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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Evaluate the Efficacy and Safety of Vedolizumab in the Prophylaxis of Intestinal Acute Graft-Versus-Host Disease in Subjects Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

    Summary
    EudraCT number
    		 2018-002141-11
    Trial protocol
    		 HU   SE   GB   NO   DE   AT   PL   ES   PT   BE   GR   IT   RO   Outside EU/EEA  
    Global end of trial date
    09 May 2022

    Results information
    Results version number
    		 v3(current)
    This version publication date
    18 Jan 2024
    First version publication date
    02 Dec 2022
    Other versions
    		 v1 , v2
    Version creation reason
    • Correction of full data set
    Update data for first secondary endpoint.

    Trial information

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    Trial identification
    Sponsor protocol code
    Vedolizumab-3035
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03657160
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Takeda
    Sponsor organisation address
    40 Landsdowne Street, Cambridge, United States, MA 02139
    Public contact
    Study Director, Takeda, TrialDisclosures@takeda.com
    Scientific contact
    Study Director, Takeda, TrialDisclosures@takeda.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000645-PIP03-18
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    09 May 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 May 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of this study is to evaluate the efficacy of vedolizumab when added to background aGvHD prophylaxis regimen compared to placebo and background aGvHD prophylaxis regimen on intestinal aGvHD-free survival by Day +180 in participants who receive allo-HSCT as treatment for a hematologic malignancy or myeloproliferative disorder.
    Protection of trial subjects
    All study participants were required to read and sign an Informed Consent Form.
    Background therapy
    		 Intestinal acute graft-versus-host disease (aGvHD) prophylaxis regimen.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    06 Feb 2019
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 12 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 20
    Country: Number of subjects enrolled
    Brazil: 4
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    Israel: 7
    Country: Number of subjects enrolled
    Japan: 37
    Country: Number of subjects enrolled
    Korea, Republic of: 22
    Country: Number of subjects enrolled
    Singapore: 4
    Country: Number of subjects enrolled
    United States: 109
    Country: Number of subjects enrolled
    Germany: 20
    Country: Number of subjects enrolled
    Greece: 7
    Country: Number of subjects enrolled
    Italy: 17
    Country: Number of subjects enrolled
    Romania: 2
    Country: Number of subjects enrolled
    Spain: 13
    Country: Number of subjects enrolled
    Switzerland: 5
    Country: Number of subjects enrolled
    Belgium: 10
    Country: Number of subjects enrolled
    Hungary: 2
    Country: Number of subjects enrolled
    Norway: 10
    Country: Number of subjects enrolled
    Portugal: 4
    Country: Number of subjects enrolled
    Russian Federation: 5
    Country: Number of subjects enrolled
    United Kingdom: 12
    Country: Number of subjects enrolled
    Austria: 3
    Country: Number of subjects enrolled
    France: 19
    Country: Number of subjects enrolled
    Poland: 2
    Country: Number of subjects enrolled
    Sweden: 3
    Country: Number of subjects enrolled
    Argentina: 5
    Worldwide total number of subjects
    343
    EEA total number of subjects
    112
    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)
    1
    Adults (18-64 years)
    264
    From 65 to 84 years
    78
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants took part in the study at 95 investigative sites in Canada, United States, Argentina, Brazil, Belgium, France, Germany, Italy, Norway, Portugal, Spain, Sweden, Switzerland, United Kingdom, Austria, Greece, Hungary, Poland, Israel, Romania, Russia, Australia, Japan, Republic of Korea and Singapore from 6 February 2019 to 9 May 2022.

    Pre-assignment
    Screening details
    		 Participants undergoing allogeneic hematopoietic stem cell transplantation (Allo-HSCT) were randomized into 1:1 ratio to receive Vedolizumab 300 mg or vedolizumab-matching placebo.

    Pre-assignment period milestones
    Number of subjects started
    		 343
    Number of subjects completed
    		 333

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Adverse event, non-fatal: 1
    Reason: Number of subjects
    		 Consent withdrawn by subject: 3
    Reason: Number of subjects
    		 Protocol Deviation: 1
    Reason: Number of subjects
    		 Reason not Specified: 5
    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Vedolizumab placebo-matching, intravenous (IV) infusion, once on Day -1 along with background graft-versus-host disease (GvHD) prophylaxis regimen prior to Allo-HSCT and once on Days +13, +41, +69, +97, +125, and +153 post Allo-HSCT.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Vedolizumab placebo-matching intravenous infusion.

    Arm title
    		 Vedolizumab 300 mg
    Arm description
    		 Vedolizumab 300 mg, IV, once on Day -1 along with background graft-versus-host disease (GvHD) prophylaxis regimen prior to Allo-HSCT and once on Days +13, +41, +69, +97, +125, and +153 post Allo-HSCT.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vedolizumab
    Investigational medicinal product code
    Other name
    MLN0002
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Vedolizumab intravenous infusion.

