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    Clinical Trial Results:
    A multi-center, randomized, double-blind, placebo controlled, study to evaluate the efficacy and safety of CSJ148 compared to placebo to prevent human cytomegalovirus (HCMV) replication in stem cell transplant patients

    Summary
    EudraCT number
    		 2014-002150-39
    Trial protocol
    		 DE   BE  
    Global end of trial date
    07 Dec 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Dec 2017
    First version publication date
    23 Dec 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CCSJ148X2201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02268526
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    07 Dec 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Dec 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy of CSJ148 on preventing active HCMV infection during the first 98 days after stem cell transplant. To assess the safety and tolerability of CSJ148 when administered to stem cell transplant recipients
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 Jun 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 12
    Country: Number of subjects enrolled
    Germany: 8
    Country: Number of subjects enrolled
    Korea, Democratic People's Republic of: 13
    Country: Number of subjects enrolled
    Singapore: 12
    Country: Number of subjects enrolled
    Taiwan: 12
    Country: Number of subjects enrolled
    United States: 29
    Worldwide total number of subjects
    86
    EEA total number of subjects
    20
    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)
    70
    From 65 to 84 years
    16
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Cohort 1: Six patients were planned for enrollment; 6 patients were enrolled. Cohort 2: Eighty patients were planned and 80 were enrolled.

    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, Monitor, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort 1: CSJ148
    Arm description
    		 Cohort 1: CSJ148 IV q 4weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    CSJ148
    Investigational medicinal product code
    CSJ148
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    CSJ148 IV infusion every 28 days (days 1, 29, 57 and 85)

    Arm title
    		 Cohort 2: CSJ148
    Arm description
    		 Cohort 2: CSJ148 IV q 4weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    CSJ148
    Investigational medicinal product code
    CSJ148
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    CSJ148 IV infusion every 28 days (days 1, 29, 57 and 85)

    Arm title
    		 Cohort 2: Placebo
    Arm description
    		 Cohort 2: Placebo IV q 4weeks
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    CSJ148
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo to match CSJ148 IV infusion every 28 days (days 1, 29, 57 and 85)

    Number of subjects in period 1
    		Cohort 1: CSJ148 Cohort 2: CSJ148 Cohort 2: Placebo
    Started
    6
    59
    21
    PD analysis set (Cohort 2)
    0 [1]
    42
    17
    Completed
    5
    38
    16
    Not completed
    1
    21
    5
         Adverse event, serious fatal
    1
    11
    -
         Physician decision
    -
    -
    1
         Adverse event, non-fatal
    -
    2
    1
         protocol deviation
    -
    1
    -
         Subject/guardian decision
    -
    7
    3
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The number is correct as recorded.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1: CSJ148
    Reporting group description
    		 Cohort 1: CSJ148 IV q 4weeks

    Reporting group title
    Cohort 2: CSJ148
    Reporting group description
    		 Cohort 2: CSJ148 IV q 4weeks

    Reporting group title
    Cohort 2: Placebo
    Reporting group description
    		 Cohort 2: Placebo IV q 4weeks

    Reporting group values
    		 Cohort 1: CSJ148 Cohort 2: CSJ148 Cohort 2: Placebo Total
    Number of subjects
    		 6 59 21 86
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 6 44 20 70
        From 65-84 years
    		 0 15 1 16
        85 years and over
    		 0 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 52.8 ± 8.70 54.7 ± 12.33 46.0 ± 14.33 -
    Gender, Male/Female
    Units: Subjects
        Female
    		 2 23 6 31
        Male
    		 4 36 15 55
    Subject analysis sets

    Subject analysis set title
    Total CSJ148 (Cohort 1 & Cohort 2)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Cohort 1: CSJ148 IV q 4weeks and Cohort 2: CSJ148 IV q 4weeks

    Subject analysis set title
    Total CSJ148 (Cohort 1 & Cohort 2)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Cohort 1: CSJ148 IV q 4weeks and Cohort 2: CSJ148 IV q 4weeks

    Subject analysis sets values
    		 Total CSJ148 (Cohort 1 & Cohort 2) Total CSJ148 (Cohort 1 & Cohort 2)
    Number of subjects
    65
    65
    Age categorical
    Units: Subjects
        In utero
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
        Newborns (0-27 days)
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
        Children (2-11 years)
    0
    0
        Adolescents (12-17 years)
    0
    0
        Adults (18-64 years)
    50
    50
        From 65-84 years
    15
    15
        85 years and over
    0
    0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    ±
    ±
    Gender, Male/Female
    Units: Subjects
        Female
        Male

