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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
    		 v2(current)
    This version publication date
    06 Aug 2023
    First version publication date
    13 Jun 2021
    Other versions
    		 v1
    Version creation reason

    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
    		 -

    Pre-assignment
    Screening details
    		 A total of 358 participants were assessed for study inclusion. Of these 56 failed screening assessments. A total of 302 participants were randomized (148 guadecitabine, 154 treatment choice [TC]). Of the randomized participants, 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
    		 Guadecitabine was administered subcutaneously (SC) at a dose of 60 milligrams per meter square (mg/m^2) for 10 days on Days 1-5 and Days 8-12 or on Days 1-10 in the first cycle. Second cycle was 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 end of Cycle 1. For Cycles ≥3, guadecitabine, 60 mg/m^2 was given for 5 days only (Days 1-5). Each cycle = 28 days.
    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), mitoxantrone, etoposide and cytarabine (MEC) and granulocyte colony-stimulating factors (G-CSF)/fludarabine, cytarabine, G-CSF and idarubicin (FLAG/FLAG-Ida), low dose cytarabine (LDAC), decitabine, azacitidine, or best supportive care (BSC) was administered only. High intensity: Intermediate or HiDAC, recommended as 1-1.5 g/m^2 every 12 hours or up to 6 g/m^2/day for ≤6 days, max. 36 g/m^2 per cycle; MEC: eg.: mitoxantrone 6-12 mg/m^2 IV, etoposide 80-200 mg/m^2 IV, and cytarabine 1000 mg/m^2 IV; each daily for 5 days; FLAG/FLAG-Ida: eg.: fludarabine 25-30 mg/m^2 IV daily Days 1-5; cytarabine 1-2 g/m^2 IV daily for up to 5 days; 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.
    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
    		 Guadecitabine was administered subcutaneously (SC) at a dose of 60 milligrams per meter square (mg/m^2) for 10 days on Days 1-5 and Days 8-12 or on Days 1-10 in the first cycle. Second cycle was 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 end of Cycle 1. For Cycles ≥3, guadecitabine, 60 mg/m^2 was given for 5 days only (Days 1-5). Each cycle = 28 days.

    Reporting group title
    Treatment Choice
    Reporting group description
    		 Intermediate or high dose cytarabine (HiDAC), mitoxantrone, etoposide and cytarabine (MEC) and granulocyte colony-stimulating factors (G-CSF)/fludarabine, cytarabine, G-CSF and idarubicin (FLAG/FLAG-Ida), low dose cytarabine (LDAC), decitabine, azacitidine, or best supportive care (BSC) was administered only. High intensity: Intermediate or HiDAC, recommended as 1-1.5 g/m^2 every 12 hours or up to 6 g/m^2/day for ≤6 days, max. 36 g/m^2 per cycle; MEC: eg.: mitoxantrone 6-12 mg/m^2 IV, etoposide 80-200 mg/m^2 IV, and cytarabine 1000 mg/m^2 IV; each daily for 5 days; FLAG/FLAG-Ida: eg.: fludarabine 25-30 mg/m^2 IV daily Days 1-5; cytarabine 1-2 g/m^2 IV daily for up to 5 days; 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.

    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
    		 Guadecitabine was administered subcutaneously (SC) at a dose of 60 milligrams per meter square (mg/m^2) for 10 days on Days 1-5 and Days 8-12 or on Days 1-10 in the first cycle. Second cycle was 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 end of Cycle 1. For Cycles ≥3, guadecitabine, 60 mg/m^2 was given for 5 days only (Days 1-5). Each cycle = 28 days.

    Reporting group title
    Treatment Choice
    Reporting group description
    		 Intermediate or high dose cytarabine (HiDAC), mitoxantrone, etoposide and cytarabine (MEC) and granulocyte colony-stimulating factors (G-CSF)/fludarabine, cytarabine, G-CSF and idarubicin (FLAG/FLAG-Ida), low dose cytarabine (LDAC), decitabine, azacitidine, or best supportive care (BSC) was administered only. High intensity: Intermediate or HiDAC, recommended as 1-1.5 g/m^2 every 12 hours or up to 6 g/m^2/day for ≤6 days, max. 36 g/m^2 per cycle; MEC: eg.: mitoxantrone 6-12 mg/m^2 IV, etoposide 80-200 mg/m^2 IV, and cytarabine 1000 mg/m^2 IV; each daily for 5 days; FLAG/FLAG-Ida: eg.: fludarabine 25-30 mg/m^2 IV daily Days 1-5; cytarabine 1-2 g/m^2 IV daily for up to 5 days; 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.