    Number of subjects in period 1 [1]
    		Placebo Vedolizumab 300 mg
    Started
    165
    168
    Completed
    98
    116
    Not completed
    67
    52
         Adverse event, serious fatal
    33
    26
         Unsatisfactory Therapeutic Response
    5
    3
         Consent withdrawn by subject
    17
    14
         Adverse event, non-fatal
    4
    6
         Protocol Deviation
    3
    -
         Site Terminated
    1
    -
         Death (COVID-19-Related)
    1
    -
         Other Reasons COVID-19-Related
    -
    1
         Reason not Specified
    3
    2
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: FAS included all participants who were randomized, received at least 1 dose of the treatment, and under-went allo HSCT.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Vedolizumab placebo-matching, intravenous (IV) infusion, once on Day -1 along with background graft-versus-host disease (GvHD) prophylaxis regimen prior to Allo-HSCT and once on Days +13, +41, +69, +97, +125, and +153 post Allo-HSCT.

    Reporting group title
    Vedolizumab 300 mg
    Reporting group description
    		 Vedolizumab 300 mg, IV, once on Day -1 along with background graft-versus-host disease (GvHD) prophylaxis regimen prior to Allo-HSCT and once on Days +13, +41, +69, +97, +125, and +153 post Allo-HSCT.

    Reporting group values
    		 Placebo Vedolizumab 300 mg Total
    Number of subjects
    		 165 168
    Age Categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 51.9 ± 14.49 50.8 ± 14.41 -
    Gender categorical
    Units: Subjects
        Male
    		 0
        Female
    		 0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 9 16 25
        Not Hispanic or Latino
    		 133 133 266
        Unknown or Not Reported
    		 23 19 42
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 36 29 65
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 2 3 5
        White
    		 114 121 235
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 13 15 28
    Gender
    Units: Subjects
        Male
    		 106 103 209
        Female
    		 59 65 124

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Vedolizumab placebo-matching, intravenous (IV) infusion, once on Day -1 along with background graft-versus-host disease (GvHD) prophylaxis regimen prior to Allo-HSCT and once on Days +13, +41, +69, +97, +125, and +153 post Allo-HSCT.

    Reporting group title
    Vedolizumab 300 mg
    Reporting group description
    		 Vedolizumab 300 mg, IV, once on Day -1 along with background graft-versus-host disease (GvHD) prophylaxis regimen prior to Allo-HSCT and once on Days +13, +41, +69, +97, +125, and +153 post Allo-HSCT.

    Primary: Intestinal aGvHD-Free Survival After Allo-HSCT by +180 Days

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    End point title
    		 Intestinal aGvHD-Free Survival After Allo-HSCT by +180 Days
    End point description
    Intestinal aGvHD Free Survival is the time from the date of first study drug administration (Day-1) to intestinal aGvHD event/death, where an event is defined as death due to any cause or Stage 1-4 intestinal involvement per Acute Graft versus-Host Disease Clinical Stage criteria. Data was censored for participants who have not had the intestinal aGvHD event or died or have had the event after pre-specified timing, e.g., last contact or Day +180 after allo HSCT whichever occurs first. FAS included all participants who were randomized, received at least 1 dose of the treatment, and under-went allo HSCT. As pre-specified in the protocol, Day -1 corresponds to Day 1 of the ADaM data set, and similarly, Day 0 corresponds to Day 2. Therefore, the total duration becomes Day 182. 99 indicates that median was not estimable due to fewer number of participants with events.
    End point type
    Primary
    End point timeframe
    From the date of first dose of study drug to first documented intestinal aGvHD or death, whichever occurs first up to Day +180
    End point values
    		 Placebo Vedolizumab 300 mg
    Number of subjects analysed
    165
    168
    Units: days
        median (full range (min-max))
    99 (14 to 182)
    99 (2 to 182)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Vedolizumab 300 mg v Placebo
    Number of subjects included in analysis
    333
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.27
         upper limit
    		 0.73

    Secondary: Intestinal aGvHD-Free and Relapse-Free Survival

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    End point title
    		 Intestinal aGvHD-Free and Relapse-Free Survival
    End point description
    Intestinal GvHD and Relapse Free Survival is the time from the date of first study drug administration (Day-1) to GvHD event/death/relapse, where an event is defined as death or aGvHD Grade 3-4 by modified Glucksberg criteria or chronic GvHD requiring system immunosuppression or relapse. Data was censored for participants who have not had the event or have had the event after pre-specified timing, e.g., last contact or Day +180 after allo HSCT whichever occurs first. FAS included all participants who were randomized, received at least 1 dose of the treatment, and under-went allo HSCT. As pre-specified in the protocol, Day -1 corresponds to Day 1 of the ADaM data set, and similarly, Day 0 corresponds to Day 2. Therefore, the total duration becomes Day 182. 99 indicates that median was not estimable due to fewer number of participants with events.
    End point type
    Secondary
    End point timeframe
    From the date of first dose of study drug to first documented intestinal aGvHD or death, whichever occurs first up to Day +180
    End point values
    		 Placebo Vedolizumab 300 mg
    Number of subjects analysed
    165
    168
    Units: days
        median (full range (min-max))
    99 (14 to 182)
    99 (2 to 182)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Vedolizumab 300 mg v Placebo
    Number of subjects included in analysis
    333
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0043
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.37
         upper limit
    		 0.86

