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    Clinical Trial Results:
    A randomized, double-blind, placebo-controlled phase III multi-center study of azacitidine with or without MBG453 for the treatment of patients with intermediate, high or very high risk myelodysplastic syndrome (MDS) as per IPSS-R, or Chronic Myelomonocytic Leukemia-2 (CMML-2)

    Summary
    EudraCT number
    		 2019-002089-11
    Trial protocol
    		 DE   FR   CZ   BE   IT   ES   AT   GB   PT   FI   LT   NL   GR  
    Global end of trial date
    02 Oct 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Oct 2025
    First version publication date
    23 Oct 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CMBG453B12301
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04266301
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma, AG
    Sponsor organisation address
    Lichtstrasse 35, Basel, Switzerland, 4056
    Public contact
    Clinical Disclosure Office, Novartis Pharma, AG, 41 613241111, novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma, AG, 41 613241111, novartis.email@novartis.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    02 Oct 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Oct 2024
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To compare overall survival (OS) in the MBG453 plus azacitidine arm vs. placebo plus azacitidine arm
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    08 Jun 2020
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 2
    Country: Number of subjects enrolled
    Australia: 17
    Country: Number of subjects enrolled
    Austria: 10
    Country: Number of subjects enrolled
    Belgium: 20
    Country: Number of subjects enrolled
    Brazil: 9
    Country: Number of subjects enrolled
    Canada: 4
    Country: Number of subjects enrolled
    Chile: 1
    Country: Number of subjects enrolled
    China: 74
    Country: Number of subjects enrolled
    Colombia: 3
    Country: Number of subjects enrolled
    Czechia: 14
    Country: Number of subjects enrolled
    Finland: 3
    Country: Number of subjects enrolled
    France: 24
    Country: Number of subjects enrolled
    Germany: 21
    Country: Number of subjects enrolled
    United Kingdom: 6
    Country: Number of subjects enrolled
    Greece: 8
    Country: Number of subjects enrolled
    India: 12
    Country: Number of subjects enrolled
    Israel: 5
    Country: Number of subjects enrolled
    Italy: 38
    Country: Number of subjects enrolled
    Japan: 49
    Country: Number of subjects enrolled
    Korea, Republic of: 31
    Country: Number of subjects enrolled
    Lebanon: 1
    Country: Number of subjects enrolled
    Lithuania: 4
    Country: Number of subjects enrolled
    Malaysia: 12
    Country: Number of subjects enrolled
    Mexico: 8
    Country: Number of subjects enrolled
    Netherlands: 2
    Country: Number of subjects enrolled
    Oman: 3
    Country: Number of subjects enrolled
    Portugal: 3
    Country: Number of subjects enrolled
    Russian Federation: 3
    Country: Number of subjects enrolled
    Saudi Arabia: 1
    Country: Number of subjects enrolled
    Singapore: 20
    Country: Number of subjects enrolled
    Spain: 41
    Country: Number of subjects enrolled
    Switzerland: 3
    Country: Number of subjects enrolled
    Taiwan: 15
    Country: Number of subjects enrolled
    Thailand: 21
    Country: Number of subjects enrolled
    Türkiye: 21
    Country: Number of subjects enrolled
    United States: 21
    Worldwide total number of subjects
    530
    EEA total number of subjects
    188
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    126
    From 65 to 84 years
    381
    85 years and over
    23

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study randomized participants in 149 centers in 36 participating countries.

    Pre-assignment
    Screening details
    		 Following completion of screening procedure, all eligible participants were randomized via Interactive Response Technology (IRT) to one of the treatment arms.

    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Sabatolimab (MBG453) + Azacitidine
    Arm description
    		 Participants were randomized to sabatolimab plus Azacitidine
    Arm type
    		 Experimental

    Investigational medicinal product name
    Azacitidine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet, Injection
    Routes of administration
    Intravenous use, Subcutaneous use
    Dosage and administration details
    100 mg or other locally available dose strengths was administeredaccording to local standard clinical practice. A standard dose ofazacitidine (75mg/m2) was given based on local azacitidinepackage insert every day for seven consecutive days on Days 1 to7 of a 28-day cycle, followed by sabatolimab.

    Investigational medicinal product name
    Sabatolimab
    Investigational medicinal product code
    MBG453
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Sabatolimab 400 mg concentrate for solution for infusion wasadministered preferably over 30 minutes, with a maximumadministration time of 2 hours.

    Arm title
    		 Placebo + Azacitidine
    Arm description
    		 Participants were randomized to placebo plus Azacitidine
    Arm type
    		 Experimental

    Investigational medicinal product name
    Azacitidine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet, Injection
    Routes of administration
    Intravenous use, Subcutaneous use
    Dosage and administration details
    100 mg or other locally available dose strengths was administeredaccording to local standard clinical practice. A standard dose ofazacitidine (75mg/m2) was given based on local azacitidinepackage insert every day for seven consecutive days on Days 1 to7 of a 28-day cycle, followed by sabatolimab.

    Investigational medicinal product name
    Sabatolimab
    Investigational medicinal product code
    MBG453
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo 400 mg concentrate for solution for infusion wasadministered preferably over 30 minutes, with a maximumadministration time of 2 hours.

    Number of subjects in period 1
    		Sabatolimab (MBG453) + Azacitidine Placebo + Azacitidine
    Started
    265
    265
    Participants Treated
    264
    264
    Participants Not treated
    1
    1
    Discontinued from treatment
    264
    264
    Entered post-treatment
    68
    71
    Did not enter post-treatment
    196
    193
    Discontinued from study
    265
    265
    Full Analysis See (FAS)
    265
    265
    Safety Set
    263
    265
    Completed
    0
    0
    Not completed
    265
    265
         Adverse event, serious fatal
    26
    35
         Participant Decision
    22
    28
         Physician decision
    14
    9
         Adverse event, non-fatal
    41
    43
         Protocol Deviation
    2
    4
         Progressive Disease
    111
    92
         Participants Not Treated
    1
    1
         Guardian Decision
    1
    -
         Study Terminated by Sponsor
    22
    27
         Lost to follow-up
    1
    -
         HSCT Planned
    22
    22
         New Therapy for Study Indication
    2
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Sabatolimab (MBG453) + Azacitidine
    Reporting group description
    		 Participants were randomized to sabatolimab plus Azacitidine

    Reporting group title
    Placebo + Azacitidine
    Reporting group description
    		 Participants were randomized to placebo plus Azacitidine

