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    Clinical Trial Results:
    A randomized, double-blind phase 3 study of vadastuximab talirine (SGN-CD33A) versus placebo in combination with azacitidine or decitabine in the treatment of older patients with newly diagnosed acute myeloid leukemia (AML)

    Summary
    EudraCT number
    		 2015-003482-28
    Trial protocol
    		 CZ   HU   GB   DE   BE   AT   ES   NL   IT  
    Global end of trial date
    03 Oct 2017

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

    Trial information

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    Trial identification
    Sponsor protocol code
    SGN33A-005
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02785900
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Seattle Genetics, Inc.
    Sponsor organisation address
    21823 30th Dr SE, Bothell, United States, 98021
    Public contact
    Chief Medical Officer, Seattle Genetics, Inc., 1 8554732436, medinfo@seagen.com
    Scientific contact
    Chief Medical Officer, Seattle Genetics, Inc., 1 8554732436, medinfo@seagen.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
    08 Feb 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Oct 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Oct 2017
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The purpose of this study in AML patients is to test whether vadastuximab talirine (SGN-CD33A; 33A) combined with either azacitidine or decitabine improves remission rates and extends overall survival as compared to placebo combined with either azacitidine or decitabine.
    Protection of trial subjects
    The protocol for this study was designed in accordance with the general ethical principles outlined in the Declaration of Helsinki. The conduct of all aspects of the study, including methods for obtaining informed consent, were also in accordance with principles enunciated in the declaration, the International Conference on Harmonisation (ICH) Good Clinical Practices (GCP), and applicable Food and Drug Administration (FDA) regulations/guidelines set forth in Title 21 CFR Parts 11, 50, 54, 56, and 312. The consent form approved by each IRB/IEC included all elements required by the applicable regional laws and regulations, including a statement that Seattle Genetics, Inc. and authorities had access to patient records. Consent was obtained from all patients before any protocol-required procedures were performed, including any procedure not part of normal patient care.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 May 2016
    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
    United States: 94
    Country: Number of subjects enrolled
    Korea, Republic of: 13
    Country: Number of subjects enrolled
    Taiwan: 10
    Country: Number of subjects enrolled
    Spain: 11
    Country: Number of subjects enrolled
    United Kingdom: 8
    Country: Number of subjects enrolled
    Austria: 3
    Country: Number of subjects enrolled
    Belgium: 12
    Country: Number of subjects enrolled
    Czech Republic: 9
    Country: Number of subjects enrolled
    France: 23
    Country: Number of subjects enrolled
    Germany: 8
    Country: Number of subjects enrolled
    Hungary: 11
    Country: Number of subjects enrolled
    Italy: 5
    Country: Number of subjects enrolled
    Israel: 12
    Country: Number of subjects enrolled
    Australia: 21
    Worldwide total number of subjects
    240
    EEA total number of subjects
    90
    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)
    6
    From 65 to 84 years
    221
    85 years and over
    13

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 The population to be studied includes patients with newly diagnosed, previously untreated, cytologically/histologically confirmed de novo or secondary acute myeloid leukemia, with intermediate or adverse cytogenetic risk per revised UK Medical Research Council classification, who are not considered candidates for alallogeneic stem cell transplant.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 33A + HMA
    Arm description
    		 33A plus azacitidine or decitabine
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vadatuximab talirine
    Investigational medicinal product code
    Other name
    SGN-CD33A
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    10 mcg/kg every 4 weeks via intravenous (IV) push

    Investigational medicinal product name
    Azacitidine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for suspension for injection
    Routes of administration
    Subcutaneous use, Intravenous use
    Dosage and administration details
    75 mg/m2 given subcutaneously (SC) or IV x 7 days, every 4 weeks

    Investigational medicinal product name
    Decitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    20 mg/m2 given IV x 5 days, every 4 weeks

    Arm title
    		 Placebo + HMA
    Arm description
    		 placebo plus azacitidine or decitabine
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Azacitidine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for suspension for injection
    Routes of administration
    Intravenous use, Subcutaneous use
    Dosage and administration details
    75 mg/m2 given subcutaneously (SC) or IV x 7 days, every 4 weeks

    Investigational medicinal product name
    Decitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    20 mg/m2 given IV x 5 days, every 4 weeks

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Volume equivalent to 10 mcg/kg, every 4 weeks via IV push

