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    Clinical Trial Results:
    A Phase 3, Multicenter, Randomized, Open-Label Study of Guadecitabine (SGI-110) versus Treatment Choice in Adults with Previously Treated Acute Myeloid Leukemia

    Summary
    EudraCT number
    		 2015-005256-97
    Trial protocol
    		 DE   BE   HU   ES   GB   FR   PL   SE   DK   IT  
    Global end of trial date
    01 Jun 2020

    Results information
    Results version number
    		 v1
    This version publication date
    13 Jun 2021
    First version publication date
    13 Jun 2021
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    SGI-110-06
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02920008
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Astex Pharmaceuticals, Inc.
    Sponsor organisation address
    4420 Rosewood Dr., Pleasanton, United States, 94588
    Public contact
    Clinical trial info. ASTRAL-2, Astex Pharmaceuticals, Inc., ASTRAL-2@astx.com
    Scientific contact
    Clinical trial info. ASTRAL-2, Astex Pharmaceuticals, Inc., ASTRAL-2@astx.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
    01 Jun 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 Jan 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Jun 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess and compare overall survival (OS) between guadecitabine and treatment choice (TC) in adults with previously treated acute myeloid leukemia (AML). TC options are: • High intensity (intermediate or high dose cytarabine [HiDAC]; mitoxantrone, etoposide, and cytarabine [MEC]; or fludarabine, cytarabine, granulocyte colony stimulating factor [G-CSF], +/- idarubicin [FLAG/FLAG-Ida]) • Low intensity (low dose cytarabine [LDAC], decitabine, or azacitidine) • Best Supportive Care (BSC) BSC will be provided to all subjects as per standard and institutional practice.
    Protection of trial subjects
    The study was conducted in accordance with the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) guidelines, local regulatory requirements, and the principles enunciated in the Declaration of Helsinki.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    08 Mar 2017
    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
    Poland: 11
    Country: Number of subjects enrolled
    Spain: 40
    Country: Number of subjects enrolled
    Sweden: 1
    Country: Number of subjects enrolled
    United Kingdom: 8
    Country: Number of subjects enrolled
    Belgium: 13
    Country: Number of subjects enrolled
    Denmark: 2
    Country: Number of subjects enrolled
    France: 38
    Country: Number of subjects enrolled
    Germany: 21
    Country: Number of subjects enrolled
    Hungary: 13
    Country: Number of subjects enrolled
    Italy: 10
    Country: Number of subjects enrolled
    Canada: 24
    Country: Number of subjects enrolled
    Japan: 36
    Country: Number of subjects enrolled
    Korea, Republic of: 24
    Country: Number of subjects enrolled
    United States: 57
    Country: Number of subjects enrolled
    Ukraine: 4
    Worldwide total number of subjects
    302
    EEA total number of subjects
    149
    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)
    164
    From 65 to 84 years
    138
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Approximately 404 subjects from approximately 100 study centers were to be randomly assigned to either guadacitabine or treatment choice (TC) in a 1:1 ratio (approximately 202 subjects per group). Enrollment was stopped with approximately 300 subjects randomly assigned to treatment based on data monitoring committee recommendation.

    Pre-assignment
    Screening details
    		 A total of 358 subjects were assessed for study inclusion. Of these 56 failed screening assessments. A total of 302 subjects were randomized (148 guadecitabine, 154 TC). Of the randomized subjects, 10 did not receive study drug (3 guadecitabine, 7 TC).

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Guadacitabine
    Arm description
    		 Guadacitabine was administered subcutaneously (SC) at a dose of 60 mg/m^2 in 28-day cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Guadecitabine
    Investigational medicinal product code
    Other name
    SGI-110
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    60 mg/m^2 subcutaneously (SC) daily on Days 1-5 and Days 8-12 or on Days 1-10 of the first 28-day cycle. Second cycle could have been 60 mg/m^2 for either 10 days (Days 1-5 and 8-12 or Days 1-10) or 5 days (Days 1-5 only) based on assessment of disease response, and hematological recovery by Day ≥28. For Cycles ≥3, guadecitabine was given for 5 days only (60 mg/m^2/day, Days 1-5).