    Primary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    Overall survival is defined as number of days from day of randomization to date of death, regardless of cause. The efficacy analysis set included data from all subjects randomly assigned to study treatment.
    End point type
    Primary
    End point timeframe
    From the date of randomization until the date of death, or approximately 34 months
    End point values
    		 Guadacitabine Treatment Choice
    Number of subjects analysed
    148
    154
    Units: days
        median (confidence interval 95%)
    191.0 (141.0 to 253.0)
    163.0 (131.0 to 213.0)
    Statistical analysis title
    		 Guadecitabine Vs Treatment Choice (TC)
    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
    Event-free survival is defined as number of days from randomization to earliest date of treatment discontinuation (for reasons other than initiation of hematopoietic cell transplant [HCT]), start of alternative anti-leukemia therapy (except HCT), or death. The efficacy analysis set included data from all subjects randomly assigned to study treatment.
    End point type
    Secondary
    End point timeframe
    From the date of randomization until the date of death, or approximately 38 months
    End point values
    		 Guadacitabine Treatment Choice
    Number of subjects analysed
    148
    154
    Units: Days
        median (confidence interval 95%)
    90.0 (73.0 to 105.0)
    71.5 (53.0 to 78.0)
    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 followed to estimate 2-year survival rate. The efficacy analysis set included data from all subjects randomly assigned to study treatment.
    End point type
    Secondary
    End point timeframe
    Up to approximately 38 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 (NDAOH)

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    End point title
    		 Number of Days Alive and Out of the Hospital (NDAOH)
    End point description
    Number of days subjects alive and out of hospital during first 6 months of the study. The efficacy analysis set included data from all subjects randomly assigned to study treatment.
    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 Rate

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    End point title
    		 Transfusion Independence Rate
    End point description
    Number of subjects without red blood cells (RBC) or platelet transfusion for any 8-week period after treatment divided by total number of subjects in efficacy analysis. The efficacy analysis set included data from all subjects randomly assigned to study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 38 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 Rate

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    End point title
    		 Complete Response Rate
    End point description
    The Complete response (CR) rate based on modified International Working Group (IWG) 2003 AML Response Criteria was calculated as the number of subjects with a best response of CR divided by the total number of subjects included in the efficacy analysis. CR as per modified 2003 IWG AML Response Criteria is absolute neutrophil count (ANC) ≥1000/μL, platelets ≥100,000/μL, independence from red blood cells (RBC) and platelet transfusions over the past week, no leukemic blasts in peripheral blood and bone marrow should contain less than 5% blast cells. The efficacy analysis set included data from all subjects randomly assigned to study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline to end of treatment, or approximately 38 months
    End point values
    		 Guadacitabine Treatment Choice
    Number of subjects analysed
    148
    154
    Units: percentage of subjects
        number (not applicable)
    12.8
    7.1
    No statistical analyses for this end point

    Secondary: Combined Complete Response and Complete Response With Partial Hematologic Recovery Rate

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    End point title
    		 Combined Complete Response and Complete Response With Partial Hematologic Recovery Rate
    End point description
    The combined CR and CR with partial hematologic recovery rate based on modified International Working Group (IWG) 2003 AML Response Criteria was calculated as number of subjects with CR and CR with partial hematologic recovery divided by the total number of subjects included in the efficacy analysis. CR as per modified 2003 IWG AML Response Criteria is absolute neutrophil count (ANC) ≥1000/μL, platelets ≥100,000/μL, independence from red blood cells (RBC) and platelet transfusions over the past week, no leukemic blasts in peripheral blood and bone marrow should contain less than 5% blast cells. The efficacy analysis set included data from all subjects randomly assigned to study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline to end of treatment, or approximately 38 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: Duration of combined CR and CR With Partial Hematologic Recovery (CRh)