    Number of subjects in period 1
    		33A + HMA Placebo + HMA
    Started
    117
    123
    Completed
    0
    0
    Not completed
    117
    123
         Adverse event, serious fatal
    46
    32
         Consent withdrawn by subject
    4
    8
         Physician decision
    3
    2
         Study Termination by Sponsor
    64
    81

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    33A + HMA
    Reporting group description
    		 33A plus azacitidine or decitabine

    Reporting group title
    Placebo + HMA
    Reporting group description
    		 placebo plus azacitidine or decitabine

    Reporting group values
    		 33A + HMA Placebo + HMA Total
    Number of subjects
    		 117 123 240
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 3 3 6
        From 65-84 years
    		 109 112 221
        85 years and over
    		 5 8 13
    Age continuous
    Units: years
        median (full range (min-max))
    		 75.0 (62 to 91) 75.0 (52 to 91) -
    Gender categorical
    Units: Subjects
        Female
    		 69 67 136
        Male
    		 48 56 104
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 3 2 5
        Not Hispanic or Latino
    		 98 111 209
        Unknown or Not Reported
    		 16 10 26
    Race/Ethnicity
    Units: Subjects
        Asian
    		 12 16 28
        Black or African American
    		 3 1 4
        White
    		 85 94 179
        Other
    		 2 1 3
        Not Reportable
    		 13 10 23
        Unknown
    		 2 1 3
    Eastern Cooperative Oncology Group (ECOG) Performance Status
    0=Normal activity; 1=Symptoms but ambulatory; 2=In bed less than 50% of the time; 3= In bed more than 50% of the time; 4=100% bedridden; 5=Dead
    Units: Subjects
        Grade 0: Normal activity
    		 23 23 46
        Grade 1: Symptoms but ambulatory
    		 78 80 158
        Grade 2: In bed less than 50% of the time
    		 16 20 36

    End points

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    End points reporting groups
    Reporting group title
    33A + HMA
    Reporting group description
    		 33A plus azacitidine or decitabine

    Reporting group title
    Placebo + HMA
    Reporting group description
    		 placebo plus azacitidine or decitabine

    Subject analysis set title
    33A + HMA (ITT)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Defined as randomized patients: 117 patients randomized to the experimental arm and 123 patients randomized to the comparator arm.

    Subject analysis set title
    33A + HMA (Safety)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety analysis set includes all patients who received any dose of blinded study treatment (vadatuximab talirine or placebo) or HMA. The safety analysis set for the experimental arm consisted of 111 patients who received at least 1 dose of vadatuximab talirine (110 patients randomized to the experimental arm, and 1 patient randomized to the comparator arm who received vadatuximab talirine in error during Cycle 1). The safety analysis set for the comparator arm consisted of 128 patients (114 patients who received both HMA and placebo, 7 patients randomized to the comparator arm who received HMA only, and 7 patients randomized to the experimental arm who received HMA only).

    Subject analysis set title
    Placebo +HMA (ITT)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Defined as randomized patients: 117 patients randomized to the experimental arm and 123 patients randomized to the comparator arm.

    Subject analysis set title
    Placebo + HMA (Safety)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety analysis set includes all patients who received any dose of blinded study treatment (vadatuximab talirine or placebo) or HMA. The safety analysis set for the experimental arm consisted of 111 patients who received at least 1 dose of vadatuximab talirine (110 patients randomized to the experimental arm, and 1 patient randomized to the comparator arm who received vadatuximab talirine in error during Cycle 1). The safety analysis set for the comparator arm consisted of 128 patients (114 patients who received both HMA and placebo, 7 patients randomized to the comparator arm who received HMA only, and 7 patients randomized to the experimental arm who received HMA only).

    Primary: Overall Survival

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    End point title
    		 Overall Survival [1]
    End point description
    End point type
    Primary
    End point timeframe
    Up to 1.5 years
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics have been reported for this outcome.
    End point values
    		 33A + HMA Placebo + HMA
    Number of subjects analysed
    117
    123
    Units: months
        median (full range (min-max))
    5.1 (0.30 to 11.99)
    999 (0.13 to 999)
    No statistical analyses for this end point