    Reporting group values
    		 Sabatolimab (MBG453) + Azacitidine Placebo + Azacitidine Total
    Number of subjects
    		 265 265 530
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 60 66 126
        From 65-84 years
    		 192 189 381
        85 years and over
    		 13 10 23
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 70.2 ( 11.46 ) 69.1 ( 11.23 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 104 79 183
        Male
    		 161 186 347
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 150 134 284
        Asian
    		 111 124 235
        Black or African American
    		 3 4 7
        American Indian or Alaska Native
    		 1 2 3
        Unknown
    		 0 1 1
    ECOG performance status
    Eastern Cooperative Oncology Group (ECOG) performance status scale is a widely used standard of care criteria used to assess the functional status of a patient with cancer to measure how the disease impacts the patient’s daily living abilities. This scale has a range from 0 - 5. The higher the grade, the worse the patient's abilities: 0 implies fully active, able to carry on all pre-disease performance without restriction and 5 implies death.
    Units: Subjects
        ECOG performance status: 0
    		 92 101 193
        ECOG performance status: 1
    		 161 141 302
        ECOG performance status: 2
    		 12 23 35

    End points

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    End points reporting groups
    Reporting group title
    Sabatolimab (MBG453) + Azacitidine
    Reporting group description
    		 Participants were randomized to sabatolimab plus Azacitidine

    Reporting group title
    Placebo + Azacitidine
    Reporting group description
    		 Participants were randomized to placebo plus Azacitidine

    Subject analysis set title
    Sabatolimab (MBG453)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received sabatolimab.

    Subject analysis set title
    Sabatolimab (MBG453)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received sabatolimab

    Subject analysis set title
    Sabatolimab (MBG453)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received sabatolimab

    Primary: Overall Survival (OS) (Final efficacy results)

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    End point title
    		 Overall Survival (OS) (Final efficacy results)
    End point description
    OS is the time from randomization until death due to any cause.
    End point type
    Primary
    End point timeframe
    Up to 5 years after last participant randomized
    End point values
    		 Sabatolimab (MBG453) + Azacitidine Placebo + Azacitidine
    Number of subjects analysed
    265
    265
    Units: Months
        median (confidence interval 95%)
    22.18 (19.55 to 24.41)
    18.83 (15.38 to 23.72)
    Statistical analysis title
    		 OS Final Analysis
    Comparison groups
    Sabatolimab (MBG453) + Azacitidine v Placebo + Azacitidine
    Number of subjects included in analysis
    530
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.863
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.693
         upper limit
    		 1.076

    Primary: Overall Survival (OS) (Primary efficacy results)

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    End point title
    		 Overall Survival (OS) (Primary efficacy results)
    End point description
    OS is the time from randomization until death due to any cause.
    End point type
    Primary
    End point timeframe
    approx. 39 months after first participant randomized
    End point values
    		 Sabatolimab (MBG453) + Azacitidine Placebo + Azacitidine
    Number of subjects analysed
    265
    265
    Units: Months
        median (confidence interval 95%)
    22.31 (19.55 to 24.74)
    18.83 (15.38 to 23.72)
    Statistical analysis title
    		 OS Primary Analysis
    Comparison groups
    Sabatolimab (MBG453) + Azacitidine v Placebo + Azacitidine
    Number of subjects included in analysis
    530
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0825 [1]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.847
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.671
         upper limit
    		 1.07
    Notes
    [1] - P Value is 1-sided

    Secondary: Key secondary endpoint 1: Time to definitive deterioration of fatigue using Functional Assessment of Cancer Therapy (FACIT)-Fatigue score

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    End point title
    		 Key secondary endpoint 1: Time to definitive deterioration of fatigue using Functional Assessment of Cancer Therapy (FACIT)-Fatigue score
    End point description
    FACIT-Fatigue score is a 13-item questionnaire designed to assess fatigue in cancer participants. All items use a 5-point scale ranging from 0 to 4 (0=Not at All to 4=Very Much). The total score ranges from 0 to 52 with higher values representing better quality of life. Time to definitive deterioration of fatigue is defined as time from randomization to at least 3 points worsening from baseline in FACIT-fatigue scores with no subsequently observed improvement above this threshold, or death due to any cause, whichever occurred first.
    End point type
    Secondary
    End point timeframe
    Up to 5 years after last participant randomized
    End point values
    		 Sabatolimab (MBG453) + Azacitidine Placebo + Azacitidine
    Number of subjects analysed
    265
    265
    Units: Months
        median (confidence interval 95%)
    13.37 (11.96 to 15.90)
    11.76 (10.15 to 13.86)
    Statistical analysis title
    		 Time to Def. Analysis
    Comparison groups
    Sabatolimab (MBG453) + Azacitidine v Placebo + Azacitidine
    Number of subjects included in analysis
    530
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.2132 [2]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.921
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.75
         upper limit
    		 1.13
    Notes
    [2] - P Value is 1-sided

    Secondary: Key secondary endpoint 2: Red Blood Cell (RBC) annualized transfusion free rate for transfusion

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    End point title
    		 Key secondary endpoint 2: Red Blood Cell (RBC) annualized transfusion free rate for transfusion
    End point description
    Annualized transfusion free rate is defined as the average number of days in RBC transfusion-free intervals in a year (i.e., the total number of days in RBC transfusion-free intervals divided by the total days in the study multiplied by 365.25), where RBC transfusion-free intervals correspond to cumulative times of intervals with no evidence of RBC transfusion for at least 8 weeks at any point after randomization until death due to any cause.
    End point type
    Secondary
    End point timeframe
    Up to 5 years after last participant randomized
    End point values
    		 Sabatolimab (MBG453) + Azacitidine Placebo + Azacitidine
    Number of subjects analysed
    265
    265
    Units: annualized transfusion-free rate (days)
        median (full range (min-max))
    184.3 (0 to 365)
    175.7 (0 to 365)
    Statistical analysis title
    		 RBC annualized
    Comparison groups
    Sabatolimab (MBG453) + Azacitidine v Placebo + Azacitidine
    Number of subjects included in analysis
    530
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.4692 [3]
    Method
    		 negative binomial regression model
    Confidence interval
    Notes
    [3] - P Value is 1-sided

    Secondary: Key secondary endpoint 3: Percentage of participants with at least 3 point confirmed improvement from baseline in FACIT-fatigue scores