    Secondary: Grade C-D aGvHD-Free Survival

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    End point title
    		 Grade C-D aGvHD-Free Survival
    End point description
    Grade C-D aGvHD Free Survival is the time from the date of first study drug administration (Day-1) to GvHD event/death, where an event is defined as Grade C-D aGvHD any organ involvement per International Bone Marrow Transplant Registry Database (IBMTR) Severity Index for aGvHD or death. It will be censored for participants who have not had the event or have had the event after pre-specified timing, eg, last contact or Day +180 after allo-HSCT whichever occurs first. FAS included all participants who were randomized, received at least 1 dose of the treatment, and under-went allo HSCT. As pre-specified in the protocol, Day -1 corresponds to Day 1 of the ADaM data set, and similarly, Day 0 corresponds to Day 2. Therefore, the total duration becomes Day 182. 99 indicates that median was not estimable due to fewer number of participants with events.
    End point type
    Secondary
    End point timeframe
    From the date of first dose of study drug to first documented intestinal aGvHD or death, whichever occurs first up to Day +180
    End point values
    		 Placebo Vedolizumab 300 mg
    Number of subjects analysed
    165
    168
    Units: days
        median (full range (min-max))
    99 (12 to 182)
    99 (12 to 182)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Vedolizumab 300 mg v Placebo
    Number of subjects included in analysis
    333
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0204
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.39
         upper limit
    		 0.91

    Secondary: Nonrelapse Mortality (NRM)

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    End point title
    		 Nonrelapse Mortality (NRM)
    End point description
    Non-relapse mortality is the time from the date of first study drug administration (Day-1) to death without occurrence of a relapse. Data was censored for participants who have not had the event or have had the event after pre-specified timing, e.g., last contact or Day +180 after allo HSCT whichever occurs first. As pre-specified in the protocol, Day -1 corresponds to Day 1 of the ADaM data set, and similarly, Day 0 corresponds to Day 2. Therefore, the total duration becomes Day 182. FAS included all participants who were randomized, received at least 1 dose of the treatment, and under-went allo HSCT. 99 indicates that median was not estimable due to fewer number of participants with events.
    End point type
    Secondary
    End point timeframe
    From the date of first dose of study drug to first documented intestinal aGvHD or death, whichever occurs first up to Day +180
    End point values
    		 Placebo Vedolizumab 300 mg
    Number of subjects analysed
    165
    168
    Units: days
        median (full range (min-max))
    99 (14 to 182)
    99 (19 to 182)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Vedolizumab 300 mg v Placebo
    Number of subjects included in analysis
    333
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0668
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.48
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.22
         upper limit
    		 1.04

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    Overall Survival by Days +180 is the time from the date of first study drug administration (Day-1) to death from any cause. FAS included all participants who were randomized, received at least 1 dose of the treatment, and under-went allo HSCT. As pre-specified in the protocol, Day -1 corresponds to Day 1 of the ADaM data set, and similarly, Day 0 corresponds to Day 2. Therefore, the total duration becomes Day 182. 99 indicates that median was not estimable due to fewer number of participants with events.
    End point type
    Secondary
    End point timeframe
    From the date of first dose of study drug to first documented death up to Day +180
    End point values
    		 Placebo Vedolizumab 300 mg
    Number of subjects analysed
    165
    168
    Units: days
        median (full range (min-max))
    99 (14 to 182)
    99 (19 to 182)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Vedolizumab 300 mg v Placebo
    Number of subjects included in analysis
    333
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1458
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.34
         upper limit
    		 1.17

    Secondary: Grade B-D aGvHD-Free Survival

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    End point title
    		 Grade B-D aGvHD-Free Survival
    End point description
    Grade B-D aGvHD Survival is the time from the date of first study drug administration (Day-1) to aGvHD event or death, where an event is defined as death or grade B-D any organ involvement per IBMTR Severity Index for aGvHD. As pre-specified in the protocol, Day -1 corresponds to Day 1 of the ADaM data set, and similarly, Day 0 corresponds to Day 2. Therefore, the total duration becomes Day 182. FAS included all participants who were randomized, received at least 1 dose of the treatment, and under-went allo HSCT. 99 indicates that median was not estimable due to fewer number of participants with events.
    End point type
    Secondary
    End point timeframe
    From the date of first dose of study drug to first documented intestinal aGvHD or death, whichever occurs first up to Day +180
    End point values
    		 Placebo Vedolizumab 300 mg
    Number of subjects analysed
    165
    168
    Units: days
        median (full range (min-max))
    99 (12 to 182)
    99 (12 to 182)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Vedolizumab 300 mg v Placebo
    Number of subjects included in analysis
    333
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0105
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.46
         upper limit
    		 0.91

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first dose of study drug up to end of study (up to 39 months)
    Adverse event reporting additional description
    At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least 1 dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Vedolizumab 300 mg
    Reporting group description
    		 Vedolizumab 300 mg, IV, once on Day -1 along with background graft-versus-host disease (GvHD) prophylaxis regimen prior to Allo-HSCT and once on Days +13, +41, +69, +97, +125, and +153 post Allo-HSCT.