    Primary: Composite Complete Remission Rate

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    End point title
    		 Composite Complete Remission Rate [2]
    End point description
    Number of patients who acheived CR or CRi
    End point type
    Primary
    End point timeframe
    Up to 1.5 years
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics have been reported for this outcome.
    End point values
    		 33A + HMA Placebo + HMA
    Number of subjects analysed
    117
    123
    Units: participants
        number (confidence interval 95%)
    30 (18 to 34.5)
    26 (14.3 to 29.4)
    No statistical analyses for this end point

    Secondary: Duration of Remission

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    End point title
    		 Duration of Remission
    End point description
    Duration of remission is calculated from the first documentation of CR or CRi to the first documentation of disease relapse or death, whichever comes first. Patients who are in remission at the time of analysis cutoff are censored at the date of last response assessment. Patients who started another anticancer therapy before relapse or death are censored at the date of last reponse assessment prior to start of new therapy.
    End point type
    Secondary
    End point timeframe
    Up to approximately 9.5 months
    End point values
    		 33A + HMA Placebo + HMA
    Number of subjects analysed
    30
    26
    Units: months
        median (full range (min-max))
    5.1 (0.03 to 6.21)
    7.5 (0.03 to 9.49)
    No statistical analyses for this end point

    Secondary: Event-free Survival

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    End point title
    		 Event-free Survival
    End point description
    Event-free survival is calculated from the time of randomization to the first documentation of progression, relapse, or death, whichever comes first. Patients who do not have event (progression, relapse, or death) prior to analysis cutoff date are consored at the date of last response assessment. Patients who started another anticancer therapy before progression, relapse, or death are censored at the date of last response assessment prior to the start of new therapy. Patients who do not have response assessment post-baseline are censored at the date of randomization.
    End point type
    Secondary
    End point timeframe
    Up to approximately 11.24 months
    End point values
    		 33A + HMA Placebo + HMA
    Number of subjects analysed
    117
    123
    Units: months
        median (confidence interval 95%)
    4.2 (3.5 to 5.1)
    6.7 (4.5 to 9.5)
    No statistical analyses for this end point

    Secondary: Leukemia-free Survival

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    End point title
    		 Leukemia-free Survival
    End point description
    Leukemia-free survival is calculated from the first documentation of blast clearance (CR, CRi, mLFS) to the first documentation of disease relapse or death, whichever comes first. Patients who are in remission at the time of analysis cutoff are censored at the date of last response assessment. Patients who started another anticancer therapy before relapse or death are censored at the date of last response assessment prior to start of new therapy.
    End point type
    Secondary
    End point timeframe
    Up to approximately 9.49 months
    End point values
    		 33A + HMA Placebo + HMA
    Number of subjects analysed
    30
    26
    Units: months
        median (full range (min-max))
    5.1 (0.03 to 8.31)
    7.5 (0.03 to 9.49)
    No statistical analyses for this end point

    Secondary: Type, Incidence, Severity, Seriousness, and Relatedness of Adverse Events

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    End point title
    		 Type, Incidence, Severity, Seriousness, and Relatedness of Adverse Events
    End point description
    Treatment-emergent adverse events (TEAEs) are presented and defined as newly occurring (not present at baseline) or worsening after first dose of investigational product. SAE = serious adverse event. "Study treatment" in this data set refers to blinded study treatment.
    End point type
    Secondary
    End point timeframe
    Up to 1.5 years
    End point values
    		 33A + HMA (Safety) Placebo + HMA (Safety)
    Number of subjects analysed
    111
    128
    Units: participants
        Patient with any TEAE
    111
    125
        Patients with any AE related to study treatment
    83
    59
        Patients with any SAE
    92
    89
        Patients with any SAE related to study treatment
    51
    20
        Patients with Grade 3 or Higher AE
    103
    112
    No statistical analyses for this end point