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    End point title
    		 Key secondary endpoint 3: Percentage of participants with at least 3 point confirmed improvement from baseline in FACIT-fatigue scores
    End point description
    FACIT-Fatigue score is a 13-item questionnaire designed to assess fatigue in cancer participants. All items use a 5-point scale ranging from 0 to 4 (0=Not at All to 4=Very Much). The total score ranges from 0 to 52 with higher values representing better quality of life. The responder is defined as having 3 points improvement from baseline confirmed by a second improvement of 3 points at any time, regardless of preceding worsening. A participant who could not improve was considered as a non-responder.
    End point type
    Secondary
    End point timeframe
    Up to 5 years after last participant randomized
    End point values
    		 Sabatolimab (MBG453) + Azacitidine Placebo + Azacitidine
    Number of subjects analysed
    265
    265
    Units: Percentage of participants with response
        number (confidence interval 95%)
    39.6 (33.7 to 45.8)
    40.8 (34.8 to 46.9)
    Statistical analysis title
    		 FACIT analysis
    Comparison groups
    Sabatolimab (MBG453) + Azacitidine v Placebo + Azacitidine
    Number of subjects included in analysis
    530
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.4865 [4]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 1.4
    Notes
    [4] - P Value is 1-sided

    Secondary: Key secondary endpoint 4: Percentage of participants with at least 10 point confirmed improvement from baseline in physical functioning using European Organization for Research and Treatment of Cancer's Core Quality of Life Questionnaire (EORTC QLQ-C30)

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    End point title
    		 Key secondary endpoint 4: Percentage of participants with at least 10 point confirmed improvement from baseline in physical functioning using European Organization for Research and Treatment of Cancer's Core Quality of Life Questionnaire (EORTC QLQ-C30)
    End point description
    EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer participants. Participants' responses to 5 questions about their physical functioning (Items 1-5) are scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A high score indicates a high / healthy level of functioning. The responder is defined as having 10 points improvement from baseline confirmed by a second improvement of 10 points at any time, regardless of preceding worsening. A participant who could not improve was considered as a non-responder.
    End point type
    Secondary
    End point timeframe
    Up to 5 years after last participant randomized
    End point values
    		 Sabatolimab (MBG453) + Azacitidine Placebo + Azacitidine
    Number of subjects analysed
    265
    265
    Units: Percentage of participants with response
        number (confidence interval 95%)
    30.2 (24.7 to 36.1)
    22.6 (17.7 to 28.2)
    Statistical analysis title
    		 EORTC Analysis
    Comparison groups
    Sabatolimab (MBG453) + Azacitidine v Placebo + Azacitidine
    Number of subjects included in analysis
    530
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.5743 [5]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.48
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1
         upper limit
    		 2.2
    Notes
    [5] - P Value is 1-sided

    Secondary: Percentage of participants with stable disease (SD) according to International Working Group for MDS (IWG-MDS) as per investigator assessment

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    End point title
    		 Percentage of participants with stable disease (SD) according to International Working Group for MDS (IWG-MDS) as per investigator assessment
    End point description
    Response rate of participants with stable disease. SD is the failure to achieve at least partial response (PR), but no evidence of progression for >8 weeks.
    End point type
    Secondary
    End point timeframe
    Up to 5 years after last participant randomized
    End point values
    		 Sabatolimab (MBG453) + Azacitidine Placebo + Azacitidine
    Number of subjects analysed
    265
    265
    Units: Percentage of participants
        number (not applicable)
    20.0
    19.6
    No statistical analyses for this end point

    Secondary: Percentage of participants with either CR, or mCR, or PR, or HI in each treatment arm according to International Working Group for MDS (IWG-MDS) as per investigator assessment

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    End point title
    		 Percentage of participants with either CR, or mCR, or PR, or HI in each treatment arm according to International Working Group for MDS (IWG-MDS) as per investigator assessment
    End point description
    Response rate of participants with complete remission (CR), or marrow remission (mCR), or partial remission (PR), or hematologic improvement (HI). CR: where the Bone marrow: ≤ 5% blasts with normal maturation of all cell lineages and Peripheral blood: where Hgb ≥ 10 g/dL AND Platelets ≥ 100*109/L AND Neutrophils ≥ 1.0*109/L AND Peripheral blasts 0%. mCR: Bone marrow: ≤ 5% blasts and blast count decrease by ≥ 50% compared to baseline; Peripheralblood/transfusion: Marrow CR may be achieved with or without improved blood counts or with or without transfusions PR: All CR criteria except bone marrow: ≥50% decrease from baseline in blasts in bone marrow AND blast count in bone marrow >5%. HI: restoration or enhancement of the function of the body's blood cell-producing system that must last as least 8 weeks.
    End point type
    Secondary
    End point timeframe
    Up to 5 years after last participant randomized
    End point values
    		 Sabatolimab (MBG453) + Azacitidine Placebo + Azacitidine
    Number of subjects analysed
    265
    265
    Units: Percentage of participants
        number (confidence interval 95%)
    58.1 (51.9 to 64.1)
    47.5 (41.4 to 53.7)
    No statistical analyses for this end point

    Secondary: Key secondary endpoint 5: Percentage of participants with at least 10 point confirmed improvement from baseline in emotional functioning using EORTC-QLQ-C30

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    End point title
    		 Key secondary endpoint 5: Percentage of participants with at least 10 point confirmed improvement from baseline in emotional functioning using EORTC-QLQ-C30
    End point description
    EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer participants. Participants' responses to 4 questions about their emotional functioning (Items 21-24) are scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A high score indicates a high / healthy level of functioning. The responder is defined as having 10 points improvement from baseline confirmed by a second improvement of 10 points at any time, regardless of preceding worsening. A participant who could not improve was considered as a non-responder.
    End point type
    Secondary
    End point timeframe
    Up to 5 years after last participant randomized
    End point values
    		 Sabatolimab (MBG453) + Azacitidine Placebo + Azacitidine
    Number of subjects analysed
    265
    265
    Units: Percentage of participants
        number (confidence interval 95%)
    31.7 (26.1 to 37.7)
    28.3 (23.0 to 34.1)
    Statistical analysis title
    		 EORTC-QLQ-C30
    Comparison groups
    Sabatolimab (MBG453) + Azacitidine v Placebo + Azacitidine
    Number of subjects included in analysis
    530
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.2126 [6]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 1.7
    Notes
    [6] - P Value is 1-sided

    Secondary: Progression Free Survival (PFS)

