or PCR. Revised language to remove the last sub-bullet in the list regarding all cause mortalities excluding the expected adverse drug reactions (ADRs) with a fatal outcome.
    20 May 2014
    The changes include: Section III – List of Abbreviations and Key Terms-Added MUGA Multi Gated Acquisition Scan Modified HCT-CI Score- Amended to "The subject’s Modified HCT-CI score should must be determined during the Screening period using the history and laboratory results obtained on the day of Screening. Pulmonary function tests (PFTs), multi gated acquisition scans (MUGAs), and/or echocardiograms performed within 6 months (180 days) prior to Screening can be used for scoring pulmonary and cardiac comorbidities."Modified HCT-CI Comorbidity Definitions and Scores - Amended to"*Pulmonary function tests (PFTs), multi gated acquisition scans (MUGAs), and/or echocardiograms performed within 6 months (180 days) prior to Screening may be used for scoring pulmonary and cardiac comorbidities." When assessing Renal function, to convert creatinine from micromoles per liter (Umole/L) to milligrams per deciliter (mg/dL), divide micromoles per liter by 88.4 (Umole/L ÷ 88.4 = mg/dL). The definitions for each comorbidity based on definitions published by Sorror in 2013 are provided below: Protocol Defined Definitions of Comoribidities for the HCT-Comorbidity Index. Arrhythmia (score 1): Any type of arrhythmia that has necessitated the delivery of a specific anti-arrhythmia treatment at any time in the patient’s past medical history. A score is assigned even if the patient was in normal sinus rhythm at the time of data acquisition or at the landmark date. No score is assigned to transient arrhythmias that never required treatment.
    04 Dec 2015
    The changes include: Parts 1 and 2 of the study design are merged into a single 1-part study. Composite endpoint of overall mortality and cytomegalovirus (CMV) end organ disease (EOD) through 1 year post-transplant will be assessed as a primary endpoint. Incidence of grade 3 treatment-emergent infections other than CMV and Time to Grade 3 treatment emergent infections other than CMV were reclassified from secondary to exploratory endpoints. Clarity provided regarding discontinuation subjects who are enrolled in the study and for whom study treatment is permanently discontinued prematurely for any reason. Specify that approximately 500 subjects will be enrolled and receive study drug in the study. Specify that with respect to incidence of other efficacy-related clinical outcomes, subjects with insufficient data to determine status will be assumed to have had the event in question.
    04 Aug 2016
    The changes include: All women < 50 years of age who are not documented to be surgically sterile must have a negative urine or serum pregnancy test at screening and prior to each dose.

    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.
    In Oct 2014 data monitoring committee informed Astellas of the results of the first futility analysis. The FDA considered data for 68 participants included in futility analysis compromised and asked that it is not included in final efficacy analysis.
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