    Secondary: Laboratory Abnormalities

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    End point title
    		 Laboratory Abnormalities
    End point description
    Participants who experienced a laboratory grade increase to Grade 3 or higher
    End point type
    Secondary
    End point timeframe
    Up to approximately 1 year
    End point values
    		 33A + HMA (Safety) Placebo + HMA (Safety)
    Number of subjects analysed
    111
    128
    Units: participants
        Alanine Aminotransferase (IU/L) - High
    0
    2
        Albumin (g/dL) - Low
    2
    4
        Alkaline Phosphatase (IU/L) - High
    0
    2
        Amylase (IU/L) - High
    1
    0
        Aspartate Aminotransferase (IU/L) - High
    1
    2
        Bilirubin (mg/dL) - High
    1
    1
        Calcium (mg/dL) - Low
    8
    3
        Creatinine (mg/dL) - High
    0
    1
        Glucose (mg/dL) - High
    12
    9
        Magnesium (mg/dL) - High
    2
    0
        Phosphate (mg/dL) - Low
    17
    9
        Potassium (mEq/L) - High
    1
    0
        Potassium (mEq/L) - Low
    5
    14
        Sodium (mEq/L) - Low
    13
    12
        Triacylglycerol Lipase (IU/L) - High
    10
    4
        Urate (mg/dL) - High
    4
    7
        Hemoglobin (g/dL) - Low
    59
    66
        Leukocytes (x10^3/uL) - High
    0
    3
        Leukocytes (x10^3/uL) - Low
    86
    70
        Lymphocytes (x10^3/uL) - High
    1
    4
        Lymphocytes (x10^3/uL) - Low
    51
    29
        Neutrophils (x10^3/uL) - Low
    63
    43
        Platelets (x10^3/uL) - Low
    77
    75
    No statistical analyses for this end point

    Secondary: Time to Complete Remission

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    End point title
    		 Time to Complete Remission
    End point description
    Time to CR or CRi is the time from randomization to the first documentation of CR/CRi
    End point type
    Secondary
    End point timeframe
    Up to 26 months
    End point values
    		 33A + HMA Placebo + HMA
    Number of subjects analysed
    30
    26
    Units: weeks
        median (full range (min-max))
    9.3 (5 to 22)
    9.4 (7 to 26)
    No statistical analyses for this end point

    Secondary: Mortality Rates at Day 30 and Day 60

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    End point title
    		 Mortality Rates at Day 30 and Day 60
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 60 days
    End point values
    		 33A + HMA Placebo + HMA
    Number of subjects analysed
    117
    123
    Units: percentage of participants
    number (confidence interval 95%)
        30-day Mortality Rate
    11 (7 to 18)
    6 (3 to 12)
        60-day Mortality Rate
    23 (16 to 32)
    13 (8 to 20)
    No statistical analyses for this end point

    Secondary: Minimal Residual Disease (MRD)-Negative Composite Complete Remission Rate

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    End point title
    		 Minimal Residual Disease (MRD)-Negative Composite Complete Remission Rate
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 1.5 years
    End point values
    		 33A + HMA Placebo + HMA
    Number of subjects analysed
    117
    123
    Units: participants
    number (confidence interval 95%)
        MRD-negative CRc rate
    18 (9.4 to 23.2)
    10 (4 to 14.4)
        MRD-negative CR rate
    8 (3 to 13)
    5 (1.3 to 9.2)
        MRD-negative CRi rate
    10 (4.2 to 15.2)
    5 (1.3 to 9.2)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 13 months
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    33A + HMA
    Reporting group description
    		 33A plus azacitidine or decitabine