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    End point title
    		 Progression Free Survival (PFS)
    End point description
    PFS is defined as the time from randomization to disease progression (including transformation to acute leukemia per WHO 2016), relapse from CR (IWG-MDS), or death. Disease progression: bone marrow blasts increase ≥ 50% over baseline, to > 5% if initially < 5%, > 10% if 5%-<10%, or > 20% if 10%-<20%. Includes a peripheral blood count decrease ≥ 50% from maximum remission/response levels: neutrophils < 1.0x109/L, platelets < 100x109/L, or hemoglobin drop ≥ 2 g/dL to < 10 g/dL, becoming transfusion-dependent. Relapse from CR: baseline bone marrow blast % return, neutrophils decrease ≥ 50% to < 1.0x109/L, platelets decrease ≥ 50% to < 100x109/L, or hemoglobin drop ≥ 1.5 g/dL to < 10 g/dL, becoming transfusion-dependent. Leukemia transformation: > 20% blasts per WHO 2016 (Arber et al 2016).
    End point type
    Secondary
    End point timeframe
    Up to 5 years after last participant randomized
    End point values
    		 Sabatolimab (MBG453) + Azacitidine Placebo + Azacitidine
    Number of subjects analysed
    265
    265
    Units: Months
        median (confidence interval 95%)
    14.26 (12.22 to 17.74)
    10.12 (8.64 to 11.14)
    Statistical analysis title
    		 PFS Analysis
    Comparison groups
    Sabatolimab (MBG453) + Azacitidine v Placebo + Azacitidine
    Number of subjects included in analysis
    530
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.576
         upper limit
    		 0.875

    Secondary: Leukemia-free survival (LFS)

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    End point title
    		 Leukemia-free survival (LFS)
    End point description
    LFS is defined as the time from randomization to ≥ 20% blasts in bone marrow/peripheral blood (per WHO 2016 classification) or diagnosis of extramedullary acute leukemia, or death due to any cause
    End point type
    Secondary
    End point timeframe
    Up to 5 years after last participant randomized
    End point values
    		 Sabatolimab (MBG453) + Azacitidine Placebo + Azacitidine
    Number of subjects analysed
    265
    265
    Units: Months
        median (confidence interval 95%)
    19.84 (17.15 to 24.21)
    13.73 (11.79 to 18.73)
    Statistical analysis title
    		 LFS Analysis
    Comparison groups
    Sabatolimab (MBG453) + Azacitidine v Placebo + Azacitidine
    Number of subjects included in analysis
    530
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.815
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.64
         upper limit
    		 1.038

    Secondary: Number of participants who become Red Blood Cells (RBC)/platelets transfusion independence after randomization

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    End point title
    		 Number of participants who become Red Blood Cells (RBC)/platelets transfusion independence after randomization
    End point description
    Improvement in RBC/Platelets transfusion independence as per International Working Group for MDS (IWG-MDS) criteria. RBC/Platelets transfusion independence was defined as having received 0 units of RBC/Platelets transfusions during at least 8 consecutive weeks after randomization. The number of participants was shown in only those with transfusion dependence at baseline (BL).
    End point type
    Secondary
    End point timeframe
    Up to 5 years after last participant randomized
    End point values
    		 Sabatolimab (MBG453) + Azacitidine Placebo + Azacitidine
    Number of subjects analysed
    265
    265
    Units: Participants
        At least 1 per. of packed RBC ind. at BL(n=96,108)
    50
    53
        At least 1 per. of PLTS ind. at BL (n=23,28)
    11
    10
    No statistical analyses for this end point

    Secondary: Pharmacokinetics of MBG453 (parameter Cmax)

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    End point title
    		 Pharmacokinetics of MBG453 (parameter Cmax)
    End point description
    Cmax is the maximum (peak) observed drug concentration after single dose administration (mass x volume-1).
    End point type
    Secondary
    End point timeframe
    0 hr (pre-dose) & 2 hrs (post-dose) of Cycle (C) 1 Day (D) 8, 0 hr (pre-dose) of C2D8, 0 hr (pre-dose) and 2 hrs (post-dose) of C3D8, 0 hr (pre-dose) in D8 of Cycle 4, 6, 9, 12 and every 6 cycles thereafter, EOT, 30 Day Follow up and 150 Day Follow up
    End point values
    		 Sabatolimab (MBG453)
    Number of subjects analysed
    8
    Units: ug/ml
    geometric mean (geometric coefficient of variation)
        Cycle 1
    232 ( 20.9 )
        Cycle 3 (n = 6)
    239 ( 39.5 )
    No statistical analyses for this end point

    Secondary: Pharmacokinetics of MBG453 (parameter AUC)

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    End point title
    		 Pharmacokinetics of MBG453 (parameter AUC)
    End point description
    AUCinf is the AUC from time zero to infinity (mass x time x volume-1).
    End point type
    Secondary
    End point timeframe
    0 hr (pre-dose) & 2 hrs (post-dose) of Cycle (C) 1 Day (D) 8, 0 hr (pre-dose) of C2D8, 0 hr (pre-dose) & 2 hrs (post-dose) of C3D8, 0 hr (pre-dose) in Day 8 of Cycle 4, 6, 9, 12 and every 6 cycles thereafter, EOT, 30 Day Follow up and 150 Day Follow up
    End point values
    		 Sabatolimab (MBG453)
    Number of subjects analysed
    4
    Units: day*ug/ml
    geometric mean (geometric coefficient of variation)
        Cycle 1
    2670 ( 45.9 )
        Cycle 3 (n = 3)
    4930 ( 1.5 )
    No statistical analyses for this end point

    Secondary: ADA prevalence at baseline and ADA incidence on-treatment

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    End point title
    		 ADA prevalence at baseline and ADA incidence on-treatment
    End point description
    ADA incidence (i.e. ADA-positive subjects) will be calculated as the number of subjects with at least one on-treatment ADA-positive sample divided by the number of subjects with a determinant baseline IG sample and at least one determinant post-baseline IG sample.
    End point type
    Secondary
    End point timeframe
    Continuously collected for patients during treatment with sabatolimab up to 150 days after last treatment, approx. 39 months
    End point values
    		 Sabatolimab (MBG453)
    Number of subjects analysed
    249
    Units: Participants
        ADA prevalence (i.e. ADA positive) @ baseline (BL)
    24
        ADA-positive participants on-treatment
    34
    No statistical analyses for this end point

    Secondary: Change from baseline in the European Quality of Life (EuroQol) - 5 Dimensions, 5 Level Questionnaire (EQ-5D-5L) score over time