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    End point title
    		 Duration of combined CR and CR With Partial Hematologic Recovery (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. The efficacy analysis set included data from all subjects randomly assigned to study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline to end of treatment, or approximately 38 months
    End point values
    		 Guadacitabine Treatment Choice
    Number of subjects analysed
    25
    12
    Units: days
        median (confidence interval 95%)
    124 (73.0 to 315.0)
    63 (8.0 to 71.0)
    No statistical analyses for this end point

    Secondary: Hematopoietic cell transplant (HCT) Rate

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    End point title
    		 Hematopoietic cell transplant (HCT) Rate
    End point description
    Number of subjects who received HCT after randomization divided by total number of subjects in efficacy analysis. The efficacy analysis set included data from all subjects randomly assigned to study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline to long term follow-up or approximately 38 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: Percentage of Participants With Adverse Events (AEs)

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    End point title
    		 Percentage of Participants With Adverse Events (AEs)
    End point description
    An AE is any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. An AE can therefore be any unfavorable and unintended sign (including a clinically significant abnormal finding in laboratory tests or other diagnostic procedures), symptom, or disease temporally associated with the use of a drug, without any judgment about causality. The safety analysis set included data from all subjects randomly assigned to study treatment who received any amount of study treatment or any component of a multi-dose study treatment regimen.
    End point type
    Secondary
    End point timeframe
    From first dose until 30 days after the last dose of study drug, or approximately 38 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. The efficacy analysis set included data from all participants randomly assigned to 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 From Baseline in EuroQoL-5 Dimension 5 Level (EQ-5D-5L) Index Scores

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    End point title
    		 Change From Baseline in EuroQoL-5 Dimension 5 Level (EQ-5D-5L) Index Scores
    End point description
    Index score is calculated based on 5-level version of the EQ-5D descriptive system using the value set for England. The range of index score is 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). The efficacy analysis set included data from all participants randomly assigned to study treatment. Overall number of participants analyzed is the number of participants with data available for analysis in this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline to 6 months
    End point values
    		 Guadacitabine Treatment Choice
    Number of subjects analysed
    148
    154
    Units: score on a scale
    least squares mean (confidence interval 95%)
        Cycle 2 Day 1(n=107,102)
    -0.027 (-0.061 to 0.007)
    -0.034 (-0.068 to 0.001)
        Cycle 3 Day 1(n=80,77)
    -0.026 (-0.063 to 0.011)
    -0.028 (-0.066 to 0.010)
        Cycle 4 Day 1(n=71,55)
    -0.008 (-0.050 to 0.034)
    -0.061 (-0.108 to -0.015)
        Cycle 5 Day 1(n=57,48)
    -0.022 (-0.072 to 0.027)
    -0.072 (-0.126 to -0.019)
        Cycle 6 Day 1(n=48,38)
    -0.027 (-0.071 to 0.017)
    -0.070 (-0.188 to -0.022)
        Cycle 7 Day 1(n=37,31)
    -0.020 (-0.071 to 0.030)
    -0.022 (-0.076 to 0.033)
    No statistical analyses for this end point

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

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    End point title
    		 Change in EQ-5D-5L Visual Analogue Scale (VAS) Score
    End point description
    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'. The efficacy analysis set included data from all subjects randomly assigned to study treatment. Overall number of subjects analysed is the number of subjects with data available for analysis in this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline to 6 months
    End point values
    		 Guadacitabine Treatment Choice
    Number of subjects analysed
    145
    147
    Units: score on a scale
    least squares mean (confidence interval 95%)
        Cycle 2 Day 1(n=107,102)
    -2.80 (-6.26 to 0.65)
    -1.86 (-5.40 to 1.67)
        Cycle 3 Day 1(n=80,77)
    -0.61 (-4.08 to 2.87)
    -1.47 (-5.02 to 2.08)
        Cycle 4 Day 1(n=71,56)
    1.13 (-2.24 to 4.51)
    -2.37 (-6.04 to 1.29)
        Cycle 5 Day 1(n=57,48)
    1.28 (-2.88 to 5.44)
    -2.30 (-6.83 to 2.22)
        Cycle 6 Day 1(n=47,38)
    0.67 (-3.51 to 4.85)
    -1.42 (-6.04 to 3.21)
        Cycle 7 Day 1(n=37,31)
    -0.44 (-5.66 to 4.78)
    -0.77 (-6.46 to 4.93)
    No statistical analyses for this end point