    Arm title
    		 Treatment Choice
    Arm description
    		 Intermediate or high dose cytarabine (HiDAC), MEC, FLAG/FLAG-Ida, LDAC, decitabine, azacitidine, or best supportive care (BSC) only.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Various treatment choice products
    Investigational medicinal product code
    Other name
    cytarabine, mitoxantrone, etoposide, fludarabine, idarubicin, decitabine, azacitidine
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use, Subcutaneous use
    Dosage and administration details
    High intensity: Intermediate or high dose cytarabine (HiDAC), recommended as 1-1.5 g/m^2 every 12 hours or up to 6 g/m^2/day for ≤6 days, maximum 36 g/m^2 per cycle; MEC: For example: mitoxantrone 6-12 mg/m^2 IV (recommended 8 mg/m^2), etoposide 80-200 mg/m^2 IV (recommended 100 mg/m^2), and cytarabine 1000 mg/m^2 IV; each daily for 5 days (Days 1-5); FLAG/FLAG-Ida: For example: fludarabine 25-30 mg/m^2 IV daily Days 1-5; cytarabine 1-2 g/m^2 IV daily for up to 5 days (recommended to be given for 4 hours after fludarabine); G-CSF SC daily from Day 6 up to white cell count recovery with or without idarubicin 8 mg/m^2 IV daily on Days 3 to 5. Low intensity: LDAC 20 mg SC or IV twice daily on Days 1-10; Decitabine 20 mg/m^2 IV daily on Days 1-5; Azacitidine 75 mg/m^2 IV or SC daily on Days 1-7. Best supportive care only.

    Number of subjects in period 1
    		Guadacitabine Treatment Choice
    Started
    148
    154
    Completed
    28
    20
    Not completed
    120
    134
         Consent withdrawn by subject
    3
    6
         Death
    117
    127
         Lost to follow-up
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Guadacitabine
    Reporting group description
    		 Guadacitabine was administered subcutaneously (SC) at a dose of 60 mg/m^2 in 28-day cycles.

    Reporting group title
    Treatment Choice
    Reporting group description
    		 Intermediate or high dose cytarabine (HiDAC), MEC, FLAG/FLAG-Ida, LDAC, decitabine, azacitidine, or best supportive care (BSC) only.

    Reporting group values
    		 Guadacitabine Treatment Choice Total
    Number of subjects
    		 148 154 302
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 72 92 164
        From 65-84 years
    		 76 62 138
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 61.8 ( 12.2 ) 59.8 ( 13.1 ) -
    Gender categorical
    Units: Subjects
        Female
    		 62 76 138
        Male
    		 86 78 164

    End points

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    End points reporting groups
    Reporting group title
    Guadacitabine
    Reporting group description
    		 Guadacitabine was administered subcutaneously (SC) at a dose of 60 mg/m^2 in 28-day cycles.

    Reporting group title
    Treatment Choice
    Reporting group description
    		 Intermediate or high dose cytarabine (HiDAC), MEC, FLAG/FLAG-Ida, LDAC, decitabine, azacitidine, or best supportive care (BSC) only.

    Subject analysis set title
    Guadecitabine vs Treatment Choice
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Arm comparison

    Primary: Overall survival

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    End point title
    		 Overall survival
    End point description
    Number of days from date of randomization to date of death
    End point type
    Primary
    End point timeframe
    From the date of randomization until the date of death, or approximately 30 months
    End point values
    		 Guadacitabine Treatment Choice
    Number of subjects analysed
    148
    154
    Units: Days
        median (confidence interval 95%)
    191 (141 to 253)
    163 (131 to 213)
    Statistical analysis title
    		 Overall survival
    Statistical analysis description
    OS between guadecitabine vs. treatment choice using stratified log-rank test. Due to pre-specified hierarchical testing plan, other endpoints were not evaluated for statistical significance.
    Comparison groups
    Guadacitabine v Treatment Choice
    Number of subjects included in analysis
    302
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3287
    Method
    		 Stratified log-rank
    Confidence interval

    Secondary: Event free survival

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    End point title
    		 Event free survival
    End point description
    Number of days from randomization to the earliest date of treatment discontinuation (for reasons other than initiation of hematopoietic cell transplant [HCT]), start of alternative anti-leukemia therapy (except for HCT), or death
    End point type
    Secondary
    End point timeframe
    From the date of randomization until treatment discontinuation, or approximately 23 months
    End point values
    		 Guadacitabine Treatment Choice
    Number of subjects analysed
    148
    154
    Units: Days
        median (confidence interval 95%)
    90 (73 to 105)
    71.5 (53 to 78)
    No statistical analyses for this end point