    Reporting group title
    Placebo
    Reporting group description
    		 Vedolizumab placebo-matching, intravenous (IV) infusion, once on Day -1 along with background graft-versus-host disease (GvHD) prophylaxis regimen prior to Allo-HSCT and once on Days +13, +41, +69, +97, +125, and +153 post Allo-HSCT.

    Serious adverse events
    		 Vedolizumab 300 mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    120 / 169 (71.01%)
    114 / 165 (69.09%)
         number of deaths (all causes)
    21
    27
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Diffuse large B-cell lymphoma recurrent
         subjects affected / exposed
    2 / 169 (1.18%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Minimal residual disease
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    T-cell lymphoma recurrent
         subjects affected / exposed
    0 / 169 (0.00%)
    2 / 165 (1.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Acute lymphocytic leukaemia recurrent
         subjects affected / exposed
    3 / 169 (1.78%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Central nervous system leukaemia
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Philadelphia positive acute lymphocytic leukaemia
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic myeloid leukaemia recurrent
         subjects affected / exposed
    3 / 169 (1.78%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Acute myeloid leukaemia recurrent
         subjects affected / exposed
    9 / 169 (5.33%)
    9 / 165 (5.45%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 13
         deaths causally related to treatment / all
    0 / 1
    0 / 4
    Chloroma
         subjects affected / exposed
    2 / 169 (1.18%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphoma
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post transplant lymphoproliferative disorder
         subjects affected / exposed
    0 / 169 (0.00%)
    2 / 165 (1.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Myelodysplastic syndrome
         subjects affected / exposed
    5 / 169 (2.96%)
    3 / 165 (1.82%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Myelofibrosis
         subjects affected / exposed
    1 / 169 (0.59%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenoma benign
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral T-cell lymphoma unspecified recurrent
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Shock haemorrhagic
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venoocclusive disease
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jugular vein thrombosis
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    2 / 169 (1.18%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (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
    1 / 169 (0.59%)
    0 / 165 (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
    1 / 169 (0.59%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperthermia
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    13 / 169 (7.69%)
    13 / 165 (7.88%)
         occurrences causally related to treatment / all
    1 / 15
    0 / 15
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    5 / 169 (2.96%)
    3 / 165 (1.82%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 5
    0 / 3
    Disease progression
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza like illness
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest discomfort
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polyserositis
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Perforated ulcer
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 165 (0.61%)
         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 in intestine
         subjects affected / exposed
    6 / 169 (3.55%)
    16 / 165 (9.70%)
         occurrences causally related to treatment / all
    1 / 6
    1 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Acute graft versus host disease in liver
         subjects affected / exposed
    5 / 169 (2.96%)
    2 / 165 (1.21%)
         occurrences causally related to treatment / all
    0 / 7
    1 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Acute graft versus host disease
         subjects affected / exposed
    2 / 169 (1.18%)
    5 / 165 (3.03%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Acute graft versus host disease in skin
         subjects affected / exposed
    3 / 169 (1.78%)
    4 / 165 (2.42%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic graft versus host disease
         subjects affected / exposed
    2 / 169 (1.18%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic graft versus host disease in liver
         subjects affected / exposed
    0 / 169 (0.00%)
    2 / 165 (1.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Engraftment syndrome
         subjects affected / exposed
    1 / 169 (0.59%)
    2 / 165 (1.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Graft versus host disease in eye
         subjects affected / exposed
    1 / 169 (0.59%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Graft versus host disease in gastrointestinal tract
         subjects affected / exposed
    1 / 169 (0.59%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute graft versus host disease oral
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 165 (0.61%)
         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 in lung
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (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 skin
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (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 oral
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Graft versus host disease in lung
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (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
    Respiratory distress
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchiolitis obliterans syndrome
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    2 / 169 (1.18%)
    3 / 165 (1.82%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Epiglottic oedema
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Idiopathic pneumonia syndrome
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (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
    0 / 169 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pulmonary alveolar haemorrhage
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngeal oedema
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (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
    2 / 169 (1.18%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    2 / 169 (1.18%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory failure
         subjects affected / exposed
    5 / 169 (2.96%)
    3 / 165 (1.82%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 3
    0 / 2
    Acute Respiratory failure
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    2 / 169 (1.18%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    3 / 169 (1.78%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    1 / 169 (0.59%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Pseudomonas test positive
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blast cell count increased
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    9 / 169 (5.33%)
    4 / 165 (2.42%)
         occurrences causally related to treatment / all
    1 / 10
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 169 (1.18%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    2 / 169 (1.18%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alanine aminotransferase abnormal
