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    Clinical Trial Results:
    RaVvA: Phase II Randomised Trial of 5-Azacitidine versus 5-Azacitidine in combination with Vorinostat in patients with Relapsed Acute Myeloid Leukaemia ineligible for Intensive Chemotherapy

    Summary
    EudraCT number
    		 2011-005207-32
    Trial protocol
    		 GB  
    Global end of trial date
    31 Dec 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Jan 2022
    First version publication date
    11 Jan 2022
    Other versions
    Summary report(s)
    		 RAvVA Primary publication_CCR_Aug 2017
    Quality of Life Outcome Data

    Trial information

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    Trial identification
    Sponsor protocol code
    RG_11-187
    Additional study identifiers
    ISRCTN number
    		 ISRCTN68224706
    US NCT number
    		 NCT01617226
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Birmingham
    Sponsor organisation address
    Edgbaston, Birmingham, United Kingdom, B15 2TT
    Public contact
    RAVVA Trials Office (Haematology), CRUK Clinical Trials Unit, +44 01213714364, ravva@trials.bham.ac.uk
    Scientific contact
    RAVVA Trials Office (Haematology), CRUK Clinical Trials Unit, +44 01213714364, ravva@trials.bham.ac.uk
    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
    16 Dec 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Dec 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the activity of azacitidine and vorinostat combined therapy, in terms of overall response (OR) (complete remission (CR), complete remission with incomplete blood count recovery (CRi) and partial remission (PR), as defined by Cheson criteria) and overall survival (OS) in patients with relapsed AML who are ineligible for intensive chemotherapy.
    Protection of trial subjects
    Analyses were supplied in confidence to an independent Data Monitoring Committee (DMC), who gave advice on whether the accumulated data from the trial, together with the results from other relevant research, justified the continuing recruitment of further patients. The DMC operated in accordance with a trial specific charter based upon the template created by the Damocles Group. The DMC could have considered recommending the discontinuation of the trial if the recruitment rate or data quality were unacceptable or if any issues were identified which may have compromised patient safety. The trial could also have stopped early if the interim analyses showed differences between treatments that were deemed to be convincing to the clinical community. A Trial Steering Committee (TSC) provided overall supervision for the trial and provided advice through its independent chair.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 Nov 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 259
    Worldwide total number of subjects
    259
    EEA total number of subjects
    0
    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)
    33
    From 65 to 84 years
    222
    85 years and over
    4

    Subject disposition

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    Recruitment
    Recruitment details
    		 This trial recruited 259 patients from the UK with newly diagnosed, relapsed, or refractory AML/high risk MDS who were ineligible for intensive chemotherapy.

    Pre-assignment
    Screening details
    		 The following tests were performed during screening to ensure the patient was eligible and fit enough to participate in the trial: physical exam (including height, weight, blood pressure and spleen measurement), full blood count, biochemistry, bone marrow, ECG and a pregnancy test (if appropriate).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Azacitidine alone - control arm
    Arm description
    		 Patients received azacitidine (75mg/m2) by subcutaneous injection on 7 consecutive days (excluding weekends), starting day 1 of 28-day cycles for up to 6 cycles. This was delivered in a 5-2-2 schedule.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Azacitidine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Azacitidine (75mg/m2) by subcutaneous injection on 7 consecutive days (excluding weekends), starting day 1 of 28-day cycles for up to 6 cycles. This should be delivered in a 5-2-2 schedule. Reconstituted azacitidine should be injected subcutaneously into the upper arm, thigh or abdomen. Injection sites should be rotated.

    Arm title
    		 Azacitidine + vorinostat
    Arm description
    		 Patients received (75mg/m2) azacitidine by subcutaneous injection on 7 consecutive days (excluding weekends), starting day 1 of 28-day cycles for up to 6 cycles. Azacitidine should be delivered in a 5-2-2 schedule. Vorinostat (300mg bid) will be taken orally for 7 consecutive days starting on day 3 of each cycle in 28-day cycles for up to 6 cycles. Day 3 is defined as the 3rd day of azacitidine administration.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Azacitidine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Azacitidine (75mg/m2) by subcutaneous injection on 7 consecutive days (excluding weekends), starting day 1 of 28-day cycles for up to 6 cycles. This should be delivered in a 5-2-2 schedule. Reconstituted azacitidine should be injected subcutaneously into the upper arm, thigh or abdomen. Injection sites should be rotated.