    Reporting group title
    Placebo + HMA
    Reporting group description
    		 -

    Serious adverse events
    		 33A + HMA Placebo + HMA
    Total subjects affected by serious adverse events
         subjects affected / exposed
    92 / 111 (82.88%)
    89 / 128 (69.53%)
         number of deaths (all causes)
    43
    34
         number of deaths resulting from adverse events
    34
    28
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia
         subjects affected / exposed
    1 / 111 (0.90%)
    3 / 128 (2.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Malignant melanoma
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastatic renal cell carcinoma
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 111 (0.90%)
    2 / 128 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    2 / 111 (1.80%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis superficial
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    8 / 111 (7.21%)
    8 / 128 (6.25%)
         occurrences causally related to treatment / all
    3 / 8
    3 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 111 (0.90%)
    2 / 128 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Fatigue
         subjects affected / exposed
    0 / 111 (0.00%)
    2 / 128 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 111 (0.00%)
    2 / 128 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Oedema peripheral
         subjects affected / exposed
    2 / 111 (1.80%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter site haemorrhage
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Extravasation
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial pain
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Social circumstances
    Blood product transfusion dependent
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory failure
         subjects affected / exposed
    3 / 111 (2.70%)
    2 / 128 (1.56%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    Epistaxis
         subjects affected / exposed
    3 / 111 (2.70%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 111 (0.90%)
    2 / 128 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood culture positive
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ejection fraction decreased
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 128 (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
    1 / 111 (0.90%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical condition abnormal
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Subdural haematoma
         subjects affected / exposed
    2 / 111 (1.80%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Fall
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiation proctitis
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin injury
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transfusion reaction
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    2 / 111 (1.80%)
    2 / 128 (1.56%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    2 / 111 (1.80%)
    2 / 128 (1.56%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 111 (0.90%)
    2 / 128 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Acute coronary syndrome
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia supraventricular
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure acute
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Myocardial infarction
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocarditis
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular arrhythmia
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nervous system disorders
    Seizure
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial paresis
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic encephalopathy
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Serotonin syndrome
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    39 / 111 (35.14%)
    31 / 128 (24.22%)
         occurrences causally related to treatment / all
    32 / 55
    11 / 39
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    6 / 111 (5.41%)
    2 / 128 (1.56%)
         occurrences causally related to treatment / all
    5 / 7
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    5 / 111 (4.50%)
    2 / 128 (1.56%)
         occurrences causally related to treatment / all
    3 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    5 / 111 (4.50%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    6 / 6
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Febrile bone marrow aplasia
         subjects affected / exposed
    3 / 111 (2.70%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    2 / 111 (1.80%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    2 / 111 (1.80%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone marrow failure
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    3 / 111 (2.70%)
    3 / 128 (2.34%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic colitis
         subjects affected / exposed
    2 / 111 (1.80%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Rectal haemorrhage
         subjects affected / exposed
    2 / 111 (1.80%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 111 (0.00%)
    2 / 128 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal fistula
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis erosive
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal angiodysplasia
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Haemorrhoids
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Irritable bowel syndrome
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal obstruction
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palatal oedema
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctitis
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hepatitis cholestatic
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Vasculitic rash
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 111 (0.90%)
    4 / 128 (3.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary bladder haemorrhage
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract pain
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendonitis
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    22 / 111 (19.82%)
    15 / 128 (11.72%)
         occurrences causally related to treatment / all
    7 / 24
    5 / 16
         deaths causally related to treatment / all
    2 / 4
    1 / 3
    Sepsis
         subjects affected / exposed
    14 / 111 (12.61%)
    7 / 128 (5.47%)
         occurrences causally related to treatment / all
    5 / 15
    1 / 10
         deaths causally related to treatment / all
    4 / 8
    0 / 3
    Cellulitis
         subjects affected / exposed
    6 / 111 (5.41%)
    8 / 128 (6.25%)