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 169 (0.59%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (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
    Subdural haematoma
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haemorrhage
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 169 (0.59%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prescribed overdose
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Engraft failure
         subjects affected / exposed
    4 / 169 (2.37%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transplant failure
         subjects affected / exposed
    3 / 169 (1.78%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delayed engraftment
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failures
         subjects affected / exposed
    1 / 169 (0.59%)
    2 / 165 (1.21%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Myocardial infarction
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocarditis
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Hemorrhage intracranial
         subjects affected / exposed
    1 / 169 (0.59%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Ataxia
         subjects affected / exposed
    1 / 169 (0.59%)
    2 / 165 (1.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral venous sinus thrombosis
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Altered state of consciousness
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 169 (0.59%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 169 (0.00%)
    2 / 165 (1.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial paralysis
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Posterior reversible encephalopathy syndrome
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 169 (0.59%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Partial seizures
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuralgia
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (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 / 169 (0.59%)
    3 / 165 (1.82%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenias
         subjects affected / exposed
    1 / 169 (0.59%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    5 / 169 (2.96%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aplastic anaemia
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (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
    7 / 169 (4.14%)
    8 / 165 (4.85%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 10
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo positional
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Neutropenic colitis
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (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
    6 / 169 (3.55%)
    4 / 165 (2.42%)
         occurrences causally related to treatment / all
    0 / 6
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    2 / 169 (1.18%)
    4 / 165 (2.42%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal food impaction
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 165 (0.61%)
         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 / 169 (1.18%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    4 / 169 (2.37%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 169 (0.59%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    5 / 169 (2.96%)
    4 / 165 (2.42%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Choleostasis
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver disorder
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (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
    2 / 169 (1.18%)
    4 / 165 (2.42%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Autoimmune hepatitis
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 165 (0.61%)
         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
    Rash macular
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (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
    Micturition urgency
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrotic syndrome
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephropathy toxic
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis haemorrhagic
         subjects affected / exposed
    4 / 169 (2.37%)
    2 / 165 (1.21%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 169 (0.59%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    3 / 169 (1.78%)
    8 / 165 (4.85%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prerenal failure
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 169 (0.00%)
    2 / 165 (1.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Pain in jaw
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Enterocolitis infectious
         subjects affected / exposed
    2 / 169 (1.18%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atypical mycobacterial infection
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acinetobacter infection
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anorectal cellulitis
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial infection
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic candida
         subjects affected / exposed
    2 / 169 (1.18%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalitis
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Extradural abscess
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    1 / 169 (0.59%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    2 / 169 (1.18%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus infection reactivation
         subjects affected / exposed
    6 / 169 (3.55%)
    2 / 165 (1.21%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus colitis
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus infection
         subjects affected / exposed
    2 / 169 (1.18%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epstein-Barr virus infection reactivation
         subjects affected / exposed
    0 / 169 (0.00%)
    2 / 165 (1.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia bacteraemia
         subjects affected / exposed
    2 / 169 (1.18%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Escherichia infection
         subjects affected / exposed
    1 / 169 (0.59%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fungal infection
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis fungal
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    2 / 169 (1.18%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Human herpesvirus 6 encephalitis
         subjects affected / exposed
    1 / 169 (0.59%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 169 (0.59%)
    2 / 165 (1.21%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 169 (0.59%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Wound infection
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella bacteraemia
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (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 / 169 (2.96%)
    8 / 165 (4.85%)
         occurrences causally related to treatment / all
    1 / 7
    1 / 8
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    Klebsiella sepsis
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheobronchitis
         subjects affected / exposed
    1 / 169 (0.59%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung abscess
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epididymitis
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 165 (0.61%)
         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