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    End point title
    		 Change from baseline in the European Quality of Life (EuroQol) - 5 Dimensions, 5 Level Questionnaire (EQ-5D-5L) score over time
    End point description
    The EQ-5D-5L comprises 5 dimensions: mobility, self-care, usual activities, pain/discomfort, anxiety/depression. For each of the 5 dimensions, subject's responses are scored on a 5-point scale (1=no problem to 5=extreme problems). Change from baseline is being presented for EQ Index score. Index score is defined as a weighted combination of the levels of the 5-dimention scales, ranging from 0 to 1. The United States value set from Pickard et al 2019 was used.
    End point type
    Secondary
    End point timeframe
    Up to 5 years after last patient randomized
    End point values
    		 Sabatolimab (MBG453) + Azacitidine Placebo + Azacitidine
    Number of subjects analysed
    238
    245
    Units: change from baseline in utility
    arithmetic mean (standard deviation)
        Baseline (BL)
    0.78 ( 0.204 )
    0.78 ( 0.239 )
        Change from BL @ Cycle (C) 3 Day (D) 1 (n=205,199)
    0.00 ( 0.215 )
    -0.03 ( 0.222 )
        Change from BL at C6D1 (n = 163, 157)
    -0.02 ( 0.260 )
    -0.02 ( 0.305 )
        Change from BL at C9D1 (n = 129, 117)
    0.03 ( 0.232 )
    -0.01 ( 0.226 )
        Change from BL at C12D1 (n = 93, 88)
    0.02 ( 0.163 )
    -0.05 ( 0.261 )
        Change from BL at C15D1 (n = 84, 61)
    -0.02 ( 0.238 )
    0.01 ( 0.221 )
        Change from BL at C18D1 (n = 65, 53)
    -0.02 ( 0.208 )
    0.00 ( 0.226 )
        Change from BL at C21D1 (n = 47, 45)
    0.00 ( 0.208 )
    0.00 ( 0.256 )
        Change from BL at C24D1 (n = 45, 41)
    0.00 ( 0.157 )
    0.02 ( 0.225 )
        Change from BL at C27D1 (n = 34, 35)
    -0.09 ( 0.283 )
    0.00 ( 0.213 )
        Change from BL at C30D1 (n = 30, 25)
    -0.03 ( 0.315 )
    0.02 ( 0.256 )
        Change from BL at C33D1 (n = 22, 22)
    -0.01 ( 0.211 )
    -0.02 ( 0.218 )
        Change from BL at C36D1 (n = 18, 15)
    -0.07 ( 0.333 )
    -0.07 ( 0.395 )
        Change from BL at C39D1 (n = 14, 10)
    -0.16 ( 0.360 )
    0.02 ( 0.143 )
        Change from BL at C42D1 (n = 9, 4)
    -0.09 ( 0.262 )
    -0.13 ( 0.309 )
        Change from BL at C45D1 (n = 6, 2)
    -0.12 ( 0.262 )
    0.17 ( 0.069 )
        Change from BL at C48D1 (n = 1, 2)
    -0.07 ( 0.000 )
    0.06 ( 0.087 )
    No statistical analyses for this end point

    Secondary: Change from baseline in the European Quality of Life (EuroQoL) - 5 Dimensions, 5 Level Questionnaire (EQ-5D-5L) Visual Analogue Scale (VAS) over time

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    End point title
    		 Change from baseline in the European Quality of Life (EuroQoL) - 5 Dimensions, 5 Level Questionnaire (EQ-5D-5L) Visual Analogue Scale (VAS) over time
    End point description
    The EQ-5D-5L VAS records the participant's self-rated health on a visual analogue scale numbered from 0 to 100, with 0 being "the worst health you can imagine" and 100 being "the best health you can imagine". Change from baseline was presented.
    End point type
    Secondary
    End point timeframe
    Up to 5 years after last participant randomized
    End point values
    		 Sabatolimab (MBG453) + Azacitidine Placebo + Azacitidine
    Number of subjects analysed
    238
    245
    Units: Change from baseline in VAS value
    arithmetic mean (standard deviation)
        Baseline (BL)
    68.91 ( 18.371 )
    68.04 ( 18.762 )
        Change from BL @ Cycle 3 Day 1 (C3D1) (n=205,199)
    1.39 ( 21.029 )
    0.40 ( 18.767 )
        Change from BL at C6D1 (n = 163, 157)
    2.60 ( 25.218 )
    2.08 ( 23.294 )
        Change from BL at C9D1 (n = 129, 117)
    5.28 ( 20.528 )
    2.55 ( 20.805 )
        Change from BL at C12D1 (n = 93, 88)
    5.55 ( 21.380 )
    1.18 ( 22.728 )
        Change from BL at C15D1 (n = 84, 61)
    2.87 ( 21.940 )
    3.72 ( 21.564 )
        Change from BL at C18D1 (n = 65, 53)
    3.80 ( 20.474 )
    6.87 ( 19.369 )
        Change from BL at C21D1 (n = 47, 45)
    3.70 ( 23.541 )
    5.71 ( 18.577 )
        Change from BL at C24D1 (n = 45, 41)
    1.73 ( 21.288 )
    7.68 ( 18.781 )
        Change from BL at C27D1 (n = 34, 35)
    -0.44 ( 21.139 )
    4.63 ( 19.792 )
        Change from BL at C30D1 (n = 30, 25)
    3.13 ( 26.829 )
    4.76 ( 14.998 )
        Change from BL at C33D1 (n = 22, 22)
    5.41 ( 26.923 )
    1.64 ( 17.705 )
        Change from BL at C36D1 (n = 18, 15)
    -1.50 ( 25.714 )
    -2.80 ( 29.617 )
        Change from BL at C39D1 (n = 14, 10)
    3.57 ( 28.281 )
    1.70 ( 20.078 )
        Change from BL at C42D1 (n = 9, 4)
    -11.89 ( 22.469 )
    -0.75 ( 26.550 )
        Change from BL at C45D1 (n = 6, 2)
    2.00 ( 15.113 )
    -2.00 ( 24.042 )
        Change from BL at C48D1 (n = 1, 2)
    7.00 ( 0.000 )
    5.50 ( 34.648 )
    No statistical analyses for this end point

    Secondary: Change from baseline of Global Health Status/Quality of Life scores using European Organization for Research and Treatment of Cancer's Core Quality of Life Questionnaire (EORTC-QLQ-C30).