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1: CSJ148
    Reporting group description
    		 Cohort 1: CSJ148 IV q 4weeks

    Reporting group title
    Cohort 2: CSJ148
    Reporting group description
    		 Cohort 2: CSJ148 IV q 4weeks

    Reporting group title
    Cohort 2: Placebo
    Reporting group description
    		 Cohort 2: Placebo IV q 4weeks

    Subject analysis set title
    Total CSJ148 (Cohort 1 & Cohort 2)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Cohort 1: CSJ148 IV q 4weeks and Cohort 2: CSJ148 IV q 4weeks

    Subject analysis set title
    Total CSJ148 (Cohort 1 & Cohort 2)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Cohort 1: CSJ148 IV q 4weeks and Cohort 2: CSJ148 IV q 4weeks

    Primary: Number of participants who require preemptive HCMV therapy

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    End point title
    		 Number of participants who require preemptive HCMV therapy [1]
    End point description
    Number of participants who require preemptive HCMV therapy. The definition of requiring preemptive anti-HCMV therapy was meeting either one of the following conditions: 1. the plasma HCMV DNA level is >= 1000 copies/mL (with or without HCMV disease) or 2. the plasma HCMV DNA level is < 1000 copies/mL, but HCMV disease was reported
    End point type
    Primary
    End point timeframe
    98 days
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The number is correct as recorded.
    End point values
    		 Cohort 2: CSJ148 Cohort 2: Placebo Total CSJ148 (Cohort 1 & Cohort 2)
    Number of subjects analysed
    59
    21
    65
    Units: participants
    23
    9
    24
    Statistical analysis title
    		 Participants who require preemptive HCMV therapy
    Comparison groups
    Cohort 2: Placebo v Total CSJ148 (Cohort 1 & Cohort 2)
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.891
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.606
         upper limit
    		 1.305
    Statistical analysis title
    		 Participants who require preemptive HCMV therapy
    Comparison groups
    Cohort 2: CSJ148 v Cohort 2: Placebo
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.941
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.639
         upper limit
    		 1.377

    Primary: Number of participants with adverse events as a measure of safety and tolerability

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    End point title
    		 Number of participants with adverse events as a measure of safety and tolerability [2] [3]
    End point description
    Number of participants with adverse events as a measure of safety and tolerability. Patients treated with CSJ148 in Cohorts 1 and 2 were pooled to simplify the safety analyses. As this is summary of safety there is no statistical analysis for this primary outcome.
    End point type
    Primary
    End point timeframe
    98 days
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As this is summary of safety there is no statistical analysis for this primary outcome.
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The number is correct as recorded.
    End point values
    		 Cohort 2: Placebo Total CSJ148 (Cohort 1 & Cohort 2)
    Number of subjects analysed
    21
    65
    Units: participants
        At least one treatment-emergent AE
    21
    65
        At least one drug-related AE
    2
    0
        At least one SAE
    15
    46
        At least one drug-related SAE
    1
    0
        Deaths
    0
    12
        At least 1 treatment-emergent AE grade 3 or higher
    17
    58
        Total deaths:those reported after study completion
    3
    19
        Discontinued study treatment due to any AE
    1
    1
    No statistical analyses for this end point

    Secondary: Time to start of preemptive HCMV therapy Cohort 2

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    End point title
    		 Time to start of preemptive HCMV therapy Cohort 2 [4]
    End point description
    The time to start preemptive therapy is defined as the number of days between initial dose of study drug and the earlier of (1) the start of preemptive therapy, and (2) the development of HCMV disease or death due to HCMV disease, or (3) censored at the EoT visit if no therapy required for Cohort 2
    End point type
    Secondary
    End point timeframe
    98 days
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The number is correct as recorded.
    End point values
    		 Cohort 2: CSJ148 Cohort 2: Placebo
    Number of subjects analysed
    42
    17
    Units: days
        arithmetic mean (standard deviation)
    62.03 ± 12.145
    49.54 ± 13.470
    No statistical analyses for this end point

    Secondary: Number of times that preemptive HCMV therapy is required -Cohort 2

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    End point title
    		 Number of times that preemptive HCMV therapy is required -Cohort 2 [5]
    End point description
    Among those who required preemptive therapy, the number of times preemptive therapy was required. (Cohort 2)
    End point type
    Secondary
    End point timeframe
    98 days
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The number is correct as recorded.
    End point values
    		 Cohort 2: CSJ148 Cohort 2: Placebo
    Number of subjects analysed
    42
    17
    Units: number of times
        least squares mean (confidence interval 90%)
    2.070 (1.369 to 3.130)
    2.540 (1.342 to 4.806)
    No statistical analyses for this end point