         occurrences causally related to treatment / all
    3 / 6
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    9 / 111 (8.11%)
    3 / 128 (2.34%)
         occurrences causally related to treatment / all
    3 / 10
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Septic shock
         subjects affected / exposed
    6 / 111 (5.41%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    2 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 111 (1.80%)
    4 / 128 (3.13%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    2 / 111 (1.80%)
    3 / 128 (2.34%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 111 (0.90%)
    3 / 128 (2.34%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    2 / 111 (1.80%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella sepsis
         subjects affected / exposed
    3 / 111 (2.70%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    2 / 111 (1.80%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal infection
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Device related infection
         subjects affected / exposed
    2 / 111 (1.80%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    2 / 111 (1.80%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomonal sepsis
         subjects affected / exposed
    2 / 111 (1.80%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Streptococcal sepsis
         subjects affected / exposed
    2 / 111 (1.80%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Acinetobacter bacteraemia
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Catheter site cellulitis
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis staphylococcal
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea infectious
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterobacter bacteraemia
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterococcal bacteraemia
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterococcal infection
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 128 (0.78%)
         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 / 111 (0.90%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Necrotising fasciitis
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Parotitis
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pilonidal cyst
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia fungal
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia influenzal
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia respiratory syncytial viral
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomonal bacteraemia
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomonas infection
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sialoadenitis
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Subcutaneous abscess
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth abscess
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 128 (0.78%)
         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
    1 / 111 (0.90%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection bacterial
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    0 / 111 (0.00%)
    2 / 128 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Dehydration
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fluid overload
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lactic acidosis
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0.05%
    Non-serious adverse events
    		 33A + HMA Placebo + HMA
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    105 / 111 (94.59%)
    123 / 128 (96.09%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    12 / 111 (10.81%)
    9 / 128 (7.03%)
         occurrences all number
    12
    11
    Haematoma
         subjects affected / exposed
    9 / 111 (8.11%)
    9 / 128 (7.03%)
         occurrences all number
    11
    12
    Hypertension
         subjects affected / exposed
    7 / 111 (6.31%)
    3 / 128 (2.34%)
         occurrences all number
    7
    3
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    33 / 111 (29.73%)
    23 / 128 (17.97%)
         occurrences all number
    38
    28
    Fatigue
         subjects affected / exposed
    25 / 111 (22.52%)
    24 / 128 (18.75%)
         occurrences all number
    27
    25
    Pyrexia
         subjects affected / exposed
    25 / 111 (22.52%)
    18 / 128 (14.06%)
         occurrences all number
    38
    31
    Asthenia
         subjects affected / exposed
    13 / 111 (11.71%)
    14 / 128 (10.94%)
         occurrences all number
    16
    14
    Injection site erythema
         subjects affected / exposed
    11 / 111 (9.91%)
    4 / 128 (3.13%)
         occurrences all number
    18
    6
    Chills
         subjects affected / exposed
    8 / 111 (7.21%)
    4 / 128 (3.13%)
         occurrences all number
    9
    5
    Localised oedema
         subjects affected / exposed
    6 / 111 (5.41%)
    0 / 128 (0.00%)
         occurrences all number
    11
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    17 / 111 (15.32%)
    28 / 128 (21.88%)
         occurrences all number
    20
    31
    Cough
         subjects affected / exposed
    20 / 111 (18.02%)
    20 / 128 (15.63%)
         occurrences all number
    22
    25
    Epistaxis
         subjects affected / exposed
    21 / 111 (18.92%)
    11 / 128 (8.59%)
         occurrences all number
    32
    12
    Pleural effusion
         subjects affected / exposed
    12 / 111 (10.81%)
    5 / 128 (3.91%)
         occurrences all number
    15
    5
    Oropharyngeal pain
         subjects affected / exposed
    6 / 111 (5.41%)
    6 / 128 (4.69%)
         occurrences all number
    7
    6
    Hypoxia
         subjects affected / exposed
    6 / 111 (5.41%)
    4 / 128 (3.13%)
         occurrences all number
    6
    5
    Pulmonary oedema
         subjects affected / exposed
    7 / 111 (6.31%)
    3 / 128 (2.34%)
         occurrences all number
    7
    3
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    21 / 111 (18.92%)
    12 / 128 (9.38%)
         occurrences all number
    22
    13
    Confusional state
         subjects affected / exposed
    7 / 111 (6.31%)
    7 / 128 (5.47%)
         occurrences all number
    9
    7
    Anxiety
         subjects affected / exposed
    8 / 111 (7.21%)
    4 / 128 (3.13%)
         occurrences all number
    8
    4
    Investigations
    Weight decreased
         subjects affected / exposed
    15 / 111 (13.51%)
    17 / 128 (13.28%)
         occurrences all number
    17
    17
    Platelet count decreased
         subjects affected / exposed
    12 / 111 (10.81%)
    10 / 128 (7.81%)
         occurrences all number
    19
    12
    Blood creatinine increased
         subjects affected / exposed
    9 / 111 (8.11%)
    7 / 128 (5.47%)