    0 / 169 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Human polyomavirus infection
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia pseudomonal
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed
    1 / 169 (0.59%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory syncytial virus bronchitis
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhinovirus infection
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    4 / 169 (2.37%)
    9 / 165 (5.45%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Bacteraemia
         subjects affected / exposed
    0 / 169 (0.00%)
    5 / 165 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    4 / 169 (2.37%)
    4 / 165 (2.42%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic embolus
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic encephalopathy
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (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
    1 / 169 (0.59%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    1 / 169 (0.59%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral toxoplasmosis
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (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
    1 / 169 (0.59%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular device infection
         subjects affected / exposed
    1 / 169 (0.59%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis viral
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Metabolic acidosis
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 165 (0.61%)
         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 / 169 (1.18%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    0 / 169 (0.00%)
    2 / 165 (1.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    2 / 169 (1.18%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 2
    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
    		 Vedolizumab 300 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    169 / 169 (100.00%)
    164 / 165 (99.39%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    54 / 169 (31.95%)
    54 / 165 (32.73%)
         occurrences all number
    63
    65
    Hypotension
         subjects affected / exposed
    19 / 169 (11.24%)
    12 / 165 (7.27%)
         occurrences all number
    21
    13
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    80 / 169 (47.34%)
    62 / 165 (37.58%)
         occurrences all number
    129
    95
    Fatigue
         subjects affected / exposed
    38 / 169 (22.49%)
    50 / 165 (30.30%)
         occurrences all number
    51
    64
    Oedema Peripheral
         subjects affected / exposed
    29 / 169 (17.16%)
    35 / 165 (21.21%)
         occurrences all number
    34
    49
    Asthenia
         subjects affected / exposed
    14 / 169 (8.28%)
    12 / 165 (7.27%)
         occurrences all number
    14
    16
    Chills
         subjects affected / exposed
    11 / 169 (6.51%)
    10 / 165 (6.06%)
         occurrences all number
    16
    11
    Oedema
         subjects affected / exposed
    7 / 169 (4.14%)
    13 / 165 (7.88%)
         occurrences all number
    7
    15
    Pain
         subjects affected / exposed
    4 / 169 (2.37%)
    11 / 165 (6.67%)
         occurrences all number
    4
    11
    Immune system disorders
    Acute Graft Versus Host Disease in Skin
         subjects affected / exposed
    67 / 169 (39.64%)
    65 / 165 (39.39%)
         occurrences all number
    84
    81
    Acute Graft Versus Host Disease In Intestine
         subjects affected / exposed
    10 / 169 (5.92%)
    15 / 165 (9.09%)
         occurrences all number
    15
    15
    Chronic Graft Versus Host Disease Oral
         subjects affected / exposed
    14 / 169 (8.28%)
    10 / 165 (6.06%)
         occurrences all number
    17
    11
    Chronic Graft Versus Host Disease In Skin
         subjects affected / exposed
    16 / 169 (9.47%)
    7 / 165 (4.24%)
         occurrences all number
    16
    7
    Chronic Graft Versus Host Disease
         subjects affected / exposed
    10 / 169 (5.92%)
    12 / 165 (7.27%)
         occurrences all number
    10
    12
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    26 / 169 (15.38%)
    25 / 165 (15.15%)
         occurrences all number
    27
    30
    Oropharyngeal Pain
         subjects affected / exposed
    25 / 169 (14.79%)
    16 / 165 (9.70%)
         occurrences all number
    27
    16
    Dyspnoea
         subjects affected / exposed
    16 / 169 (9.47%)
    22 / 165 (13.33%)
         occurrences all number
    18
    28
    Epistaxis
         subjects affected / exposed
    18 / 169 (10.65%)
    17 / 165 (10.30%)
         occurrences all number
    25
    18
    Dyspnoea Exertional
         subjects affected / exposed
    7 / 169 (4.14%)
    15 / 165 (9.09%)
         occurrences all number
    10
    16
    Rhinorrhoea
         subjects affected / exposed
    12 / 169 (7.10%)
    9 / 165 (5.45%)
         occurrences all number
    14
    10
    Pneumonia
         subjects affected / exposed
    9 / 169 (5.33%)
    9 / 165 (5.45%)
         occurrences all number
    9
    9
    Hypoxia
         subjects affected / exposed
    7 / 169 (4.14%)
    11 / 165 (6.67%)
         occurrences all number
    9
    13
    Productive Cough
         subjects affected / exposed
    6 / 169 (3.55%)
    9 / 165 (5.45%)
         occurrences all number
    6
    9
    Nasopharyngitis
         subjects affected / exposed
    9 / 169 (5.33%)
    4 / 165 (2.42%)
         occurrences all number
    11
    6
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    35 / 169 (20.71%)
    32 / 165 (19.39%)
         occurrences all number
    36
    35
    Anxiety
         subjects affected / exposed
    14 / 169 (8.28%)
    14 / 165 (8.48%)
         occurrences all number
    15
    14
    Depression
         subjects affected / exposed
    13 / 169 (7.69%)
    6 / 165 (3.64%)
         occurrences all number
    15
    6
    Confusional State
         subjects affected / exposed
    3 / 169 (1.78%)
    10 / 165 (6.06%)
         occurrences all number
    3
    10
    Investigations
    Platelet Count Decreased
         subjects affected / exposed
    38 / 169 (22.49%)
    47 / 165 (28.48%)
         occurrences all number
    52
    56
    Alanine Aminotransferase Increased
         subjects affected / exposed
    36 / 169 (21.30%)
    26 / 165 (15.76%)
         occurrences all number
    53
    34
    Blood Creatinine Increased
         subjects affected / exposed
    24 / 169 (14.20%)
    35 / 165 (21.21%)
         occurrences all number
    34
    40
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    30 / 169 (17.75%)
    25 / 165 (15.15%)
         occurrences all number
    40
    27
    Blood Bilirubin Increased
         subjects affected / exposed
    21 / 169 (12.43%)
    27 / 165 (16.36%)
         occurrences all number
    25
    27
    Blood Alkaline Phosphatase Increased
         subjects affected / exposed
    16 / 169 (9.47%)
    15 / 165 (9.09%)
         occurrences all number
    17
    19
    Neutrophil Count Decreased
         subjects affected / exposed
    13 / 169 (7.69%)
    15 / 165 (9.09%)
         occurrences all number
    18
    19
    White Blood Cell Count Decreased
         subjects affected / exposed
    10 / 169 (5.92%)
    18 / 165 (10.91%)
         occurrences all number
    13
    21
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    8 / 169 (4.73%)
    9 / 165 (5.45%)
         occurrences all number
    9
    11
    Infusion Related Reaction