    Secondary: Long-term survival

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    End point title
    		 Long-term survival
    End point description
    Survival rate at 1 year after randomization; subjects were also be followed to estimate 2-year survival rate
    End point type
    Secondary
    End point timeframe
    Up to approximately 30 months
    End point values
    		 Guadacitabine Treatment Choice
    Number of subjects analysed
    148
    154
    Units: Proportion
    number (confidence interval 95%)
        12-month survival rate
    0.32 (0.25 to 0.40)
    0.26 (0.20 to 0.34)
        24-month survival rate
    0.19 (0.12 to 0.26)
    0.10 (0.05 to 0.17)
    No statistical analyses for this end point

    Secondary: Number of days alive and out of the hospital

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    End point title
    		 Number of days alive and out of the hospital
    End point description
    Number of days alive and out of the hospital
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    		 Guadacitabine Treatment Choice
    Number of subjects analysed
    148
    154
    Units: Days
        least squares mean (confidence interval 95%)
    73.2 (53.2 to 93.2)
    73.9 (53.8 to 94.1)
    No statistical analyses for this end point

    Secondary: Transfusion independence

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    End point title
    		 Transfusion independence
    End point description
    Number of subjects without red blood cell (RBC) or platelet transfusion for any period of 8 weeks after treatment divided by the total number of subjects included in the efficacy analysis
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 26 months
    End point values
    		 Guadacitabine Treatment Choice
    Number of subjects analysed
    148
    154
    Units: Percentage of subjects
    number (not applicable)
        Overall transfusion independence
    20.3
    13.0
        Platelet transfusion independence
    23.6
    21.4
        RBC transfusion independence
    21.6
    14.3
    No statistical analyses for this end point

    Secondary: Complete response and complete response with partial hematologic recovery

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    End point title
    		 Complete response and complete response with partial hematologic recovery
    End point description
    Number of subjects with complete response (CR) and CR with partial hematologic recovery divided by the total number of subjects included in the efficacy analysis
    End point type
    Secondary
    End point timeframe
    Baseline to end of treatment, or approximately 26 months
    End point values
    		 Guadacitabine Treatment Choice
    Number of subjects analysed
    148
    154
    Units: Percentage of subjects
        number (not applicable)
    16.9
    7.8
    No statistical analyses for this end point

    Secondary: Composite complete response (CRc)

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    End point title
    		 Composite complete response (CRc)
    End point description
    Number of subjects with complete response plus CR with incomplete blood count recovery (CRi) plus CR with incomplete platelet recovery (CRp) divided by the total number of subjects included in the efficacy analysis
    End point type
    Secondary
    End point timeframe
    Baseline to end of treatment, or approximately 26 months
    End point values
    		 Guadacitabine Treatment Choice
    Number of subjects analysed
    148
    154
    Units: Percentage of subjects
        number (not applicable)
    27.0
    14.3
    No statistical analyses for this end point

    Secondary: Hematopoietic cell transplant (HCT)

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    End point title
    		 Hematopoietic cell transplant (HCT)
    End point description
    Number of subjects who underwent HCT divided by the total number of subjects included in the efficacy analysis
    End point type
    Secondary
    End point timeframe
    Baseline to end of treatment, or approximately 26 months
    End point values
    		 Guadacitabine Treatment Choice
    Number of subjects analysed
    148
    154
    Units: Percentage of subjects
        number (not applicable)
    17.6
    16.2
    No statistical analyses for this end point

    Secondary: Duration of combined CR and CRh

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    End point title
    		 Duration of combined CR and CRh
    End point description
    Time from first CR or CRh to time of relapse; the date of the earliest of the following 3 events: (1) relapse (defined as the earliest time point whereby BM assessment or PB assessment by the investigator indicate relapse/disease progression due to confirmed reappearance of leukemic blasts in PB or ≥5% leukemic blasts in BM, or clinical progression determined by the investigator), (2) start of alternative therapy (except HCT) or (3) death
    End point type
    Secondary
    End point timeframe
    Baseline to end of treatment, or approximately 26 months
    End point values
    		 Guadacitabine Treatment Choice
    Number of subjects analysed
    25
    12
    Units: Days
        median (confidence interval 95%)
    124 (73 to 315)
    63 (8 to 71)
    No statistical analyses for this end point