         occurrences all number
    10
    9
    Neutrophil count decreased
         subjects affected / exposed
    6 / 111 (5.41%)
    8 / 128 (6.25%)
         occurrences all number
    8
    13
    White blood cell count decreased
         subjects affected / exposed
    6 / 111 (5.41%)
    5 / 128 (3.91%)
         occurrences all number
    8
    10
    Blood bilirubin increased
         subjects affected / exposed
    6 / 111 (5.41%)
    1 / 128 (0.78%)
         occurrences all number
    6
    1
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    11 / 111 (9.91%)
    7 / 128 (5.47%)
         occurrences all number
    14
    11
    Fall
         subjects affected / exposed
    10 / 111 (9.01%)
    5 / 128 (3.91%)
         occurrences all number
    13
    5
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    8 / 111 (7.21%)
    3 / 128 (2.34%)
         occurrences all number
    8
    3
    Sinus tachycardia
         subjects affected / exposed
    7 / 111 (6.31%)
    3 / 128 (2.34%)
         occurrences all number
    7
    3
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    6 / 111 (5.41%)
    17 / 128 (13.28%)
         occurrences all number
    6
    18
    Headache
         subjects affected / exposed
    5 / 111 (4.50%)
    17 / 128 (13.28%)
         occurrences all number
    7
    18
    Dysgeusia
         subjects affected / exposed
    7 / 111 (6.31%)
    5 / 128 (3.91%)
         occurrences all number
    7
    5
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    49 / 111 (44.14%)
    59 / 128 (46.09%)
         occurrences all number
    78
    105
    Thrombocytopenia
         subjects affected / exposed
    39 / 111 (35.14%)
    47 / 128 (36.72%)
         occurrences all number
    73
    67
    Neutropenia
         subjects affected / exposed
    19 / 111 (17.12%)
    24 / 128 (18.75%)
         occurrences all number
    35
    34
    Febrile neutropenia
         subjects affected / exposed
    25 / 111 (22.52%)
    12 / 128 (9.38%)
         occurrences all number
    29
    18
    Leukopenia
         subjects affected / exposed
    13 / 111 (11.71%)
    8 / 128 (6.25%)
         occurrences all number
    23
    9
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    6 / 111 (5.41%)
    2 / 128 (1.56%)
         occurrences all number
    8
    3
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    39 / 111 (35.14%)
    54 / 128 (42.19%)
         occurrences all number
    48
    64
    Nausea
         subjects affected / exposed
    37 / 111 (33.33%)
    45 / 128 (35.16%)
         occurrences all number
    49
    56
    Diarrhoea
         subjects affected / exposed
    34 / 111 (30.63%)
    34 / 128 (26.56%)
         occurrences all number
    47
    52
    Vomiting
         subjects affected / exposed
    15 / 111 (13.51%)
    31 / 128 (24.22%)
         occurrences all number
    25
    41
    Abdominal pain
         subjects affected / exposed
    11 / 111 (9.91%)
    12 / 128 (9.38%)
         occurrences all number
    13
    15
    Mouth ulceration
         subjects affected / exposed
    7 / 111 (6.31%)
    9 / 128 (7.03%)
         occurrences all number
    7
    9
    Stomatitis
         subjects affected / exposed
    8 / 111 (7.21%)
    6 / 128 (4.69%)
         occurrences all number
    10
    7
    Dyspepsia
         subjects affected / exposed
    10 / 111 (9.01%)
    1 / 128 (0.78%)
         occurrences all number
    10
    1
    Haemorrhoids
         subjects affected / exposed
    4 / 111 (3.60%)
    7 / 128 (5.47%)
         occurrences all number
    5
    7
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    11 / 111 (9.91%)
    15 / 128 (11.72%)
         occurrences all number
    15
    19
    Pruritus
         subjects affected / exposed
    7 / 111 (6.31%)
    13 / 128 (10.16%)
         occurrences all number
    8
    13
    Erythema
         subjects affected / exposed
    3 / 111 (2.70%)
    8 / 128 (6.25%)
         occurrences all number
    4
    10
    Purpura
         subjects affected / exposed
    6 / 111 (5.41%)
    2 / 128 (1.56%)
         occurrences all number
    6
    2
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    6 / 111 (5.41%)
    6 / 128 (4.69%)
         occurrences all number
    6
    8
    Urinary retention
         subjects affected / exposed
    6 / 111 (5.41%)
    2 / 128 (1.56%)
         occurrences all number
    6
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    10 / 111 (9.01%)
    10 / 128 (7.81%)
         occurrences all number
    10
    12
    Back pain
         subjects affected / exposed
    5 / 111 (4.50%)
    9 / 128 (7.03%)
         occurrences all number
    5
    10
    Pain in extremity
         subjects affected / exposed
    7 / 111 (6.31%)
    6 / 128 (4.69%)
         occurrences all number
    12
    6
    Muscular weakness
         subjects affected / exposed
    6 / 111 (5.41%)
    3 / 128 (2.34%)
         occurrences all number
    6
    3
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    10 / 111 (9.01%)
    10 / 128 (7.81%)
         occurrences all number
    11
    10
    Oral candidiasis
         subjects affected / exposed
    6 / 111 (5.41%)
    9 / 128 (7.03%)
         occurrences all number
    7
    10
    Pneumonia
         subjects affected / exposed
    10 / 111 (9.01%)
    3 / 128 (2.34%)
         occurrences all number
    11
    3
    Oral herpes
         subjects affected / exposed
    2 / 111 (1.80%)
    10 / 128 (7.81%)
         occurrences all number
    2
    12
    Urinary tract infection
         subjects affected / exposed
    4 / 111 (3.60%)
    8 / 128 (6.25%)
         occurrences all number
    4
    9
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    28 / 111 (25.23%)
    30 / 128 (23.44%)
         occurrences all number
    43
    36
    Decreased appetite
         subjects affected / exposed
    29 / 111 (26.13%)
    28 / 128 (21.88%)
         occurrences all number
    36
    29
    Hypomagnesaemia
         subjects affected / exposed
    11 / 111 (9.91%)
    13 / 128 (10.16%)
         occurrences all number
    17
    16
    Hyponatraemia
         subjects affected / exposed
    10 / 111 (9.01%)
    13 / 128 (10.16%)
         occurrences all number
    12
    22
    Hypoalbuminaemia
         subjects affected / exposed
    9 / 111 (8.11%)
    10 / 128 (7.81%)
         occurrences all number
    10
    10
    Hypocalcaemia
         subjects affected / exposed
    10 / 111 (9.01%)
    8 / 128 (6.25%)
         occurrences all number
    11
    8
    Hypophosphataemia
         subjects affected / exposed
    8 / 111 (7.21%)
    9 / 128 (7.03%)
         occurrences all number
    10
    9
    Fluid overload
         subjects affected / exposed
    3 / 111 (2.70%)
    7 / 128 (5.47%)
         occurrences all number
    3
    8