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    End point title
    		 Change from baseline of Global Health Status/Quality of Life scores using European Organization for Research and Treatment of Cancer's Core Quality of Life Questionnaire (EORTC-QLQ-C30).
    End point description
    EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer participants. Participant's responses to 2 questions (Items 29+30: "How would you rate your overall health during the past week?" and "How would you rate your overall quality of life during the past week?") are scored on a 7-point scale (1=Very Poor to 7=Excellent). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A higher score indicates a better overall outcome. Change from baseline to Cycle 12 Day 1 as presented.
    End point type
    Secondary
    End point timeframe
    Up to Cycle 12 Day 1 (C12D1) (1 cycle = 28 days)
    End point values
    		 Sabatolimab (MBG453) + Azacitidine Placebo + Azacitidine
    Number of subjects analysed
    64
    62
    Units: scores on a scale
        arithmetic mean (standard deviation)
    8.72 ( 23.071 )
    8.20 ( 19.932 )
    No statistical analyses for this end point

    Post-hoc: All Collected Deaths

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    End point title
    		 All Collected Deaths
    End point description
    Deaths were collected from randomization until the end of the trial, approx. 52 months, including post-treatment survival follow up period.
    End point type
    Post-hoc
    End point timeframe
    from randomization until end of trial, approx. 52 months
    End point values
    		 Sabatolimab (MBG453) + Azacitidine Placebo + Azacitidine
    Number of subjects analysed
    265
    265
    Units: Participants
        Pre-treatment deaths
    0
    1
        On-treatment deaths
    18
    37
        Post-treatment deaths (n = 247, 228)
    143
    122
        All deaths
    161
    160
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All-cause mortality: deaths were collected from first dose of study treatment up to approx. 52 months, including post-treatment survival follow up period. Serious and Other Adverse Events: from first dose of study treatment until 30 days after last dose
    Adverse event reporting additional description
    Any sign or symptom that occurred during the conduct of the trial and the safety follow-up. Deaths in the post-treatment survival follow-up period are not considered adverse events.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    27.1
    Reporting groups
    Reporting group title
    Sabatolimab (MBG453) + Azacitidine
    Reporting group description
    		 Participants received sabatolimab plus azacitidine.

    Reporting group title
    Placebo + Azacitidine
    Reporting group description
    		 Participants received placebo plus azacitidine.