    Secondary: Incidence of adverse events

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    End point title
    		 Incidence of adverse events
    End point description
    Number of subjects with any adverse event (AE) divided by the total number of subjects included in the safety analysis
    End point type
    Secondary
    End point timeframe
    From first dose until 30 days after the last dose of study drug, or approximately 26 months
    End point values
    		 Guadacitabine Treatment Choice
    Number of subjects analysed
    145
    147
    Units: Percentage of subjects
        number (not applicable)
    96.6
    97.3
    No statistical analyses for this end point

    Secondary: All-cause mortality

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    End point title
    		 All-cause mortality
    End point description
    All-cause mortality in the first 30 days and first 60 days after the start of treatment divided by the total number of subjects receiving at least one dose of study treatment
    End point type
    Secondary
    End point timeframe
    From the first dose until 60 days after the first dose of study drug
    End point values
    		 Guadacitabine Treatment Choice
    Number of subjects analysed
    145
    147
    Units: Percentage of subjects
    number (not applicable)
        Within 30 days
    11.7
    9.5
        Within 60 days
    24.8
    20.4
    No statistical analyses for this end point

    Secondary: Change in EQ-5D-5L Index Score

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    End point title
    		 Change in EQ-5D-5L Index Score
    End point description
    Change from baseline in EQ-5D-5L index scores in the first 6 months; index score is calculated based on a 5 point scoring scale where scores range from -0.281 (for the worst health state, score of 5 for all categories) to 1 (for the best health state, score of 1 for all categories).
    End point type
    Secondary
    End point timeframe
    Baseline to 6 months
    End point values
    		 Guadacitabine Treatment Choice Guadecitabine vs Treatment Choice
    Number of subjects analysed
    148
    154
    Units: Score on a scale
    least squares mean (confidence interval 95%)
        Cycle 2 Day 1
    -0.027 (-0.061 to 0.007)
    -0.034 (-0.068 to 0.001)
    0.006 (-0.042 to 0.055)
        Cycle 3 Day 1
    -0.026 (-0.063 to 0.011)
    -0.028 (-0.066 to 0.010)
    0.002 (-0.051 to 0.055)
        Cycle 4 Day 1
    -0.008 (-0.050 to 0.034)
    -0.061 (-0.108 to -0.015)
    0.053 (-0.010 to 0.116)
        Cycle 5 Day 1
    -0.022 (-0.072 to 0.027)
    -0.072 (-0.126 to -0.019)
    0.050 (-0.023 to 0.123)
        Cycle 6 Day 1
    -0.027 (-0.071 to 0.017)
    -0.070 (-0.188 to -0.022)
    0.043 (-0.022 to 0.108)
        Cycle 7 Day 1
    -0.020 (-0.071 to 0.030)
    -0.022 (-0.076 to 0.033)
    0.002 (-0.073 to 0.076)
    No statistical analyses for this end point

    Secondary: Change in EQ-5D-5L Visual Analogue Scale Score

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    End point title
    		 Change in EQ-5D-5L Visual Analogue Scale Score
    End point description
    Change from baseline in EQ-5D-5L visual analogue scale (VAS) score in the first 6 months; VAS score is obtained using vertical 20-cm visual analogue scale with the top value of 100 labelled as 'the best health you can imagine' and the bottom value of 0 labelled as 'the worst health you can imagine'
    End point type
    Secondary
    End point timeframe
    Baseline to 6 months
    End point values
    		 Guadacitabine Treatment Choice Guadecitabine vs Treatment Choice
    Number of subjects analysed
    148
    154
    Units: Score on a scale
    least squares mean (confidence interval 95%)
        Cycle 2 Day 1
    -2.80 (-6.26 to 0.65)
    -1.86 (-5.40 to 1.67)
    -0.94 (-5.88 to 4.00)
        Cycle 3 Day 1
    -0.61 (-4.08 to 2.87)
    -1.47 (-5.02 to 2.08)
    0.86 (-4.11 to 5.83)
        Cycle 4 Day 1
    1.13 (-2.24 to 4.51)
    -2.37 (-6.04 to 1.29)
    3.51 (-1.48 to 8.49)
        Cycle 5 Day 1
    1.28 (-2.88 to 5.44)
    -2.30 (-6.83 to 2.22)
    3.58 (-2.57 to 9.72)
        Cycle 6 Day 1
    0.67 (-3.51 to 4.85)
    -1.42 (-6.04 to 3.21)
    2.09 (-4.14 to 8.32)
        Cycle 7 Day 1
    -0.44 (-5.66 to 4.78)
    -0.77 (-6.46 to 4.93)
    0.33 (-7.40 to 8.05)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline to approximately 26 months
    Adverse event reporting additional description
    Adverse events are recorded from the start of study treatment until 30 days after the last dose of study treatment or until the subject starts a new anti-AML treatment, whichever occurs first. Guadacitabine subjects received a median of 3.0 cycles (range 1-24) and TC subjects received a median of 2.0 cycles (range 1-17).
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Guadacitabine
    Reporting group description
    		 Guadacitabine was administered subcutaneously (SC) at a dose of 60 mg/m2 in 28-day cycles.