    Secondary: Proportion of participants developing HCMV disease

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    End point title
    		 Proportion of participants developing HCMV disease [6]
    End point description
    Proportion of participants developing HCMV disease
    End point type
    Secondary
    End point timeframe
    98 days
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The number is correct as recorded.
    End point values
    		 Cohort 2: CSJ148 Cohort 2: Placebo
    Number of subjects analysed
    42
    17
    Units: proportion of participants
        number (confidence interval 90%)
    0.119 (0.048 to 0.234)
    0 (0 to 0.162)
    No statistical analyses for this end point

    Secondary: Area under the serum concentration-time curve during the dosing interval (AUCtau) for CSJ148 only

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    End point title
    		 Area under the serum concentration-time curve during the dosing interval (AUCtau) for CSJ148 only
    End point description
    PK parameters were calculated from plasma concentration-time data using non-compartmental methods. The AUCtau was calculated using a linear trapezoidal method
    End point type
    Secondary
    End point timeframe
    Day 1, Day 29, Day 57, Day 85
    End point values
    		 Total CSJ148 (Cohort 1 & Cohort 2)
    Number of subjects analysed
    65
    Units: day*ug/mL
    arithmetic mean (standard deviation)
        Day 1
    7310 ± 2310
        Day 29
    9890 ± 3470
        Day 57
    11400 ± 4020
        Day 85
    12900 ± 4380
    No statistical analyses for this end point

    Secondary: Maximum serum concentration during the dosing interval (Cmax) for CSJ148 only

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    End point title
    		 Maximum serum concentration during the dosing interval (Cmax) for CSJ148 only
    End point description
    Cmax is the observed maximum plasma (or serum or blood) concentration following drug administration [ug / mL] for CSJ148 only
    End point type
    Secondary
    End point timeframe
    Day 1, Day 29, Day 57, Day 85
    End point values
    		 Total CSJ148 (Cohort 1 & Cohort 2)
    Number of subjects analysed
    65
    Units: ug/mL
    arithmetic mean (standard deviation)
        Day 1
    1040 ± 356
        Day 29
    1100 ± 282
        Day 57
    1180 ± 316
        Day 85
    1230 ± 458
    No statistical analyses for this end point

    Secondary: Trough serum concentration (Ctrough) for CSJ148 only

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    End point title
    		 Trough serum concentration (Ctrough) for CSJ148 only
    End point description
    Ctrough is The observed plasma (or serum or blood) concentration at the end of a drug administration dosing interval [ug / mL]
    End point type
    Secondary
    End point timeframe
    Day 1, Day 29, Day 57, Day 85
    End point values
    		 Total CSJ148 (Cohort 1 & Cohort 2)
    Number of subjects analysed
    65
    Units: ug/mL
    arithmetic mean (standard deviation)
        Day 1
    104 ± 59.7
        Day 29
    167 ± 85.5
        Day 57
    214 ± 152
        Day 85
    223 ± 104
    No statistical analyses for this end point

    Secondary: Accumulation ratio(Racc) for CSJ148 only at Day 85

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    End point title
    		 Accumulation ratio(Racc) for CSJ148 only at Day 85
    End point description
    Accumulation ratio(Racc) is Racc: Accumulation ratio, calculated by AUCtau (Day 85) divided by AUCtau (for the 1st dose).
    End point type
    Secondary
    End point timeframe
    Day 1 and Day 85
    End point values
    		 Total CSJ148 (Cohort 1 & Cohort 2)
    Number of subjects analysed
    65
    Units: Ratio
        arithmetic mean (standard deviation)
    1.83 ± 0.531
    No statistical analyses for this end point

    Secondary: Half-life (T1/2) for CSJ148 only at Day 85

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    End point title
    		 Half-life (T1/2) for CSJ148 only at Day 85
    End point description
    T1/2 is the terminal elimination half-life [time]
    End point type
    Secondary
    End point timeframe
    Day 1 and Day 85
    End point values
    		 Total CSJ148 (Cohort 1 & Cohort 2)
    Number of subjects analysed
    65
    Units: day
        arithmetic mean (standard deviation)
    19.7 ± 7.18
    No statistical analyses for this end point