    Serious adverse events
    		 Sabatolimab (MBG453) + Azacitidine Placebo + Azacitidine
    Total subjects affected by serious adverse events
         subjects affected / exposed
    174 / 263 (66.16%)
    164 / 265 (61.89%)
         number of deaths (all causes)
    161
    159
         number of deaths resulting from adverse events
    7
    6
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Hepatocellular carcinoma
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal adenocarcinoma
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liposarcoma
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nodular melanoma
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal adenocarcinoma
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestine adenocarcinoma
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Arterial thrombosis
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    2 / 263 (0.76%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    2 / 263 (0.76%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White coat hypertension
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery thrombosis
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 263 (0.38%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest discomfort
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (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
    2 / 263 (0.76%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    2 / 263 (0.76%)
    2 / 265 (0.75%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 263 (0.38%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Oedema
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral swelling
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    17 / 263 (6.46%)
    19 / 265 (7.17%)
         occurrences causally related to treatment / all
    9 / 21
    7 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sudden death
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Immune system disorders
    Haemophagocytic lymphohistiocytosis
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Prostatitis
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspiration
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 263 (0.76%)
    3 / 265 (1.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Emphysema
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity pneumonitis
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (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 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Lung infiltration
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    2 / 263 (0.76%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 263 (0.38%)
    2 / 265 (0.75%)
         occurrences causally related to treatment / all
    2 / 2
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary toxicity
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    3 / 263 (1.14%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hypoxia
         subjects affected / exposed
    2 / 263 (0.76%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    1 / 263 (0.38%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hallucination
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anti-platelet antibody positive
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ejection fraction decreased
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test increased
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    5 / 263 (1.90%)
    2 / 265 (0.75%)
         occurrences causally related to treatment / all
    8 / 9
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    10 / 263 (3.80%)
    7 / 265 (2.64%)
         occurrences causally related to treatment / all
    12 / 12
    9 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Troponin T increased
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    1 / 263 (0.38%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    3 / 263 (1.14%)
    4 / 265 (1.51%)
         occurrences causally related to treatment / all
    4 / 5
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    4 / 263 (1.52%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Allergic transfusion reaction
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Extradural haematoma
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    3 / 263 (1.14%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural haemorrhage
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 263 (0.00%)
    2 / 265 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple injuries
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 263 (0.38%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Refractoriness to platelet transfusion
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stoma site inflammation
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transfusion reaction
         subjects affected / exposed
    2 / 263 (0.76%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    4 / 263 (1.52%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial flutter
         subjects affected / exposed
    1 / 263 (0.38%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    2 / 263 (0.76%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 263 (0.38%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    3 / 263 (1.14%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 263 (0.38%)
    2 / 265 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    1 / 2
    Left ventricular dysfunction
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Mitral valve incompetence
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    2 / 263 (0.76%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    6 / 263 (2.28%)
    2 / 265 (0.75%)
         occurrences causally related to treatment / all
    2 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Altered state of consciousness
         subjects affected / exposed
    1 / 263 (0.38%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Central nervous system haemorrhage
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 263 (0.38%)
    2 / 265 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Cerebrovascular accident
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    2 / 263 (0.76%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 263 (0.38%)
    2 / 265 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic intolerance
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    11 / 263 (4.18%)
    11 / 265 (4.15%)
         occurrences causally related to treatment / all
    5 / 13
    8 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Agranulocytosis
         subjects affected / exposed
    1 / 263 (0.38%)
    3 / 265 (1.13%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia of malignant disease
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Autoimmune haemolytic anaemia
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile bone marrow aplasia
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    49 / 263 (18.63%)
    31 / 265 (11.70%)
         occurrences causally related to treatment / all
    39 / 63
    22 / 45
         deaths causally related to treatment / all
    1 / 2
    0 / 1
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenitis
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myelosuppression
         subjects affected / exposed
    0 / 263 (0.00%)
    3 / 265 (1.13%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    4 / 263 (1.52%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    3 / 263 (1.14%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    6 / 263 (2.28%)
    2 / 265 (0.75%)
         occurrences causally related to treatment / all
    4 / 6
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aplastic anaemia
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Haematotympanum
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoacusis
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertigo
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Vision blurred
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Enterocolitis
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    2 / 263 (0.76%)
    2 / 265 (0.75%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 263 (0.38%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 263 (0.38%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 263 (0.38%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Food poisoning
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal ulcer
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer haemorrhage
         subjects affected / exposed
    2 / 263 (0.76%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 263 (0.76%)
    3 / 265 (1.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastrointestinal motility disorder
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids thrombosed
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 263 (0.38%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 263 (0.00%)
    2 / 265 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstructive pancreatitis
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Overflow diarrhoea
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctalgia
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctitis
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric dysplasia
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal haemorrhage
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 263 (0.00%)
    3 / 265 (1.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 263 (0.38%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary colic
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis acute
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertransaminasaemia
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Portal hypertension
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Portal vein thrombosis
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         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
    Cutaneous vasculitis
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatitis
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erythema nodosum
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyoderma gangrenosum
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 263 (0.76%)
    5 / 265 (1.89%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Calculus bladder
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (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
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cyst haemorrhage
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Foot deformity
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthropathy
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chondrocalcinosis
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint effusion
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tenosynovitis
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal infection
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    6 / 263 (2.28%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    4 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    2 / 263 (0.76%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis infective
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspergillus infection
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 263 (0.00%)
    3 / 265 (1.13%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial infection
         subjects affected / exposed
    1 / 263 (0.38%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (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
    12 / 263 (4.56%)
    9 / 265 (3.40%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 9
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Herpes zoster
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Candida infection
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    6 / 263 (2.28%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    1 / 7
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    4 / 263 (1.52%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalitis viral
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterococcal sepsis
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis infectious
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epididymitis
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    1 / 263 (0.38%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Eyelid infection
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 263 (0.38%)
    2 / 265 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes dermatitis
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    4 / 263 (1.52%)
    9 / 265 (3.40%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 9
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Infection
         subjects affected / exposed
    1 / 263 (0.38%)
    3 / 265 (1.13%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Legionella infection
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    3 / 263 (1.14%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    3 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Necrotising fasciitis
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Opportunistic infection
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis externa
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Perineal abscess
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periodontitis
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periorbital cellulitis
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    5 / 263 (1.90%)
    2 / 265 (0.75%)
         occurrences causally related to treatment / all
    3 / 5
    1 / 2
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    Pneumonia
         subjects affected / exposed
    35 / 263 (13.31%)
    36 / 265 (13.58%)
         occurrences causally related to treatment / all
    19 / 38
    16 / 36
         deaths causally related to treatment / all
    3 / 3
    2 / 7
    Pneumonia aspiration
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia bacterial
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia escherichia
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia fungal
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia klebsiella
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomonas infection
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary mucormycosis
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal abscess
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal abscess
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 263 (0.00%)
    3 / 265 (1.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhinovirus infection
         subjects affected / exposed
    2 / 263 (0.76%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rotavirus infection
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    3 / 263 (1.14%)
    10 / 265 (3.77%)
         occurrences causally related to treatment / all
    0 / 5
    4 / 10
         deaths causally related to treatment / all
    0 / 1
    1 / 4
    Septic shock
         subjects affected / exposed
    6 / 263 (2.28%)
    8 / 265 (3.02%)
         occurrences causally related to treatment / all
    4 / 6
    4 / 8
         deaths causally related to treatment / all
    1 / 1
    2 / 3
    Sialoadenitis
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    7 / 263 (2.66%)
    5 / 265 (1.89%)
         occurrences causally related to treatment / all
    1 / 8
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    2 / 263 (0.76%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 263 (0.00%)
    2 / 265 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic infection
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 263 (1.14%)
    3 / 265 (1.13%)
         occurrences causally related to treatment / all
    2 / 4
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    2 / 263 (0.76%)
    2 / 265 (0.75%)
         occurrences causally related to treatment / all
    1 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection enterococcal
         subjects affected / exposed
    1 / 263 (0.38%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 263 (0.38%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    2 / 263 (0.76%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lactic acidosis
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Sabatolimab (MBG453) + Azacitidine Placebo + Azacitidine
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    256 / 263 (97.34%)
    255 / 265 (96.23%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    17 / 263 (6.46%)
    14 / 265 (5.28%)
         occurrences all number
    28
    19
    Hypertension
         subjects affected / exposed
    21 / 263 (7.98%)
    12 / 265 (4.53%)
         occurrences all number
    28
    12
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    24 / 263 (9.13%)
    33 / 265 (12.45%)
         occurrences all number
    29
    43
    Asthenia
         subjects affected / exposed
    31 / 263 (11.79%)
    29 / 265 (10.94%)
         occurrences all number
    41
    36
    Fatigue
         subjects affected / exposed
    50 / 263 (19.01%)
    33 / 265 (12.45%)
         occurrences all number
    58
    36
    Injection site reaction
         subjects affected / exposed
    16 / 263 (6.08%)
    20 / 265 (7.55%)
         occurrences all number
    45
    39
    Pyrexia
         subjects affected / exposed
    71 / 263 (27.00%)
    59 / 265 (22.26%)
         occurrences all number
    94
    115
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    15 / 263 (5.70%)
    17 / 265 (6.42%)
         occurrences all number
    26
    30
    Dyspnoea
         subjects affected / exposed
    24 / 263 (9.13%)
    15 / 265 (5.66%)
         occurrences all number
    28
    18
    Cough
         subjects affected / exposed
    35 / 263 (13.31%)
    27 / 265 (10.19%)
         occurrences all number
    45
    37
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    29 / 263 (11.03%)
    21 / 265 (7.92%)
         occurrences all number
    43
    21
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    19 / 263 (7.22%)
    12 / 265 (4.53%)
         occurrences all number
    39
    12
    Aspartate aminotransferase increased
         subjects affected / exposed
    12 / 263 (4.56%)
    18 / 265 (6.79%)
         occurrences all number
    20
    37
    Alanine aminotransferase increased
         subjects affected / exposed
    15 / 263 (5.70%)
    24 / 265 (9.06%)
         occurrences all number
    29
    40
    C-reactive protein increased
         subjects affected / exposed
    18 / 263 (6.84%)
    6 / 265 (2.26%)
         occurrences all number
    23
    6
    White blood cell count decreased
         subjects affected / exposed
    48 / 263 (18.25%)
    52 / 265 (19.62%)
         occurrences all number
    182
    205
    Weight decreased
         subjects affected / exposed
    34 / 263 (12.93%)
    25 / 265 (9.43%)
         occurrences all number
    38
    26
    Platelet count decreased
         subjects affected / exposed
    62 / 263 (23.57%)
    56 / 265 (21.13%)
         occurrences all number
    207
    216
    Neutrophil count decreased
         subjects affected / exposed
    61 / 263 (23.19%)
    54 / 265 (20.38%)
         occurrences all number
    213
    241
    Lymphocyte count decreased
         subjects affected / exposed
    14 / 263 (5.32%)
    20 / 265 (7.55%)
         occurrences all number
    56
    56
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    15 / 263 (5.70%)
    5 / 265 (1.89%)
         occurrences all number
    17
    5
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    21 / 263 (7.98%)
    15 / 265 (5.66%)
         occurrences all number
    26
    17
    Headache
         subjects affected / exposed
    23 / 263 (8.75%)
    20 / 265 (7.55%)
         occurrences all number
    32
    25
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    67 / 263 (25.48%)
    58 / 265 (21.89%)
         occurrences all number
    167
    142
    Neutropenia
         subjects affected / exposed
    96 / 263 (36.50%)
    76 / 265 (28.68%)
         occurrences all number
    333
    225
    Leukopenia
         subjects affected / exposed
    17 / 263 (6.46%)
    22 / 265 (8.30%)
         occurrences all number
    57
    44
    Febrile neutropenia
         subjects affected / exposed
    19 / 263 (7.22%)
    21 / 265 (7.92%)
         occurrences all number
    19
    34
    Anaemia
         subjects affected / exposed
    107 / 263 (40.68%)
    91 / 265 (34.34%)
         occurrences all number
    276
    222
    Gastrointestinal disorders
    Stomatitis
         subjects affected / exposed
    14 / 263 (5.32%)
    12 / 265 (4.53%)
         occurrences all number
    15
    13
    Diarrhoea
         subjects affected / exposed
    61 / 263 (23.19%)
    46 / 265 (17.36%)
         occurrences all number
    90
    67
    Constipation
         subjects affected / exposed
    141 / 263 (53.61%)
    114 / 265 (43.02%)
         occurrences all number
    218
    179
    Abdominal pain
         subjects affected / exposed
    26 / 263 (9.89%)
    15 / 265 (5.66%)
         occurrences all number
    34
    18
    Vomiting
         subjects affected / exposed
    48 / 263 (18.25%)
    45 / 265 (16.98%)
         occurrences all number
    61
    70
    Nausea
         subjects affected / exposed
    87 / 263 (33.08%)
    66 / 265 (24.91%)
         occurrences all number
    114
    94
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    30 / 263 (11.41%)
    26 / 265 (9.81%)
         occurrences all number
    36
    35
    Pruritus
         subjects affected / exposed
    22 / 263 (8.37%)
    18 / 265 (6.79%)
         occurrences all number
    36
    23
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    43 / 263 (16.35%)
    26 / 265 (9.81%)
         occurrences all number
    54
    32
    Back pain
         subjects affected / exposed
    31 / 263 (11.79%)
    19 / 265 (7.17%)
         occurrences all number
    34
    21
    Pain in extremity
         subjects affected / exposed
    18 / 263 (6.84%)
    9 / 265 (3.40%)
         occurrences all number
    21
    10
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    24 / 263 (9.13%)
    17 / 265 (6.42%)
         occurrences all number
    32
    30
    Upper respiratory tract infection
         subjects affected / exposed
    21 / 263 (7.98%)
    20 / 265 (7.55%)
         occurrences all number
    31
    25
    Pneumonia
         subjects affected / exposed
    30 / 263 (11.41%)
    27 / 265 (10.19%)
         occurrences all number
    30
    29
    Cellulitis
         subjects affected / exposed
    14 / 263 (5.32%)
    12 / 265 (4.53%)
         occurrences all number
    15
    15
    COVID-19
         subjects affected / exposed
    44 / 263 (16.73%)
    35 / 265 (13.21%)
         occurrences all number
    48
    36
    Metabolism and nutrition disorders
    Hyperuricaemia
         subjects affected / exposed
    16 / 263 (6.08%)
    18 / 265 (6.79%)
         occurrences all number
    22
    28
    Hyperglycaemia
         subjects affected / exposed
    15 / 263 (5.70%)
    25 / 265 (9.43%)
         occurrences all number
    28
    35
    Decreased appetite
         subjects affected / exposed
    26 / 263 (9.89%)
    26 / 265 (9.81%)
         occurrences all number
    41
    28
    Hypoalbuminaemia
         subjects affected / exposed
    20 / 263 (7.60%)
    23 / 265 (8.68%)
         occurrences all number
    33
    52
    Hypokalaemia
         subjects affected / exposed
    39 / 263 (14.83%)
    33 / 265 (12.45%)
         occurrences all number
    60
    57
    Hyponatraemia
         subjects affected / exposed
    15 / 263 (5.70%)
    13 / 265 (4.91%)
         occurrences all number
    31
    33
    Hypocalcaemia
         subjects affected / exposed
    7 / 263 (2.66%)
    15 / 265 (5.66%)
         occurrences all number
    19
    54