    Investigational medicinal product name
    Vorinostat
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Vorinostat (300mg bid) will be taken orally for 7 consecutive days starting on day 3 of each cycle in 28-day cycles for up to 6 cycles. Day 3 is defined as the 3rd day of azacitidine administration.

    Number of subjects in period 1
    		Azacitidine alone - control arm Azacitidine + vorinostat
    Started
    129
    130
    Completed
    129
    130

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Azacitidine alone - control arm
    Reporting group description
    		 Patients received azacitidine (75mg/m2) by subcutaneous injection on 7 consecutive days (excluding weekends), starting day 1 of 28-day cycles for up to 6 cycles. This was delivered in a 5-2-2 schedule.

    Reporting group title
    Azacitidine + vorinostat
    Reporting group description
    		 Patients received (75mg/m2) azacitidine by subcutaneous injection on 7 consecutive days (excluding weekends), starting day 1 of 28-day cycles for up to 6 cycles. Azacitidine should be delivered in a 5-2-2 schedule. Vorinostat (300mg bid) will be taken orally for 7 consecutive days starting on day 3 of each cycle in 28-day cycles for up to 6 cycles. Day 3 is defined as the 3rd day of azacitidine administration.

    Reporting group values
    		 Azacitidine alone - control arm Azacitidine + vorinostat Total
    Number of subjects
    		 129 130 259
    Age categorical
    Units: Subjects
        Less than 70 years old
    		 48 48 96
        Greater than or equal to 70 years old
    		 81 82 163
    Gender categorical
    Units: Subjects
        Female
    		 54 49 103
        Male
    		 75 81 156
    Type of disease
    Units: Subjects
        AML
    		 108 109 217
        MDS
    		 21 21 42
    Stage of Disease
    Units: Subjects
        Newly diagnosed
    		 73 74 147
        Relapsed
    		 38 40 78
        Refractory
    		 18 16 34
    Age - stratification variable
    Units: Subjects
        < 70 years
    		 48 48 96
        >=70 years old
    		 81 82 163
    Relevant medical history
    Units: Subjects
        Yes
    		 108 115 223
        No
    		 21 14 35
        Missing
    		 0 1 1
    Active Symptoms
    Units: Subjects
        Yes
    		 82 94 176
        No
    		 47 35 82
        Missing
    		 0 1 1
    ECOG performance status
    Units: Subjects
        ECOG 0
    		 52 32 84
        ECOG 1
    		 63 70 133
        ECOG 2
    		 9 17 26
        Missing
    		 5 11 16
    ECG result
    Units: Subjects
        Normal
    		 82 87 169
        Abnormal
    		 42 38 80
        Missing
    		 5 5 10
    Bone marrow cellularity
    Units: Subjects
        Hypocellular
    		 24 24 48
        Normal
    		 16 12 28
        Hypercellular
    		 73 67 140
        Not known
    		 15 21 36
        Missing
    		 1 6 7
    Pulse
    Units: bpm
        arithmetic mean (standard deviation)
    		 79.6 ( 16.5 ) 82.3 ( 13.5 ) -
    Weight
    Units: Kg
        arithmetic mean (standard deviation)
    		 75.5 ( 14.2 ) 74.8 ( 15.4 ) -
    Height
    Units: Cm
        arithmetic mean (standard deviation)
    		 168.4 ( 9.3 ) 168.0 ( 10.4 ) -
    Time from diagnosis
    Units: Months
        arithmetic mean (standard deviation)
    		 8.8 ( 14.8 ) 7.5 ( 10.2 ) -
    Body surface area
    Units: m2
        arithmetic mean (standard deviation)
    		 1.9 ( 0.2 ) 1.8 ( 0.3 ) -
    Bone marrow morphology
    Units: % blasts
        arithmetic mean (standard deviation)
    		 48.4 ( 27.8 ) 44.4 ( 29.1 ) -
    Bone marrow immunophenotyping
    Units: % blasts
        arithmetic mean (standard deviation)
    		 38.0 ( 25.5 ) 38.1 ( 29.0 ) -
    Bone marrow trephine
    Units: % blasts
        arithmetic mean (standard deviation)
    		 44.3 ( 28.3 ) 46.6 ( 32.8 ) -

    End points

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    End points reporting groups
    Reporting group title
    Azacitidine alone - control arm
    Reporting group description
    		 Patients received azacitidine (75mg/m2) by subcutaneous injection on 7 consecutive days (excluding weekends), starting day 1 of 28-day cycles for up to 6 cycles. This was delivered in a 5-2-2 schedule.