    Secondary: Lambda_z for CSJ148 only at Day 85

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    End point title
    		 Lambda_z for CSJ148 only at Day 85
    End point description
    Lambda_z is the terminal elimination rate constant [1/day] at Day 85
    End point type
    Secondary
    End point timeframe
    Day 1 and Day 85
    End point values
    		 Total CSJ148 (Cohort 1 & Cohort 2)
    Number of subjects analysed
    65
    Units: 1/day
        arithmetic mean (standard deviation)
    0.0409 ± 0.0175
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All adverse events reported in this record are from date of First Patient First Treatment until Last Patient Last Visit.
    Adverse event reporting additional description
    Novartis has reported the SAE field“# of deaths resulting from AEs” all those deaths,resulting from SAEs deemed to be causally related to treatment by the investigator. Additional deaths: 2 in placebo during follow-up (Day 100-183) after early treatment/study discontinuation. 1 in placebo and 7 in CSJ148 post end of study (Day 183).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Total CSJ148
    Reporting group description
    		 Total CSJ148

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Serious adverse events
    		 Total CSJ148 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    46 / 65 (70.77%)
    15 / 21 (71.43%)
         number of deaths (all causes)
    12
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia recurrent
         subjects affected / exposed
    4 / 65 (6.15%)
    2 / 21 (9.52%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Chronic myeloid leukaemia recurrent
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Chronic myelomonocytic leukaemia
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 21 (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
    1 / 65 (1.54%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Prostate cancer metastatic
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer recurrent
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 21 (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
    1 / 65 (1.54%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 65 (3.08%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    3 / 65 (4.62%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 21 (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
    2 / 65 (3.08%)
    2 / 21 (9.52%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Acute graft versus host disease
         subjects affected / exposed
    9 / 65 (13.85%)
    2 / 21 (9.52%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Acute graft versus host disease in liver
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute graft versus host disease in skin
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaphylactic shock
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic graft versus host disease in liver
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    4 / 65 (6.15%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Asthma
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemothorax
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 21 (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 / 65 (1.54%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory failure
         subjects affected / exposed
    3 / 65 (4.62%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Hallucination
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 65 (3.08%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    2 / 65 (3.08%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus test positive
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lipase increased
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Engraft failure
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 21 (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 / 65 (1.54%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transplant failure
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    2 / 65 (3.08%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac tamponade
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracardiac mass
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Facial paresis
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic encephalopathy
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Posterior reversible encephalopathy syndrome
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 21 (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
    Anaemia
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    8 / 65 (12.31%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 13
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Microangiopathic haemolytic anaemia
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Splenic lesion
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombotic microangiopathy
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombotic thrombocytopenic purpura
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    2 / 65 (3.08%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis erosive
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 65 (3.08%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 65 (3.08%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestinal ulcer
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 65 (3.08%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedematous pancreatitis
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal lesion