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Aug 2020
    As of the release of this amendment, approximately 13 participants were randomized in this study. The purpose of this amendment was to clarify the inclusion criteria related to the eligibility for intensive chemotherapy and stem cell transplantation, as well as the exclusion criteria related to cardiac abnormalities. Additionally, as new treatment options were available for participants with AML, study treatment beyond progression in case of acute leukemia was not permitted. Definitions of the RBC or platelet transfusion dependence and transfusion independence were updated. The same pre-specified period of observation (i.e., 8 weeks) was used to determine the transfusion status throughout the study. The interval of 8 weeks was selected, as it was in line with the assessment of transfusions for hematologic improvement and was acceptable to evaluate the transfusion status of higher-risk MDS participants at baseline (IWG 2006, IWG 2018). Transfusion independence was defined as absence of any transfusion during a given period of observation. Clarifications about the estimand definition and methods for statistical analyses of PRO data were added. In addition, the need for TLS risk monitoring was further emphasized.
    14 Jul 2021
    As of the release of this amendment, approximately 324 participants were randomized in this study. The main purpose of this amendment was to clarify inclusion criterion related to MDS/CMML-2 status of the Participant and exclusion criterion related to myelofibrosis. It was clarified that the IPSS-R score used for MDS participants in this study was solely based on the publication Greenberg et al 2012 to ensure consistency across the participating sites. For CMML-2, it was clarified that in alignment with the WHO classification 2016. Furthermore, the new Novartis standard language, referred to as disruption proofing language, added to specify trial conduct during public health emergencies. The added language addressed study participant safety and trial integrity. Additional guidance for COVID-19 vaccinations was added to avoid overlapping adverse events with study treatment, and several updates were made to clarify the visit windows in case of delay of administration of study treatment and time windows for certain assessments. Lastly, the definition of withdrawal of consent and management of biological samples was updated as per latest protocol template.
    23 Jun 2022
    The purpose of this protocol amendment was to adjust the group-sequential statistical plan based on independent information that became available from the final progression free survival (PFS) analysis of CMBG453B12201 which was conducted in a similar participant population and study treatment. Based on these data, a delayed treatment effect was considered for this study which justified an increase in overall survival (OS) events to retain statistical power for the primary analysis at 85%. As of the release of this amendment, accrual was completed: 530 participants had been randomized. The DMC, who had been informed about the outcome of CMBG453B12201, had completed the safety & preplanned futility assessment of this study at 74 OS events (data cutoff as of 20-Nov-2021) and recommended to continue the study.

    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.
    Two participants didn’t receive treatment and were excluded from the Safety Set. One withdrew consent, another progressed to AML before treatment. One sabatolimab participant progressed to AML, received azacitidine only, and was analyzed as placebo.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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