    Reporting group title
    Azacitidine + vorinostat
    Reporting group description
    		 Patients received (75mg/m2) azacitidine by subcutaneous injection on 7 consecutive days (excluding weekends), starting day 1 of 28-day cycles for up to 6 cycles. Azacitidine should be delivered in a 5-2-2 schedule. Vorinostat (300mg bid) will be taken orally for 7 consecutive days starting on day 3 of each cycle in 28-day cycles for up to 6 cycles. Day 3 is defined as the 3rd day of azacitidine administration.

    Primary: Overall Response

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    End point title
    		 Overall Response
    End point description
    End point type
    Primary
    End point timeframe
    Within 6 cycles of treatment
    End point values
    		 Azacitidine alone - control arm Azacitidine + vorinostat
    Number of subjects analysed
    129
    130
    Units: Number of patients
        Response
    53
    55
        No Response
    76
    75
    Statistical analysis title
    		 Overall Response
    Comparison groups
    Azacitidine alone - control arm v Azacitidine + vorinostat
    Number of subjects included in analysis
    259
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.84
    Method
    		 Chi-squared
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.64
         upper limit
    		 1.72

    Primary: Overall Survival - 1 year

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    End point title
    		 Overall Survival - 1 year
    End point description
    End point type
    Primary
    End point timeframe
    From randomisation until 1 year
    End point values
    		 Azacitidine alone - control arm Azacitidine + vorinostat
    Number of subjects analysed
    129
    130
    Units: percent
        number (confidence interval 95%)
    43.7 (34.9 to 52.2)
    42.2 (33.5 to 50.7)
    Statistical analysis title
    		 1 year overall survival
    Statistical analysis description
    Kaplan Meir curves were created and log rank tests were used to compare treatment arms and provide point estimates
    Comparison groups
    Azacitidine alone - control arm v Azacitidine + vorinostat
    Number of subjects included in analysis
    259
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.29
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.147
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.89
         upper limit
    		 1.48

    Secondary: Toxicity - number of patients experiencing a grade 3 or higher adverse event or serious adverse event

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    End point title
    		 Toxicity - number of patients experiencing a grade 3 or higher adverse event or serious adverse event
    End point description
    End point type
    Secondary
    End point timeframe
    Duration of treatment
    End point values
    		 Azacitidine alone - control arm Azacitidine + vorinostat
    Number of subjects analysed
    129
    130
    Units: Number of patients
        Experienced toxicity
    107
    112
        Not experienced a toxicity
    22
    18
    No statistical analyses for this end point

    Secondary: Complete Remission

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    End point title
    		 Complete Remission
    End point description
    Complete remission within 6 cycles of treatment as defined by modified Cheson criteria1 for AML and IWG response criteria for MDS
    End point type
    Secondary
    End point timeframe
    Within 6 cycles of treatment
    End point values
    		 Azacitidine alone - control arm Azacitidine + vorinostat
    Number of subjects analysed
    129
    130
    Units: Number of patients
        CR
    9
    14
        CRi or Marrow CR
    20
    20
        PR
    24
    21
        Stable Disease
    4
    6
        Disease Progression
    2
    1
        Failure or No Response
    26
    23
        Induction death
    20
    21
        Missing response
    24
    24
    No statistical analyses for this end point

    Secondary: Dose Intensity

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    End point title
    		 Dose Intensity
    End point description
    End point type
    Secondary
    End point timeframe
    Over all treatment cycles
    End point values
    		 Azacitidine alone - control arm Azacitidine + vorinostat
    Number of subjects analysed
    129
    130
    Units: proportion
        median (inter-quartile range (Q1-Q3))
    1.00 (0.99 to 1.01)
    1.0 (0.97 to 1.01)
    No statistical analyses for this end point

    Secondary: Medical resource use - days in hospital including SAEs

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    End point title
    		 Medical resource use - days in hospital including SAEs
    End point description
    End point type
    Secondary
    End point timeframe
    From date of randomisation to 6 months post randomisation.
    End point values
    		 Azacitidine alone - control arm Azacitidine + vorinostat
    Number of subjects analysed
    129
    130
    Units: Days
        median (inter-quartile range (Q1-Q3))
    10 (4 to 23)
    15 (6 to 23)
    No statistical analyses for this end point