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 21 (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
    2 / 65 (3.08%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic lesion
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis cholestatic
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 21 (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
    0 / 65 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis bullous
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash erythematous
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 21 (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 / 65 (1.54%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    4 / 65 (6.15%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal disorder
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 21 (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
    Muscular weakness
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 21 (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
    Atypical pneumonia
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteriuria
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus chorioretinitis
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus colitis
         subjects affected / exposed
    2 / 65 (3.08%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus gastritis
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus infection
         subjects affected / exposed
    2 / 65 (3.08%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus viraemia
         subjects affected / exposed
    2 / 65 (3.08%)
    2 / 21 (9.52%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disseminated tuberculosis
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterobacter bacteraemia
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epididymitis tuberculous
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 21 (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
    2 / 65 (3.08%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia bacteraemia
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    2 / 65 (3.08%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Human herpesvirus 6 infection
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    JC virus infection
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella infection
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningoencephalitis herpetic
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ophthalmic herpes zoster
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    5 / 65 (7.69%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia fungal
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pseudomonal bacteraemia
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomonal sepsis
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pseudomonas infection
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhinovirus infection
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    4 / 65 (6.15%)
    2 / 21 (9.52%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    3 / 65 (4.62%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    2 / 65 (3.08%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stenotrophomonas infection
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 21 (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
         subjects affected / exposed
    2 / 65 (3.08%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypophagia
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 21 (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
    0 / 65 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Total CSJ148 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    65 / 65 (100.00%)
    21 / 21 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    23 / 65 (35.38%)
    5 / 21 (23.81%)
         occurrences all number
    25
    5
    Hypotension
         subjects affected / exposed
    9 / 65 (13.85%)
    4 / 21 (19.05%)
         occurrences all number
    12
    4
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    7 / 65 (10.77%)
    2 / 21 (9.52%)
         occurrences all number
    7
    2
    Catheter site erythema
         subjects affected / exposed
    4 / 65 (6.15%)
    2 / 21 (9.52%)
         occurrences all number
    4
    2
    Catheter site pain
         subjects affected / exposed
    6 / 65 (9.23%)
    1 / 21 (4.76%)
         occurrences all number
    6
    3
    Chest discomfort
         subjects affected / exposed
    5 / 65 (7.69%)
    1 / 21 (4.76%)
         occurrences all number
    7
    1
    Chills
         subjects affected / exposed
    15 / 65 (23.08%)
    4 / 21 (19.05%)
         occurrences all number
    20
    4
    Fatigue
         subjects affected / exposed
    18 / 65 (27.69%)
    7 / 21 (33.33%)
         occurrences all number
    23
    7
    Generalised oedema
         subjects affected / exposed
    7 / 65 (10.77%)
    0 / 21 (0.00%)
         occurrences all number
    9
    0
    Non-cardiac chest pain
         subjects affected / exposed
    8 / 65 (12.31%)
    1 / 21 (4.76%)
         occurrences all number
    10
    1
    Oedema peripheral
         subjects affected / exposed
    12 / 65 (18.46%)
    2 / 21 (9.52%)
         occurrences all number
    15
    4
    Pain
         subjects affected / exposed
    6 / 65 (9.23%)
    0 / 21 (0.00%)
         occurrences all number
    7
    0
    Pyrexia
         subjects affected / exposed
    38 / 65 (58.46%)
    10 / 21 (47.62%)
         occurrences all number
    56
    14
    Immune system disorders