         subjects affected / exposed
    9 / 169 (5.33%)
    3 / 165 (1.82%)
         occurrences all number
    10
    3
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    12 / 169 (7.10%)
    6 / 165 (3.64%)
         occurrences all number
    13
    9
    Nervous system disorders
    Headache
         subjects affected / exposed
    58 / 169 (34.32%)
    58 / 165 (35.15%)
         occurrences all number
    76
    80
    Dizziness
         subjects affected / exposed
    21 / 169 (12.43%)
    23 / 165 (13.94%)
         occurrences all number
    23
    33
    Dysgeusia
         subjects affected / exposed
    23 / 169 (13.61%)
    21 / 165 (12.73%)
         occurrences all number
    25
    22
    Tremor
         subjects affected / exposed
    19 / 169 (11.24%)
    21 / 165 (12.73%)
         occurrences all number
    21
    23
    Neuropathy Peripheral
         subjects affected / exposed
    10 / 169 (5.92%)
    9 / 165 (5.45%)
         occurrences all number
    11
    10
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    68 / 169 (40.24%)
    72 / 165 (43.64%)
         occurrences all number
    86
    91
    Febrile Neutropenia
         subjects affected / exposed
    67 / 169 (39.64%)
    54 / 165 (32.73%)
         occurrences all number
    71
    58
    Thrombocytopenia
         subjects affected / exposed
    43 / 169 (25.44%)
    31 / 165 (18.79%)
         occurrences all number
    54
    42
    Neutropenia
         subjects affected / exposed
    40 / 169 (23.67%)
    32 / 165 (19.39%)
         occurrences all number
    46
    38
    Eye disorders
    Dry Eye
         subjects affected / exposed
    34 / 169 (20.12%)
    21 / 165 (12.73%)
         occurrences all number
    36
    25
    Vision Blurred
         subjects affected / exposed
    10 / 169 (5.92%)
    11 / 165 (6.67%)
         occurrences all number
    10
    12
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    95 / 169 (56.21%)
    102 / 165 (61.82%)
         occurrences all number
    142
    141
    Stomatitis
         subjects affected / exposed
    90 / 169 (53.25%)
    90 / 165 (54.55%)
         occurrences all number
    104
    102
    Nausea
         subjects affected / exposed
    85 / 169 (50.30%)
    83 / 165 (50.30%)
         occurrences all number
    109
    110
    Vomiting
         subjects affected / exposed
    41 / 169 (24.26%)
    55 / 165 (33.33%)
         occurrences all number
    58
    75
    Constipation
         subjects affected / exposed
    43 / 169 (25.44%)
    47 / 165 (28.48%)
         occurrences all number
    48
    53
    Abdominal Pain
         subjects affected / exposed
    34 / 169 (20.12%)
    35 / 165 (21.21%)
         occurrences all number
    45
    47
    Dry Mouth
         subjects affected / exposed
    27 / 169 (15.98%)
    28 / 165 (16.97%)
         occurrences all number
    32
    31
    Dyspepsia
         subjects affected / exposed
    13 / 169 (7.69%)
    20 / 165 (12.12%)
         occurrences all number
    13
    22
    Abdominal Pain Upper
         subjects affected / exposed
    16 / 169 (9.47%)
    16 / 165 (9.70%)
         occurrences all number
    21
    19
    Abdominal Distension
         subjects affected / exposed
    13 / 169 (7.69%)
    11 / 165 (6.67%)
         occurrences all number
    14
    12
    Proctalgia
         subjects affected / exposed
    9 / 169 (5.33%)
    15 / 165 (9.09%)
         occurrences all number
    9
    15
    Haemorrhoids
         subjects affected / exposed
    14 / 169 (8.28%)
    8 / 165 (4.85%)
         occurrences all number
    14
    8
    Gastrooesophageal Reflux Disease
         subjects affected / exposed
    9 / 169 (5.33%)
    12 / 165 (7.27%)
         occurrences all number
    10
    12
    Oral Pain
         subjects affected / exposed
    12 / 169 (7.10%)
    7 / 165 (4.24%)
         occurrences all number
    13
    8
    Flatulence
         subjects affected / exposed
    4 / 169 (2.37%)
    10 / 165 (6.06%)
         occurrences all number
    4
    10
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    43 / 169 (25.44%)
    36 / 165 (21.82%)
         occurrences all number
    55
    44
    Pruritus
         subjects affected / exposed
    28 / 169 (16.57%)
    33 / 165 (20.00%)
         occurrences all number
    33
    42
    Dry Skin
         subjects affected / exposed
    23 / 169 (13.61%)
    22 / 165 (13.33%)
         occurrences all number
    26
    26
    Erythema
         subjects affected / exposed
    23 / 169 (13.61%)
    13 / 165 (7.88%)
         occurrences all number
    32
    17
    Rash Maculo-Papular
         subjects affected / exposed
    18 / 169 (10.65%)
    15 / 165 (9.09%)
         occurrences all number
    23
    20
    Urticaria
         subjects affected / exposed
    9 / 169 (5.33%)
    4 / 165 (2.42%)
         occurrences all number
    9
    4
    Renal and urinary disorders
    Acute Kidney Injury
         subjects affected / exposed
    21 / 169 (12.43%)
    20 / 165 (12.12%)
         occurrences all number
    24
    21
    Dysuria
         subjects affected / exposed
    13 / 169 (7.69%)
    12 / 165 (7.27%)
         occurrences all number
    13
    13
    Haematuria
         subjects affected / exposed
    9 / 169 (5.33%)
    13 / 165 (7.88%)
         occurrences all number
    9
    13
    Pollakiuria
         subjects affected / exposed
    9 / 169 (5.33%)
    7 / 165 (4.24%)
         occurrences all number
    9
    8
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    36 / 169 (21.30%)
    20 / 165 (12.12%)
         occurrences all number
    41
    20
    Arthralgia
         subjects affected / exposed
    24 / 169 (14.20%)
    19 / 165 (11.52%)
         occurrences all number
    34
    25
    Pain In Extremity
         subjects affected / exposed
    17 / 169 (10.06%)
    16 / 165 (9.70%)
         occurrences all number
    21
    20
    Infections and infestations
    Cytomegalovirus Infection Reactivation
         subjects affected / exposed
    37 / 169 (21.89%)
    28 / 165 (16.97%)
         occurrences all number
    48
    40
    Metabolism and nutrition disorders
    Hypomagnesaemia
         subjects affected / exposed
    60 / 169 (35.50%)
    52 / 165 (31.52%)
         occurrences all number
    73
    57
    Hypokalaemia
         subjects affected / exposed
    47 / 169 (27.81%)
    54 / 165 (32.73%)
         occurrences all number
    58
    70
    Decreased Appetite
         subjects affected / exposed
    45 / 169 (26.63%)
    40 / 165 (24.24%)
         occurrences all number
    52
    52
    Hyperglycaemia
         subjects affected / exposed
    19 / 169 (11.24%)
    22 / 165 (13.33%)
         occurrences all number
    21
    35
    Hypocalcaemia
         subjects affected / exposed
    22 / 169 (13.02%)
    16 / 165 (9.70%)
         occurrences all number
    23
    17
    Hypoalbuminaemia
         subjects affected / exposed
    17 / 169 (10.06%)
    17 / 165 (10.30%)
         occurrences all number
    17
    18
    Hyponatraemia
         subjects affected / exposed
    15 / 169 (8.88%)
    18 / 165 (10.91%)
         occurrences all number
    15
    21
    Hypophosphataemia
         subjects affected / exposed
    18 / 169 (10.65%)
    14 / 165 (8.48%)
         occurrences all number
    20
    17
    Hyperkalaemia
         subjects affected / exposed
    12 / 169 (7.10%)
    6 / 165 (3.64%)
         occurrences all number
    12
    7
    Hypervolaemia
         subjects affected / exposed
    7 / 169 (4.14%)
    9 / 165 (5.45%)
         occurrences all number
    8
    11