    Reporting group title
    Treatment Choice
    Reporting group description
    		 Intermediate or high dose cytarabine (HiDAC), MEC, FLAG/FLAG-Ida, LDAC, decitabine, azacitidine, or best supportive care (BSC) only.

    Serious adverse events
    		 Guadacitabine Treatment Choice
    Total subjects affected by serious adverse events
         subjects affected / exposed
    113 / 145 (77.93%)
    91 / 147 (61.90%)
         number of deaths (all causes)
    114
    126
         number of deaths resulting from adverse events
    40
    30
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant melanoma
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningioma
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour associated fever
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Embolism
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 145 (0.69%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    2 / 145 (1.38%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 147 (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
    5 / 145 (3.45%)
    6 / 147 (4.08%)
         occurrences causally related to treatment / all
    1 / 5
    1 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    1 / 145 (0.69%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Acute respiratory distress syndrome
         subjects affected / exposed
    2 / 145 (1.38%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    3 / 145 (2.07%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 145 (0.69%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    1 / 145 (0.69%)
    2 / 147 (1.36%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Lung infiltration
         subjects affected / exposed
    1 / 145 (0.69%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 145 (0.69%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 145 (0.69%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Pulmonary oedema
         subjects affected / exposed
    0 / 145 (0.00%)
    2 / 147 (1.36%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory distress
         subjects affected / exposed
    2 / 145 (1.38%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 145 (0.69%)
    2 / 147 (1.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Psychiatric disorders
    Suicidal ideation
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 147 (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 / 145 (0.69%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Troponin T increased
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 147 (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
    Anaphylactic transfusion reaction
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ilium fracture
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative respiratory distress
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 147 (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
    2 / 145 (1.38%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Aplasia
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 145 (0.69%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    4 / 145 (2.76%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 4
    0 / 0
    Cardiac failure
         subjects affected / exposed
    3 / 145 (2.07%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Cardiac failure acute
         subjects affected / exposed
    2 / 145 (1.38%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 145 (0.69%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 145 (0.00%)
    2 / 147 (1.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Brain stem infarction
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 145 (0.69%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Cerebral ischaemia
         subjects affected / exposed
    0 / 145 (0.00%)
    2 / 147 (1.36%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Haemorrhage intracranial
         subjects affected / exposed
    2 / 145 (1.38%)
    2 / 147 (1.36%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Peripheral motor neuropathy
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 147 (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 / 145 (0.69%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 145 (0.69%)
    2 / 147 (1.36%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone marrow failure
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile bone marrow aplasia
         subjects affected / exposed
    4 / 145 (2.76%)
    3 / 147 (2.04%)
         occurrences causally related to treatment / all
    4 / 4
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    41 / 145 (28.28%)
    33 / 147 (22.45%)
         occurrences causally related to treatment / all
    33 / 67
    11 / 42
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Neutropenia
         subjects affected / exposed
    2 / 145 (1.38%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    3 / 145 (2.07%)
    2 / 147 (1.36%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Deafness unilateral
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 145 (1.38%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mouth haemorrhage
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic colitis
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal mucosal tear
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral mucosal erythema
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Salivary gland enlargement
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    2 / 145 (1.38%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tongue oedema
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 147 (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
    1 / 145 (0.69%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Drug reaction with eosinophilia and systemic symptoms
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 147 (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 / 145 (0.00%)
    1 / 147 (0.68%)
         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
    0 / 145 (0.00%)
    2 / 147 (1.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    2 / 145 (1.38%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal infection