    Secondary: Composite Complete Response Rate

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    End point title
    		 Composite Complete Response Rate
    End point description
    Composite complete response rate based on modified IWG 2003 AML Response Criteria defined as number of subjects with best response of CR, CR with incomplete platelet recovery (CRp), or CR with incomplete blood count recovery (CRi) divided by total number of subjects in efficacy analysis. CR as per modified 2003 IWG AML Response Criteria is ANC ≥1000/μL, platelets ≥100,000/μL, independence from RBC and platelet transfusions over the past week, no leukemic blasts in peripheral blood and bone marrow should contain less than 5% blast cells. CRp is defined as ANC ≥1000/μL, Platelets <100,000/μL, independence from RBC transfusions over the past week, no leukemic blasts and bone marrow should contain less than 5% blast cells. CRi is defined as ANC <1000/μL, no leukemic blasts and bone marrow should contain less than 5% blast cells. The efficacy analysis set included data from all subjects randomly assigned to study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline to end of treatment, or approximately 38 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

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose until 30 days after the last dose of study drug, or approximately 38 months
    Adverse event reporting additional description
    All-cause mortality is reported for enrolled participants in the study. The serious and other adverse events is reported for safety analysis set which included data from all participants randomly assigned to study treatment who received any amount of study treatment or any component of a multi-dose study treatment regimen.
    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
    		 Guadecitabine was administered SC at a dose of 60 mg/m^2 for 10 days on Days 1-5 and Days 8-12 or on Days 1-10 in the first cycle. Second cycle was 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 end of Cycle 1. For Cycles ≥3, guadecitabine, 60 mg/m^2 was given for 5 days only (Days 1-5). Each cycle = 28 days.

    Reporting group title
    Treatment Choice
    Reporting group description
    		 Intermediate or high dose cytarabine (HiDAC), mitoxantrone, etoposide and cytarabine (MEC) and granulocyte colony-stimulating factors (G-CSF)/fludarabine, cytarabine, G-CSF and idarubicin (FLAG/FLAG-Ida), low dose cytarabine (LDAC), decitabine, azacitidine, or best supportive care (BSC) was administered only. High intensity: Intermediate or HiDAC, recommended as 1-1.5 g/m^2 every 12 hours or up to 6 g/m^2/day for ≤6 days, max. 36 g/m^2 per cycle; MEC: eg.: mitoxantrone 6-12 mg/m^2 IV, etoposide 80-200 mg/m^2 IV, and cytarabine 1000 mg/m^2 IV; each daily for 5 days; FLAG/FLAG-Ida: eg.: fludarabine 25-30 mg/m^2 IV daily Days 1-5; cytarabine 1-2 g/m^2 IV daily for up to 5 days; 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.