    Acute graft versus host disease
         subjects affected / exposed
    10 / 65 (15.38%)
    3 / 21 (14.29%)
         occurrences all number
    10
    4
    Acute graft versus host disease in intestine
         subjects affected / exposed
    4 / 65 (6.15%)
    0 / 21 (0.00%)
         occurrences all number
    4
    0
    Acute graft versus host disease in skin
         subjects affected / exposed
    14 / 65 (21.54%)
    3 / 21 (14.29%)
         occurrences all number
    16
    3
    Chronic graft versus host disease
         subjects affected / exposed
    6 / 65 (9.23%)
    4 / 21 (19.05%)
         occurrences all number
    7
    5
    Chronic graft versus host disease in skin
         subjects affected / exposed
    5 / 65 (7.69%)
    1 / 21 (4.76%)
         occurrences all number
    5
    1
    Reproductive system and breast disorders
    Scrotal pain
         subjects affected / exposed
    0 / 65 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    25 / 65 (38.46%)
    9 / 21 (42.86%)
         occurrences all number
    29
    10
    Dyspnoea
         subjects affected / exposed
    13 / 65 (20.00%)
    3 / 21 (14.29%)
         occurrences all number
    14
    3
    Epistaxis
         subjects affected / exposed
    8 / 65 (12.31%)
    2 / 21 (9.52%)
         occurrences all number
    14
    2
    Haemoptysis
         subjects affected / exposed
    4 / 65 (6.15%)
    0 / 21 (0.00%)
         occurrences all number
    7
    0
    Hiccups
         subjects affected / exposed
    4 / 65 (6.15%)
    2 / 21 (9.52%)
         occurrences all number
    4
    2
    Hypoxia
         subjects affected / exposed
    7 / 65 (10.77%)
    0 / 21 (0.00%)
         occurrences all number
    9
    0
    Nasal congestion
         subjects affected / exposed
    4 / 65 (6.15%)
    2 / 21 (9.52%)
         occurrences all number
    4
    2
    Oropharyngeal pain
         subjects affected / exposed
    12 / 65 (18.46%)
    3 / 21 (14.29%)
         occurrences all number
    12
    3
    Pharyngeal inflammation
         subjects affected / exposed
    5 / 65 (7.69%)
    1 / 21 (4.76%)
         occurrences all number
    5
    1
    Pleural effusion
         subjects affected / exposed
    9 / 65 (13.85%)
    1 / 21 (4.76%)
         occurrences all number
    9
    1
    Productive cough
         subjects affected / exposed
    4 / 65 (6.15%)
    1 / 21 (4.76%)
         occurrences all number
    5
    1
    Rhinorrhoea
         subjects affected / exposed
    3 / 65 (4.62%)
    3 / 21 (14.29%)
         occurrences all number
    4
    3
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    5 / 65 (7.69%)
    0 / 21 (0.00%)
         occurrences all number
    5
    0
    Confusional state
         subjects affected / exposed
    7 / 65 (10.77%)
    0 / 21 (0.00%)
         occurrences all number
    8
    0
    Hallucination
         subjects affected / exposed
    5 / 65 (7.69%)
    0 / 21 (0.00%)
         occurrences all number
    5
    0
    Insomnia
         subjects affected / exposed
    15 / 65 (23.08%)
    6 / 21 (28.57%)
         occurrences all number
    15
    7
    Sleep disorder
         subjects affected / exposed
    1 / 65 (1.54%)
    2 / 21 (9.52%)
         occurrences all number
    1
    2
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    5 / 65 (7.69%)
    2 / 21 (9.52%)
         occurrences all number
    5
    2
    Aspartate aminotransferase increased
         subjects affected / exposed
    4 / 65 (6.15%)
    1 / 21 (4.76%)
         occurrences all number
    4
    1
    Blood bilirubin increased
         subjects affected / exposed
    7 / 65 (10.77%)
    1 / 21 (4.76%)
         occurrences all number
    7
    2
    Blood creatinine increased
         subjects affected / exposed
    8 / 65 (12.31%)
    3 / 21 (14.29%)
         occurrences all number
    9
    3
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    6 / 65 (9.23%)
    0 / 21 (0.00%)
         occurrences all number
    6
    0
    Skin abrasion
         subjects affected / exposed
    4 / 65 (6.15%)
    0 / 21 (0.00%)
         occurrences all number
    4
    0
    Transfusion reaction
         subjects affected / exposed
    5 / 65 (7.69%)
    1 / 21 (4.76%)
         occurrences all number
    5
    1
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    8 / 65 (12.31%)
    2 / 21 (9.52%)
         occurrences all number
    8
    2
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    16 / 65 (24.62%)
    3 / 21 (14.29%)
         occurrences all number
    18
    3
    Headache
         subjects affected / exposed
    24 / 65 (36.92%)
    6 / 21 (28.57%)
         occurrences all number
    33
    6
    Neuropathy peripheral
         subjects affected / exposed
    6 / 65 (9.23%)
    1 / 21 (4.76%)
         occurrences all number
    6
    1
    Syncope
         subjects affected / exposed
    4 / 65 (6.15%)
    0 / 21 (0.00%)
         occurrences all number
    4
    0
    Tremor
         subjects affected / exposed
    4 / 65 (6.15%)
    1 / 21 (4.76%)
         occurrences all number
    4
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    6 / 65 (9.23%)
    4 / 21 (19.05%)
         occurrences all number
    10
    5
    Febrile neutropenia
         subjects affected / exposed
    25 / 65 (38.46%)
    10 / 21 (47.62%)
         occurrences all number
    30
    11
    Neutropenia
         subjects affected / exposed
    6 / 65 (9.23%)
    5 / 21 (23.81%)
         occurrences all number
    10
    6
    Thrombocytopenia