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Anal abscess
         subjects affected / exposed
    2 / 145 (1.38%)
    2 / 147 (1.36%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal infection
         subjects affected / exposed
    1 / 145 (0.69%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anorectal infection
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspergillus infection
         subjects affected / exposed
    1 / 145 (0.69%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    4 / 145 (2.76%)
    5 / 147 (3.40%)
         occurrences causally related to treatment / all
    1 / 5
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bartholinitis
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    4 / 145 (2.76%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 0
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    Cellulitis
         subjects affected / exposed
    4 / 145 (2.76%)
    2 / 147 (1.36%)
         occurrences causally related to treatment / all
    2 / 4
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    2 / 145 (1.38%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Corynebacterium bacteraemia
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus viraemia
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermo-hypodermitis
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    4 / 145 (2.76%)
    3 / 147 (2.04%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disseminated varicella zoster vaccine virus infection
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ecthyma
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis infectious
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterobacter infection
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterococcal bacteraemia
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    External ear cellulitis
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fungal infection
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Genital infection
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Groin abscess
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes simplex
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infective myositis
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal sepsis
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella bacteraemia
         subjects affected / exposed
    1 / 145 (0.69%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucormycosis
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 147 (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 / 145 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic infection
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral infection
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis media
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parvovirus B19 infection
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 147 (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 / 145 (0.00%)
    1 / 147 (0.68%)
         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 / 145 (0.69%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    2 / 145 (1.38%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    27 / 145 (18.62%)
    25 / 147 (17.01%)
         occurrences causally related to treatment / all
    9 / 31
    7 / 32
         deaths causally related to treatment / all
    1 / 6
    2 / 8
    Pseudomonal bacteraemia
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    2 / 145 (1.38%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sepsis
         subjects affected / exposed
    15 / 145 (10.34%)
    16 / 147 (10.88%)
         occurrences causally related to treatment / all
    6 / 18
    5 / 16
         deaths causally related to treatment / all
    0 / 4
    3 / 7
    Septic shock
         subjects affected / exposed
    7 / 145 (4.83%)
    5 / 147 (3.40%)
         occurrences causally related to treatment / all
    2 / 8
    4 / 7
         deaths causally related to treatment / all
    0 / 3
    1 / 2
    Sinusitis fungal
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 147 (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
    0 / 145 (0.00%)
    3 / 147 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    1 / 145 (0.69%)
    2 / 147 (1.36%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal bacteraemia
         subjects affected / exposed
    2 / 145 (1.38%)
    2 / 147 (1.36%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal sepsis
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth abscess
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 145 (1.38%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia bacteraemia
         subjects affected / exposed
    1 / 145 (0.69%)
    2 / 147 (1.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypercalcaemia
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Guadacitabine Treatment Choice
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    138 / 145 (95.17%)
    137 / 147 (93.20%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    15 / 145 (10.34%)
    4 / 147 (2.72%)
         occurrences all number
    20
    4
    Hypotension
         subjects affected / exposed
    19 / 145 (13.10%)
    11 / 147 (7.48%)
         occurrences all number
    20
    14
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    11 / 145 (7.59%)
    15 / 147 (10.20%)
         occurrences all number
    15
    20
    Fatigue
         subjects affected / exposed
    20 / 145 (13.79%)
    27 / 147 (18.37%)
         occurrences all number
    23
    32
    Injection site reaction
         subjects affected / exposed
    29 / 145 (20.00%)
    12 / 147 (8.16%)
         occurrences all number
    35
    12
    Oedema peripheral
         subjects affected / exposed
    23 / 145 (15.86%)
    23 / 147 (15.65%)
         occurrences all number
    28
    28
    Pyrexia
         subjects affected / exposed
    33 / 145 (22.76%)
    36 / 147 (24.49%)
         occurrences all number
    50
    50
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    22 / 145 (15.17%)
    27 / 147 (18.37%)
         occurrences all number
    28
    31
    Dyspnoea