    Secondary: Medical resource use - days in hospital excluding SAEs

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    End point title
    		 Medical resource use - days in hospital excluding SAEs
    End point description
    End point type
    Secondary
    End point timeframe
    From date of randomisation to 6 months post randomisation.
    End point values
    		 Azacitidine alone - control arm Azacitidine + vorinostat
    Number of subjects analysed
    129
    130
    Units: Days
        median (inter-quartile range (Q1-Q3))
    15 (6 to 23)
    9 (2 to 25)
    No statistical analyses for this end point

    Secondary: Medical resource - Blood product useage

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    End point title
    		 Medical resource - Blood product useage
    End point description
    End point type
    Secondary
    End point timeframe
    From date of randomisation to 6 months post randomisation.
    End point values
    		 Azacitidine alone - control arm Azacitidine + vorinostat
    Number of subjects analysed
    129
    130
    Units: Units
    median (inter-quartile range (Q1-Q3))
        Blood
    15 (7 to 28)
    17 (9 to 26)
        Platelets
    10 (5 to 21)
    8 (4 to 18)
    No statistical analyses for this end point

    Secondary: Medical resource - day on anti-infectives

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    End point title
    		 Medical resource - day on anti-infectives
    End point description
    End point type
    Secondary
    End point timeframe
    From date of randomisation to 6 months post randomisation.
    End point values
    		 Azacitidine alone - control arm Azacitidine + vorinostat
    Number of subjects analysed
    129
    130
    Units: Days
    median (inter-quartile range (Q1-Q3))
        Bacterial
    53 (25 to 106)
    64 (19 to 165)
        Fungal
    79 (28 to 188)
    121 (20 to 232)
        Viral
    111 (20 to 188)
    183 (21 to 247)
    No statistical analyses for this end point

    Secondary: Overall Survival - 6 months

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    End point title
    		 Overall Survival - 6 months
    End point description
    End point type
    Secondary
    End point timeframe
    6 months from randomisation
    End point values
    		 Azacitidine alone - control arm Azacitidine + vorinostat
    Number of subjects analysed
    129
    130
    Units: percent
        number (confidence interval 95%)
    69.6 (60.7 to 76.9)
    76.3 (67.9 to 82.8)
    No statistical analyses for this end point

    Secondary: Overall Survival - 24 months

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    End point title
    		 Overall Survival - 24 months
    End point description
    End point type
    Secondary
    End point timeframe
    From randomisation until 24 months
    End point values
    		 Azacitidine alone - control arm Azacitidine + vorinostat
    Number of subjects analysed
    129
    130
    Units: percent
        number (confidence interval 95%)
    20.2 (13.7 to 27.7)
    15.4 (9.7 to 22.4)
    No statistical analyses for this end point

    Secondary: Treatment Related Toxicity - number of patients experiencing a grade 3 or higher adverse event or serious adverse event

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    End point title
    		 Treatment Related Toxicity - number of patients experiencing a grade 3 or higher adverse event or serious adverse event
    End point description
    End point type
    Secondary
    End point timeframe
    During trial treatment
    End point values
    		 Azacitidine alone - control arm Azacitidine + vorinostat
    Number of subjects analysed
    129
    130
    Units: Patients
        Experienced toxicity
    63
    72
        Not experienced a toxicity
    66
    58
    No statistical analyses for this end point

    Secondary: Median duration of response

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    End point title
    		 Median duration of response
    End point description
    End point type
    Secondary
    End point timeframe
    During treatment for responders
    End point values
    		 Azacitidine alone - control arm Azacitidine + vorinostat
    Number of subjects analysed
    129
    130
    Units: Months
        number (confidence interval 95%)
    10.6 (7.6 to 14.5)
    11.3 (8.2 to 16.7)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the date of commencement of protocol defined treatment until 28 days after the administration of the last treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4
    Reporting groups
    Reporting group title
    Safety Population
    Reporting group description
    		 -