         subjects affected / exposed
    9 / 65 (13.85%)
    3 / 21 (14.29%)
         occurrences all number
    11
    5
    Eye disorders
    Dry eye
         subjects affected / exposed
    14 / 65 (21.54%)
    5 / 21 (23.81%)
         occurrences all number
    15
    6
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    6 / 65 (9.23%)
    1 / 21 (4.76%)
         occurrences all number
    6
    1
    Abdominal distension
         subjects affected / exposed
    6 / 65 (9.23%)
    3 / 21 (14.29%)
         occurrences all number
    8
    3
    Abdominal pain
         subjects affected / exposed
    16 / 65 (24.62%)
    5 / 21 (23.81%)
         occurrences all number
    19
    5
    Abdominal pain upper
         subjects affected / exposed
    5 / 65 (7.69%)
    5 / 21 (23.81%)
         occurrences all number
    5
    5
    Constipation
         subjects affected / exposed
    19 / 65 (29.23%)
    8 / 21 (38.10%)
         occurrences all number
    23
    9
    Diarrhoea
         subjects affected / exposed
    43 / 65 (66.15%)
    12 / 21 (57.14%)
         occurrences all number
    66
    19
    Dry mouth
         subjects affected / exposed
    11 / 65 (16.92%)
    3 / 21 (14.29%)
         occurrences all number
    13
    3
    Dyspepsia
         subjects affected / exposed
    7 / 65 (10.77%)
    3 / 21 (14.29%)
         occurrences all number
    7
    3
    Epigastric discomfort
         subjects affected / exposed
    2 / 65 (3.08%)
    2 / 21 (9.52%)
         occurrences all number
    2
    2
    Gastrointestinal inflammation
         subjects affected / exposed
    8 / 65 (12.31%)
    0 / 21 (0.00%)
         occurrences all number
    8
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    6 / 65 (9.23%)
    0 / 21 (0.00%)
         occurrences all number
    7
    0
    Haemorrhoids
         subjects affected / exposed
    13 / 65 (20.00%)
    2 / 21 (9.52%)
         occurrences all number
    13
    2
    Lip dry
         subjects affected / exposed
    1 / 65 (1.54%)
    2 / 21 (9.52%)
         occurrences all number
    1
    2
    Melaena
         subjects affected / exposed
    4 / 65 (6.15%)
    0 / 21 (0.00%)
         occurrences all number
    6
    0
    Mouth haemorrhage
         subjects affected / exposed
    3 / 65 (4.62%)
    2 / 21 (9.52%)
         occurrences all number
    3
    2
    Nausea
         subjects affected / exposed
    45 / 65 (69.23%)
    14 / 21 (66.67%)
         occurrences all number
    66
    19
    Oesophagitis
         subjects affected / exposed
    9 / 65 (13.85%)
    1 / 21 (4.76%)
         occurrences all number
    9
    1
    Stomatitis
         subjects affected / exposed
    36 / 65 (55.38%)
    15 / 21 (71.43%)
         occurrences all number
    43
    17
    Tongue ulceration
         subjects affected / exposed
    1 / 65 (1.54%)
    2 / 21 (9.52%)
         occurrences all number
    1
    2
    Vomiting
         subjects affected / exposed
    38 / 65 (58.46%)
    14 / 21 (66.67%)
         occurrences all number
    59
    17
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    4 / 65 (6.15%)
    2 / 21 (9.52%)
         occurrences all number
    4
    4
    Skin and subcutaneous tissue disorders
    Blister
         subjects affected / exposed
    4 / 65 (6.15%)
    0 / 21 (0.00%)
         occurrences all number
    5
    0
    Decubitus ulcer
         subjects affected / exposed
    5 / 65 (7.69%)
    0 / 21 (0.00%)
         occurrences all number
    6
    0
    Dry skin
         subjects affected / exposed
    6 / 65 (9.23%)
    4 / 21 (19.05%)
         occurrences all number
    7
    4
    Eczema
         subjects affected / exposed
    1 / 65 (1.54%)
    2 / 21 (9.52%)
         occurrences all number
    1
    3
    Erythema
         subjects affected / exposed
    4 / 65 (6.15%)
    3 / 21 (14.29%)
         occurrences all number
    5
    5
    Petechiae
         subjects affected / exposed
    4 / 65 (6.15%)
    1 / 21 (4.76%)
         occurrences all number
    4
    1
    Pruritus
         subjects affected / exposed
    18 / 65 (27.69%)
    4 / 21 (19.05%)
         occurrences all number
    25
    6
    Rash
         subjects affected / exposed
    24 / 65 (36.92%)
    7 / 21 (33.33%)
         occurrences all number
    29
    7
    Rash generalised
         subjects affected / exposed
    1 / 65 (1.54%)
    2 / 21 (9.52%)
         occurrences all number
    1
    2
    Rash macular
         subjects affected / exposed
    1 / 65 (1.54%)
    2 / 21 (9.52%)
         occurrences all number
    1
    2
    Urticaria
         subjects affected / exposed
    6 / 65 (9.23%)
    2 / 21 (9.52%)
         occurrences all number
    8
    4
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    5 / 65 (7.69%)
    1 / 21 (4.76%)
         occurrences all number
    7
    1
    Chronic kidney disease
         subjects affected / exposed
    0 / 65 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    2
    Dysuria
         subjects affected / exposed
    5 / 65 (7.69%)
    2 / 21 (9.52%)
         occurrences all number
    6
    2
    Haematuria
         subjects affected / exposed
    10 / 65 (15.38%)
    1 / 21 (4.76%)
         occurrences all number
    11
    1
    Pollakiuria
         subjects affected / exposed
    8 / 65 (12.31%)
    2 / 21 (9.52%)
         occurrences all number
    8
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    12 / 65 (18.46%)
    1 / 21 (4.76%)
         occurrences all number
    13
    1
    Back pain
         subjects affected / exposed