         subjects affected / exposed
    20 / 145 (13.79%)
    17 / 147 (11.56%)
         occurrences all number
    21
    18
    Epistaxis
         subjects affected / exposed
    16 / 145 (11.03%)
    16 / 147 (10.88%)
         occurrences all number
    22
    30
    Oropharyngeal pain
         subjects affected / exposed
    4 / 145 (2.76%)
    9 / 147 (6.12%)
         occurrences all number
    8
    9
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    14 / 145 (9.66%)
    13 / 147 (8.84%)
         occurrences all number
    16
    14
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    12 / 145 (8.28%)
    7 / 147 (4.76%)
         occurrences all number
    15
    15
    Aspartate aminotransferase increased
         subjects affected / exposed
    11 / 145 (7.59%)
    8 / 147 (5.44%)
         occurrences all number
    13
    12
    Blood alkaline phosphatase increased
         subjects affected / exposed
    6 / 145 (4.14%)
    8 / 147 (5.44%)
         occurrences all number
    6
    15
    Blood bilirubin increased
         subjects affected / exposed
    8 / 145 (5.52%)
    9 / 147 (6.12%)
         occurrences all number
    14
    11
    Blood creatinine increased
         subjects affected / exposed
    8 / 145 (5.52%)
    4 / 147 (2.72%)
         occurrences all number
    11
    6
    Weight decreased
         subjects affected / exposed
    5 / 145 (3.45%)
    9 / 147 (6.12%)
         occurrences all number
    6
    10
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    11 / 145 (7.59%)
    6 / 147 (4.08%)
         occurrences all number
    11
    7
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    8 / 145 (5.52%)
    11 / 147 (7.48%)
         occurrences all number
    9
    14
    Headache
         subjects affected / exposed
    30 / 145 (20.69%)
    20 / 147 (13.61%)
         occurrences all number
    39
    26
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    37 / 145 (25.52%)
    41 / 147 (27.89%)
         occurrences all number
    68
    108
    Febrile neutropenia
         subjects affected / exposed
    25 / 145 (17.24%)
    29 / 147 (19.73%)
         occurrences all number
    32
    35
    Leukopenia
         subjects affected / exposed
    14 / 145 (9.66%)
    14 / 147 (9.52%)
         occurrences all number
    23
    19
    Neutropenia
         subjects affected / exposed
    47 / 145 (32.41%)
    28 / 147 (19.05%)
         occurrences all number
    87
    55
    Thrombocytopenia
         subjects affected / exposed
    43 / 145 (29.66%)
    46 / 147 (31.29%)
         occurrences all number
    77
    137
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    11 / 145 (7.59%)
    11 / 147 (7.48%)
         occurrences all number
    12
    16
    Constipation
         subjects affected / exposed
    33 / 145 (22.76%)
    33 / 147 (22.45%)
         occurrences all number
    36
    42
    Diarrhoea
         subjects affected / exposed
    36 / 145 (24.83%)
    32 / 147 (21.77%)
         occurrences all number
    46
    40
    Dyspepsia
         subjects affected / exposed
    12 / 145 (8.28%)
    5 / 147 (3.40%)
         occurrences all number
    12
    5
    Haemorrhoids
         subjects affected / exposed
    11 / 145 (7.59%)
    9 / 147 (6.12%)
         occurrences all number
    12
    9
    Nausea
         subjects affected / exposed
    42 / 145 (28.97%)
    38 / 147 (25.85%)
         occurrences all number
    58
    52
    Stomatitis
         subjects affected / exposed
    16 / 145 (11.03%)
    20 / 147 (13.61%)
         occurrences all number
    21
    21
    Vomiting
         subjects affected / exposed
    24 / 145 (16.55%)
    20 / 147 (13.61%)
         occurrences all number
    35
    33
    Skin and subcutaneous tissue disorders
    Petechiae
         subjects affected / exposed
    12 / 145 (8.28%)
    7 / 147 (4.76%)
         occurrences all number
    13
    8
    Rash
         subjects affected / exposed
    11 / 145 (7.59%)
    9 / 147 (6.12%)
         occurrences all number
    12
    17
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    8 / 145 (5.52%)
    2 / 147 (1.36%)
         occurrences all number
    9
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    12 / 145 (8.28%)
    10 / 147 (6.80%)
         occurrences all number
    14
    11
    Back pain
         subjects affected / exposed
    15 / 145 (10.34%)
    12 / 147 (8.16%)
         occurrences all number
    16
    13
    Myalgia
         subjects affected / exposed
    8 / 145 (5.52%)
    5 / 147 (3.40%)
         occurrences all number
    9
    5
    Pain in extremity
         subjects affected / exposed
    11 / 145 (7.59%)
    7 / 147 (4.76%)
         occurrences all number
    15
    13
    Infections and infestations
    Oral herpes
         subjects affected / exposed
    8 / 145 (5.52%)
    5 / 147 (3.40%)
         occurrences all number
    8
    5
    Pneumonia
         subjects affected / exposed
    15 / 145 (10.34%)
    14 / 147 (9.52%)
         occurrences all number
    16
    17
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    27 / 145 (18.62%)
    20 / 147 (13.61%)
         occurrences all number
    32
    24
    Hyperkalaemia
         subjects affected / exposed
    9 / 145 (6.21%)
    3 / 147 (2.04%)
         occurrences all number
    11
    8
    Hypoalbuminaemia
         subjects affected / exposed
    10 / 145 (6.90%)
    7 / 147 (4.76%)
         occurrences all number
    12
    8
    Hypocalcaemia
         subjects affected / exposed
    9 / 145 (6.21%)
    5 / 147 (3.40%)
         occurrences all number
    12
    5
    Hypokalaemia
         subjects affected / exposed
    29 / 145 (20.00%)
    38 / 147 (25.85%)
         occurrences all number
    47
    63
    Hypomagnesaemia
         subjects affected / exposed
    14 / 145 (9.66%)
    16 / 147 (10.88%)
         occurrences all number
    26
    25
    Hyponatraemia
         subjects affected / exposed
    10 / 145 (6.90%)
    3 / 147 (2.04%)
         occurrences all number
    19
    4
    Hypophosphataemia
         subjects affected / exposed
    13 / 145 (8.97%)
    9 / 147 (6.12%)
         occurrences all number
    21
    20