    Serious adverse events
    		 Safety Population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    193 / 244 (79.10%)
         number of deaths (all causes)
    232
         number of deaths resulting from adverse events
    Vascular disorders
    Haematoma
         subjects affected / exposed
    3 / 244 (1.23%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Thromboembolic event
         subjects affected / exposed
    2 / 244 (0.82%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Edema limbs
         subjects affected / exposed
    2 / 244 (0.82%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Fatigue
         subjects affected / exposed
    2 / 244 (0.82%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Fever
         subjects affected / exposed
    25 / 244 (10.25%)
         occurrences causally related to treatment / all
    32 / 33
         deaths causally related to treatment / all
    2 / 2
    Flu like symptoms
         subjects affected / exposed
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions - Other, specify
         subjects affected / exposed
    2 / 244 (0.82%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Injection site reaction
         subjects affected / exposed
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Localised edema
         subjects affected / exposed
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pain
         subjects affected / exposed
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Sudden death NOS
         subjects affected / exposed
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Social circumstances
    Social cirumstances - Other, specify
         subjects affected / exposed
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Reproductive system and breast disorders - Other, specify
         subjects affected / exposed
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dyspnea
         subjects affected / exposed
    5 / 244 (2.05%)
         occurrences causally related to treatment / all
    2 / 7
         deaths causally related to treatment / all
    0 / 0
    Epistaxis
         subjects affected / exposed
    5 / 244 (2.05%)
         occurrences causally related to treatment / all
    5 / 7
         deaths causally related to treatment / all
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pleuritic pain
         subjects affected / exposed
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Pulmonary edema
         subjects affected / exposed
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Respiratory failure
         subjects affected / exposed
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Respiratory, thoracic and mediastinal disorders - Other, specify
         subjects affected / exposed
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Confusion
         subjects affected / exposed
    2 / 244 (0.82%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Hallucinations
         subjects affected / exposed
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Creatinine increased
         subjects affected / exposed
    4 / 244 (1.64%)
         occurrences causally related to treatment / all
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    Electrocardiogram QT corrected interval prolonged
         subjects affected / exposed
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    INR increased
         subjects affected / exposed
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    3 / 244 (1.23%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Fracture
         subjects affected / exposed
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    4 / 244 (1.64%)
         occurrences causally related to treatment / all
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    Chest pain - cardiac
         subjects affected / exposed
    6 / 244 (2.46%)
         occurrences causally related to treatment / all
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    Heart failure
         subjects affected / exposed
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sinus bradycardia
         subjects affected / exposed
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 244 (0.82%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Headache
         subjects affected / exposed
    3 / 244 (1.23%)
         occurrences causally related to treatment / all
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    Intracranial hemorrhage
         subjects affected / exposed
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Lethargy
         subjects affected / exposed
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Stroke
         subjects affected / exposed
    2 / 244 (0.82%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Syncope
         subjects affected / exposed
    4 / 244 (1.64%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 244 (1.23%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders - Other, specify
         subjects affected / exposed
    3 / 244 (1.23%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    76 / 244 (31.15%)
         occurrences causally related to treatment / all
    139 / 145
         deaths causally related to treatment / all
    3 / 4
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    3 / 244 (1.23%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Anal pain
         subjects affected / exposed
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Colonic hemorrhage
         subjects affected / exposed
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Constipation
         subjects affected / exposed
    10 / 244 (4.10%)
         occurrences causally related to treatment / all
    6 / 10
         deaths causally related to treatment / all
    1 / 1
    Diarrhoea
         subjects affected / exposed
    12 / 244 (4.92%)
         occurrences causally related to treatment / all
    9 / 14
         deaths causally related to treatment / all
    0 / 0
    Dysphagia
         subjects affected / exposed
    2 / 244 (0.82%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Fecal incontinence
         subjects affected / exposed
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders - Other, specify
         subjects affected / exposed
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nausea
         subjects affected / exposed
    5 / 244 (2.05%)
         occurrences causally related to treatment / all
    6 / 7
         deaths causally related to treatment / all
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Stomach pain
         subjects affected / exposed
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 244 (0.82%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Vomiting
         subjects affected / exposed
    10 / 244 (4.10%)
         occurrences causally related to treatment / all
    9 / 12
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Purpura
         subjects affected / exposed
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Rash acneiform
         subjects affected / exposed
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders - Other, specify
         subjects affected / exposed
    2 / 244 (0.82%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    4 / 244 (1.64%)
         occurrences causally related to treatment / all
    3 / 4
         deaths causally related to treatment / all
    1 / 2
    Haematuria
         subjects affected / exposed
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders - Other, specify
         subjects affected / exposed
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    3 / 244 (1.23%)
         occurrences causally related to treatment / all
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    Chest wall pain
         subjects affected / exposed
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Joint effusion
         subjects affected / exposed
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Muscle weakness lower limb
         subjects affected / exposed
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders - Other, specify
         subjects affected / exposed
    2 / 244 (0.82%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Soft tissue necrosis lower limb
         subjects affected / exposed
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Bronchial infection
         subjects affected / exposed
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Device related infection
         subjects affected / exposed
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations - Other, specify
         subjects affected / exposed
    3 / 244 (1.23%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations - Not listed
         subjects affected / exposed
    25 / 244 (10.25%)
         occurrences causally related to treatment / all
    31 / 31
         deaths causally related to treatment / all
    0 / 0
    Lung infection
         subjects affected / exposed
    2 / 244 (0.82%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Mucosal infection
         subjects affected / exposed
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    50 / 244 (20.49%)
         occurrences causally related to treatment / all
    51 / 59
         deaths causally related to treatment / all
    2 / 5
    Sinusitis
         subjects affected / exposed
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin infection
         subjects affected / exposed
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Upper respiratory infection
         subjects affected / exposed
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 244 (0.82%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    2 / 244 (0.82%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 244 (0.41%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    2 / 244 (0.82%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Safety Population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    152 / 244 (62.30%)
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    54 / 244 (22.13%)
         occurrences all number
    298
    Platelet count decreased
         subjects affected / exposed
    65 / 244 (26.64%)
         occurrences all number
    530
    White blood cell count decreased
         subjects affected / exposed
    35 / 244 (14.34%)
         occurrences all number
    216
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    43 / 244 (17.62%)
         occurrences all number
    248
    Febrile neutropenia
         subjects affected / exposed
    28 / 244 (11.48%)
         occurrences all number
    120
    Infections and infestations
    Sepsis
         subjects affected / exposed
    13 / 244 (5.33%)
         occurrences all number
    32