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Jun 2019
    The following is a summary of the changes made in the amendment 06: • Consolidation of the previous local amendments to meet local regulations into a single global amendment. • Addition of final results from the completed Study Vedolizumab-1015. • Clarification of the screening window and that subjects may be rescreened. • Clarification that randomization may occur within 2 days of the first dose of study drug on Day -1. • Clarification of the inclusion and exclusion criteria. • Clarification of the excluded and permitted concomitant medications. • Addition of a criterion for withdrawal of a subject from the study for lack of efficacy. • Clarification of the management of clinical events. • Clarification regarding unscheduled PK sample collection. • Clarification regarding AEs: management of clinical events, specification of AESIs, and reporting periods for collection of AEs and SAEs. • Clarification of the timing of the primary analysis for efficacy and safety. • Clarifications to the footnotes of the schedule of events to align with updates to text.
    18 Sep 2019
    The following is a summary of the changes made in the amendment 07: 1. Clarification of the description of the disease to be treated in adolescent subjects. 2. Addition of results from nonclinical studies related to inclusion of adolescent subjects. 3. Updated human experience as reported in the 9th development safety update report. 4. Update to the study rationale to support the inclusion of adolescent subjects. 5. Update to the benefit:risk profile to support the inclusion of adolescent subjects. 6. Addition of data supporting the dose regimen in adolescent subjects. 7. Update of the inclusion criteria impacted by inclusion of adolescent subjects. 8. Update to permitted medications to include use of topical anesthetic in adolescent subjects. 9. Clarification to the procedures to be conducted after discontinuation or withdrawal of a subject. 10. Added assessment of height to be collected at the end of study visit. 11. Updated the pregnancy testing and contraception requirements to include female adolescent subjects aged 12 years and greater. 12. Addition of necessary age-appropriate documentation that must be completed for adolescent subjects. 13. Addition of blood collection volumes for adolescent and adult subjects. 14. Update to the version of Common Terminology Criteria for Adverse Events to be used for the grading of adverse events. 15. Update to stratification to include age group and data assessments in adolescent subjects. 16. Updates to Appendix A, Schedule of Events footnotes, to align with updates in text. 17. Update to Appendix B regarding methotrexate treatment to support the inclusion of adolescent subjects. 18. Update to Appendix F to include age-appropriate assessments of aGvHD clinical stage and Mount Sinai Acute GVHD International Consortium severity index for aGvHD.

    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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