    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)
    117
    129
         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
    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
    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
    Respiratory, thoracic and mediastinal disorders
    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
    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 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 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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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 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
    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 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 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
    Nervous system disorders
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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 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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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 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
    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
    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
    Hypotension
         subjects affected / exposed
    19 / 145 (13.10%)
    11 / 147 (7.48%)
         occurrences all number
    20
    14
    Hypertension
         subjects affected / exposed
    15 / 145 (10.34%)
    4 / 147 (2.72%)
         occurrences all number
    20
    4
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    23 / 145 (15.86%)
    23 / 147 (15.65%)
         occurrences all number
    28
    28
    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
    Pyrexia
         subjects affected / exposed
    33 / 145 (22.76%)
    36 / 147 (24.49%)
         occurrences all number
    50
    50
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    4 / 145 (2.76%)
    9 / 147 (6.12%)
         occurrences all number
    8
    9
    Epistaxis
         subjects affected / exposed
    16 / 145 (11.03%)
    16 / 147 (10.88%)
         occurrences all number
    22
    30
    Dyspnoea
         subjects affected / exposed
    20 / 145 (13.79%)
    17 / 147 (11.56%)
         occurrences all number
    21
    18
    Cough
         subjects affected / exposed
    22 / 145 (15.17%)
    27 / 147 (18.37%)
         occurrences all number
    28
    31
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    14 / 145 (9.66%)
    13 / 147 (8.84%)
         occurrences all number
    16
    14
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    8 / 145 (5.52%)
    9 / 147 (6.12%)
         occurrences all number
    14
    11
    Blood alkaline phosphatase increased
         subjects affected / exposed
    6 / 145 (4.14%)
    8 / 147 (5.44%)
         occurrences all number
    6
    15
    Aspartate aminotransferase increased
         subjects affected / exposed
    11 / 145 (7.59%)
    8 / 147 (5.44%)
         occurrences all number
    13
    12
    Alanine aminotransferase increased
         subjects affected / exposed
    12 / 145 (8.28%)
    7 / 147 (4.76%)
         occurrences all number
    15
    15
    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
    Headache
         subjects affected / exposed
    30 / 145 (20.69%)
    20 / 147 (13.61%)
         occurrences all number
    39
    26
    Dizziness
         subjects affected / exposed
    8 / 145 (5.52%)
    11 / 147 (7.48%)
         occurrences all number
    9
    14
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    43 / 145 (29.66%)
    46 / 147 (31.29%)
         occurrences all number
    77
    137
    Neutropenia
         subjects affected / exposed
    47 / 145 (32.41%)
    28 / 147 (19.05%)
         occurrences all number
    87
    55
    Leukopenia
         subjects affected / exposed
    14 / 145 (9.66%)
    14 / 147 (9.52%)
         occurrences all number
    23
    19
    Febrile neutropenia
         subjects affected / exposed
    25 / 145 (17.24%)
    29 / 147 (19.73%)
         occurrences all number
    32
    35
    Anaemia
         subjects affected / exposed
    37 / 145 (25.52%)
    41 / 147 (27.89%)
         occurrences all number
    68
    108
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    36 / 145 (24.83%)
    32 / 147 (21.77%)
         occurrences all number
    46
    40
    Abdominal pain
         subjects affected / exposed
    11 / 145 (7.59%)
    11 / 147 (7.48%)
         occurrences all number
    12
    16
    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
    Constipation
         subjects affected / exposed
    33 / 145 (22.76%)
    33 / 147 (22.45%)
         occurrences all number
    36
    42
    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
    Pain in extremity
         subjects affected / exposed
    11 / 145 (7.59%)
    7 / 147 (4.76%)
         occurrences all number
    15
    13
    Myalgia
         subjects affected / exposed
    8 / 145 (5.52%)
    5 / 147 (3.40%)
         occurrences all number
    9
    5
    Back pain
         subjects affected / exposed
    15 / 145 (10.34%)
    12 / 147 (8.16%)
         occurrences all number
    16
    13
    Arthralgia
         subjects affected / exposed
    12 / 145 (8.28%)
    10 / 147 (6.80%)
         occurrences all number
    14
    11
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    15 / 145 (10.34%)
    14 / 147 (9.52%)
         occurrences all number
    16
    17
    Oral herpes
         subjects affected / exposed
    8 / 145 (5.52%)
    5 / 147 (3.40%)
         occurrences all number
    8
    5
    Metabolism and nutrition disorders
    Hypophosphataemia
         subjects affected / exposed
    13 / 145 (8.97%)
    9 / 147 (6.12%)
         occurrences all number
    21
    20
    Hyponatraemia
         subjects affected / exposed
    10 / 145 (6.90%)
    3 / 147 (2.04%)
         occurrences all number
    19
    4
    Hypomagnesaemia
         subjects affected / exposed
    14 / 145 (9.66%)
    16 / 147 (10.88%)
         occurrences all number
    26
    25
    Hypokalaemia
         subjects affected / exposed
    29 / 145 (20.00%)
    38 / 147 (25.85%)
         occurrences all number
    47
    63
    Hypocalcaemia
         subjects affected / exposed
    9 / 145 (6.21%)
    5 / 147 (3.40%)
         occurrences all number
    12
    5
    Hypoalbuminaemia
         subjects affected / exposed
    10 / 145 (6.90%)
    7 / 147 (4.76%)
         occurrences all number
    12
    8
    Hyperkalaemia
         subjects affected / exposed
    9 / 145 (6.21%)
    3 / 147 (2.04%)
         occurrences all number
    11
    8
    Decreased appetite
         subjects affected / exposed
    27 / 145 (18.62%)
    20 / 147 (13.61%)
         occurrences all number
    32
    24

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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
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