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 May 2012
    References to Phase I have been removed; vorinostat dose in combination with azacitidine has been stipulated as 300mg bid; monitoring of PT and INR for patients administered warfarin concomitantly with vorinostat; monitoring of serum glucose for patients administered vorinostat; bone marrow sample required for Leukaemic Stem Cell Quantification has been stipulated as at least 6mls; Adverse Event reporting relating to pregnancy includes requesting information to be collected from patients who become pregnant on trial as well as partners of patients who become pregnant whilst the patient is on trial.
    03 Jan 2013
    Primary outcome measure further clarified; exclusion criterion amended; screening assessment to include research bone marrow sample; azacitidine administration schedule is further clarified; sample collection section amended to include additional samples; patient follow up further clarified.
    10 Apr 2013
    Patient inclusion criteria amended to include patients with newly diagnosed, refractory AML and high risk MDS; IWG response criteria to be used for MDS; Females of childbearing potential to use contraception for 90 days after treatment discontinuation; Stratification will be used to randomise patients to treatment; Trial Steering Committee membership has been amended; Test for Primary Outcome Measure Analysis has been changed.
    14 May 2014
    AML response criteria has been modified to remove platelet and neutrophil count requirements for Partial Remission (PR) criteria (Appendix 8); Quality of Life questionnaire completion time-points have been clarified (monthly for the first 6 months and then at 12 and 24 months); Medical resource use data collection has been amended (data to be collected until 6 months follow up); Exclusion criteria amended, (removal of autologous haematopoietic stem cell transplant); Inclusion of home administration of azacitidine; Patients continuing beyond 6 cycles, treatment can be adjusted up to 6-weekly cycles at the discretion of the Investigator; Quality of Life questionnaire at screening has been removed (section 5.1); Treatment schedule has to be followed until treatment discontinuation; Blood biochemistry, haematology and bone marrow assessment results can be obtained locally if results are available (section 7.3); Follow up section amended; An aliquot from the blood sample will be sent for central HLA tissue typing and delivery method of samples has been amended (section 7.4.1); Adverse Event reporting has been amended (see section 8.1.1); Appendix 7 (IPSS table) corrected.
    14 Aug 2014
    The sample size calculation has been amended and the recruitment has been increased to 260 patients. A copy of the Quality of Life questionnaires are to be kept by sites.
    28 Nov 2014
    Requirement of sites to keep a copy of Quality of Life questionnaires has been removed. Additional wording of bone marrow samples to be sent every 3 cycles post cycle 6 (section 7.4.2). Adverse event reporting has been amended (section 8.1). Physical examination can be done within 7 days prior to start of cycle (section 7.3). Physical examination no longer required at end of treatment (section 7.2).
    20 Apr 2015
    Extension of study to 37 months. Patient’s on 6 weekly cycles to have day 22 bloods on day 36. Change to dose modifications on the combined arm (section 7.5). Updated trial office contact details. Addition of wording to trial treatment regarding unit closures (section 7.1).

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

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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/28765326
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