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Nov 2017
    •Incorporated the changes from previous region-specific amendments • Clarified clinical response assessment using bone marrow and peripheral blood samples. • Clarified inclusion and exclusion criteria. • Clarified what was meant by “alternative anti-leukemia therapy” in this protocol and when the safety follow-up visit was to be performed. • Provided information and references on cytogenetics-based risk classification. • Amended the timing of the planned primary analysis of overall survival if the number of death events had not occurred within a reasonable duration. • Clarified when electrocardiogram (ECG) and vital sign safety assessments were performed for subjects in the BSC group. • Clarified long-term follow-up procedures. • Implemented administrative updates.
    14 Feb 2018
    • Added the efficacy variable “complete response with partial hematological recovery (CRh)” based on recent Food and Drug Administration (FDA) marketing approvals for relapsed/refractory (r/r) AML treatments based on this variable. • Combined CRh with CR for calculation of duration of response to include important response criteria in the duration calculation. • Allowed subjects randomly assigned to guadecitabine to receive hydroxyurea in the first 30 days of treatment to enable subjects to receive at least 2 cycles of study treatment, as guadecitabine may not adequately control proliferative disease from one cycle only. • Excluded subjects with high PB blasts >50% AND poor ECOG PS of 2, which indicates highly aggressive proliferative disease, as subjects may be at imminent risk of death. • Clarified that, after discontinuing study treatment, subjects should not withdraw consent just because they wished to participate in another experimental study. • Allowed the 10-day regimen of guadecitabine to be given on Days 1-10 (rather than Days 1-5 and 8-12) to facilitate quicker control of apparent progression in the first 2 cycles. • Allowed concomitant intrathecal treatment to control central nervous system (CNS) disease, as study treatment is not active in CNS disease. • Allowed donor lymphocytes infusion (DLI) if it was part of standard practice in certain subjects with r/r AML.
    29 Oct 2018
    • Study closed to further enrollment based on recommendation from DMC. • Revised plan for interim analysis to describe futility analysis. • Specified study follow-up stop date to be Q3 2019 or when the last subject was off study and removed provision for subjects to continue receiving guadecitabine after study completion. • Administrative changes.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    12 Sep 2018
    Based on data from 278 randomly assigned subjects, the Data Monitoring Committee (DMC) recommended to stop further enrollment into the trial based on futility analysis that showed the trial was unlikely to show superiority of guadecitabine over treatment choice (TC) for the primary endpoint of overall survival (OS). Consequently, the study was closed to further enrollment in September 2018 (Amendment 4).
    -

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