    17 / 65 (26.15%)
    5 / 21 (23.81%)
         occurrences all number
    19
    5
    Bone pain
         subjects affected / exposed
    9 / 65 (13.85%)
    1 / 21 (4.76%)
         occurrences all number
    11
    1
    Musculoskeletal pain
         subjects affected / exposed
    4 / 65 (6.15%)
    0 / 21 (0.00%)
         occurrences all number
    4
    0
    Myalgia
         subjects affected / exposed
    7 / 65 (10.77%)
    1 / 21 (4.76%)
         occurrences all number
    7
    1
    Pain in extremity
         subjects affected / exposed
    5 / 65 (7.69%)
    2 / 21 (9.52%)
         occurrences all number
    5
    4
    Infections and infestations
    Candida infection
         subjects affected / exposed
    5 / 65 (7.69%)
    0 / 21 (0.00%)
         occurrences all number
    5
    0
    Clostridium difficile infection
         subjects affected / exposed
    5 / 65 (7.69%)
    0 / 21 (0.00%)
         occurrences all number
    5
    0
    Device related infection
         subjects affected / exposed
    3 / 65 (4.62%)
    2 / 21 (9.52%)
         occurrences all number
    3
    2
    Folliculitis
         subjects affected / exposed
    7 / 65 (10.77%)
    2 / 21 (9.52%)
         occurrences all number
    8
    2
    Herpes zoster
         subjects affected / exposed
    4 / 65 (6.15%)
    2 / 21 (9.52%)
         occurrences all number
    4
    2
    Human herpesvirus 6 infection
         subjects affected / exposed
    4 / 65 (6.15%)
    1 / 21 (4.76%)
         occurrences all number
    6
    1
    Oral candidiasis
         subjects affected / exposed
    5 / 65 (7.69%)
    3 / 21 (14.29%)
         occurrences all number
    5
    3
    Oral herpes
         subjects affected / exposed
    4 / 65 (6.15%)
    1 / 21 (4.76%)
         occurrences all number
    5
    1
    Papilloma viral infection
         subjects affected / exposed
    0 / 65 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    2
    Pneumonia
         subjects affected / exposed
    4 / 65 (6.15%)
    0 / 21 (0.00%)
         occurrences all number
    4
    0
    Rhinovirus infection
         subjects affected / exposed
    1 / 65 (1.54%)
    2 / 21 (9.52%)
         occurrences all number
    1
    2
    Staphylococcal bacteraemia
         subjects affected / exposed
    5 / 65 (7.69%)
    3 / 21 (14.29%)
         occurrences all number
    5
    3
    Upper respiratory tract infection
         subjects affected / exposed
    8 / 65 (12.31%)
    4 / 21 (19.05%)
         occurrences all number
    8
    4
    Urinary tract infection
         subjects affected / exposed
    5 / 65 (7.69%)
    1 / 21 (4.76%)
         occurrences all number
    10
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    27 / 65 (41.54%)
    7 / 21 (33.33%)
         occurrences all number
    33
    8
    Fluid overload
         subjects affected / exposed
    5 / 65 (7.69%)
    1 / 21 (4.76%)
         occurrences all number
    7
    1
    Hyperglycaemia
         subjects affected / exposed
    8 / 65 (12.31%)
    1 / 21 (4.76%)
         occurrences all number
    8
    1
    Hyperkalaemia
         subjects affected / exposed
    6 / 65 (9.23%)
    1 / 21 (4.76%)
         occurrences all number
    8
    1
    Hypocalcaemia
         subjects affected / exposed
    7 / 65 (10.77%)
    1 / 21 (4.76%)
         occurrences all number
    9
    1
    Hypokalaemia
         subjects affected / exposed
    20 / 65 (30.77%)
    5 / 21 (23.81%)
         occurrences all number
    27
    5
    Hypomagnesaemia
         subjects affected / exposed
    9 / 65 (13.85%)
    4 / 21 (19.05%)
         occurrences all number
    10
    4
    Hypophosphataemia
         subjects affected / exposed
    6 / 65 (9.23%)
    3 / 21 (14.29%)
         occurrences all number
    10
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Sep 2014
    Amendment 1 introduced the following changes: 1) New weight inclusion criterion to comply with the WHO limit for total human exposure to DNA (< 10ng/dose). Based on the DNA content of the current formulation and limitations of the current purification process, an upper body weight of 120 kg is the maximum permitted to comply with the total human exposure and allow for minor variability in the residual DNA content of the formulation. 2) Other changes made included those that facilitated the execution of the trial, added safety data from the first-in- human study CCSJ148X2101, and made administrative modifications and corrected typographical errors.
    12 Aug 2015
    Amendment 2 introduced the following changes: 1) Modified the PK collection time points at 120 minutes and 132 minutes post dose to one PK time point at 3 hour in order to allow all blood draws to be taken from a central catheter and not from direct venipuncture. 2) Increased the threshold for exclusion of severe liver injury. Liver abnormalities are not expected toxicities based on the type of compound (mAb), pre-clinical and first in human data. Additionally, many patients have mildly elevated liver function tests (LFTs) at screening (around 3 ULN) and go ahead Hematopoietic Stem Cell Transplantation (HSCT) procedure. Appendix 2 (Liver event definitions and follow up) was eliminated. 3) Other changes made included those that facilitated the execution of the trial, added safety data from the first-in- human study CCSJ148X2101, and made administrative modifications and corrected typographical errors.

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

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