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Mar 2016
    - Duration of remission has been added as a secondary objective/endpoint of the study. - Exclusion criteria added: Patients who are medically fit and willing to receive standard intensive induction chemotherapy. - Exclusion criteria added: Any other condition which, in the opinion of the investigator, would compromise patient safety or interfere with data interpretation. - RBC count and MCV have been added to the list of clinical laboratory tests - Definition of the end of the trial added.
    20 May 2016
    - Lower age limit for study eligibility changed from =>65 to =>18 years. - The eligibility criteria have been revised to require females of childbearing potential to have a negative pregnancy test prior to enrollment as well as to use 2 effective contraceptive methods during the study. Female patients who are breastfeeding have also been excluded from enrollment. - Language edited to better emphasize the recommendations for prophylaxis of neutropenia for patients on the study. - Added: requirement of pregnancy testing at screening and end of treatment for females of childbearing potential. - Added: The modified intent-to-treat (mITT) analysis set will include all patients from the ITT analysis set who receive any dose of blinded study treatment (vadastuximab talirine or placebo) or HMA. Patients will be included in the treatment group assigned at randomization regardless of the actual treatment received. - Added: All efficacy endpoints will be analyzed using the ITT analysis set. Supplemental analyses will be performed using the mITT analysis set. - Language added to specify a blinded interim safety analysis to detect differences in early mortality between the arms.
    27 Mar 2017
    - Composite complete remission rate (CRc) has been changed from a secondary endpoint to an independent primary endpoint of the trial. The endpoints/objectives have also been re-ordered and revised to clarify that the MRD negative CRc rate will be compared between the treatment arms. - Study stopping criteria added for events of sinusoidal obstructive syndrome/veno-occlusive disease (SOS/VOD). - Inclusion criteria revised to clarify contraceptive requirements for male and female patients as well as clarify restrictions on breastfeeding, pregnancy, and sperm/ova donation. - Inclusion criteria revised to specify that patients 80 years and older must have an ECOG performance status of 0 or 1. - Inclusion criteria revised to clarify contraceptive requirements for male and female patients as well as clarify restrictions on breastfeeding, pregnancy, and sperm/ova donation. - Exclusion criteria added: Patients with supplemental oxygen requirement or resting oxygen saturation of <90%. - Exclusion criteria added: History of clinically significant chronic liver disease (e.g. liver cirrhosis) and/or ongoing alcohol abuse. - Dose modification section revised to ensure patient safety. - Prohibited concomitant medications revised to clarify that allogenic stem cell transplantation is prohibited during treatment period and within 30 days of last dose of blinded study treatment. - Addition of pregnancy test on Day 1 of each cycle of study treatment to ensure patient safety per EU CTFG "Recommendations Related to Contraception and Pregnancy Testing in Clinical Trials." - Pulse oximetry test added at baseline to assess oxygen saturation level at room air. - Measurement of vital signs has been added pre- and within 30 minutes post-blinded study treatment administration. -Follow-up assessments section revised for clarity and to provide information regarding follow-up of adverse events of special interest.

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

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