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    Clinical Trial Results:
    A phase II study of the use of azacitidine for the treatment of patients with chronic graft-versus-host-disease who have failed therapy with corticosteroids

    Summary
    EudraCT number
    		 2014-005659-19
    Trial protocol
    		 GB  
    Global end of trial date
    18 Aug 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 Aug 2021
    First version publication date
    05 Aug 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    RG_14-287
    Additional study identifiers
    ISRCTN number
    		 ISRCTN15649711
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Birmingham
    Sponsor organisation address
    Edgbaston, Birmingham, United Kingdom, B15 2TH
    Public contact
    Sonia Fox, University of Birmingham, 0044 01214159181, aztec@trials.bham.ac.uk
    Scientific contact
    Sonia Fox, University of Birmingham, 0044 01214159181, aztec@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
    18 Nov 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Aug 2020
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To investigate the safety and activity (in terms of best overall response within 6 months) of azacitidine in the treatment of patients with cGVHD who have failed therapy with corticosteroids
    Protection of trial subjects
    Azactidine is licensed for use in intermediate-2 and high-risk myelodysplastic syndromes (MDS) according to the International Prognostic Scoring System (IPSS), chronic myelomonocytic leukaemia (CMML) with 10-29 % marrow blasts without myeloproliferative disorder and acute myeloid leukaemia (AML) with 20-30% blasts and multi-lineage dysplasia, according to World Health Organisation (WHO) classification. Azacitidine has been used following allogeneic stem cell transplantation (ASCT) in clinical trials as maintenance therapy. To our knowledge, it has not been used to treat patients with cGvHD. The dose of azacitidine planned in the AZTEC trial is the same as the dose stipulated in published data of patients who have received a ASCT (i.e. roughly half the dose used in standard practice - 36mg/m2 rather than 75mg/m2 given over 5 days rather than 7 days). In standard practice azacitidine is injected subcutaneously, whereas in this trial it can be administered either by subcutaneous injections or via intravenous infusion (IV). The option of the IV route is because subcutaneous injection often causes a reaction at the injection site. As there is a strong likelihood that some of this patient population will have severe skin complications; it is considered safer to administer the azacitidine intravenously to these patients. The safety profile of azacitidine is well understood and all participating sites will be familiar with expected adverse reactions (ARs) and their management. Detailed information was described in the protocol to decrease the incidence of any and relieve the symptoms of possible unwanted events.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Oct 2015
    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: 14
    Worldwide total number of subjects
    14
    EEA total number of subjects
    14
    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)
    12
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Fifteen patients were registered to the trial, of which, 14 patients are evaluable and data for 14 patients will be presented. A single patient was found to be ineligible post randomisation and therefore was withdrawn from the trial.

    Pre-assignment
    Screening details
    		 Screening commenced following consent and prior to patient registration in order to confirm eligibility. The Investigator will conduct a full screening evaluation to ensure that the patient satisfies all inclusion and exclusion criteria. Detailed screening formation was described in the protocol.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Registered patients
    Arm description
    		 Patients will receive treatment with 36mg/m2 of azacitidine of days 1-5 of each cycle. Each cycle will last 28 days. Azacitidine may be administered via subcutaneous injection or intravenously to avoid potential complications of administering subcutaneously if the patient has extensive skin cGvHD. If a patient starts treatment with azacitidine being administered intravenously but subsequently can tolerate subcutaneous injection then the method of administration can be changed. This also applies if the patient starts on subcutaneous injection but can no longer tolerate this, the administration can be changed to intravenous. Patients will receive 6 cycles of azacitidine treatment. Patients may continue beyond 6 cycles (maximum of 10) if clinical benefit is observed.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Azacitidine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for suspension for injection
    Routes of administration
    Intravenous use, Subcutaneous use
    Dosage and administration details
    Patients will receive treatment with 36mg/m2 of azacitidine of days 1-5 of each cycle. Each cycle will last 28 days. Azacitidine may be administered via subcutaneous injection or intravenously to avoid potential complications of administering subcutaneously if the patient has extensive skin cGvHD. The dose of azacitidine to be administered should be calculated based upon the patient’s body surface area (BSA). Method of subcutaneous injection: Reconstituted azacitidine should be injected subcutaneously into the upper arm, thigh or abdomen. Injection sites should be rotated. New injections should be given at least 2.5 cm from the previous site and never into areas where the site is tender, bruised, red or hardened. Method of infusion: The total dose of azacitidine should be administered over a period of 10-40 minutes. Please note the administration must be completed within 1 hour of reconstitution.

    Number of subjects in period 1
    		Registered patients
    Started
    14
    Completed
    14

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall Trial Total
    Number of subjects
    		 14 14
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 12 12
        From 65-84 years
    		 2 2
    Gender categorical
    Units: Subjects
        Male
    		 14 14
    Progression of Chronic GvHD on 1 mg/kg/day prednisolone over 2 weeks.
    Units: Subjects
        No
    		 14 14
    Stable Chronic GvHD on ≥ 0.5mg/kg/day prednisolone over 4 weeks
    Units: Subjects
        No
    		 14 14
    Inability to taper prednisolone below 0.5mg/kg/day without recurrence of clinical manifestations.
    Units: Subjects
        No
    		 4 4
        Yes
    		 10 10
    Inability to tolerate first line therapy (eg steroid myopathy, calcineurin inhibitor-induced renal t
    Units: Subjects
        No
    		 11 11
        yes
    		 3 3
    Progressive, recurrent or delayed-onset Acute GvHD
    Units: Subjects
        no
    		 9 9
        yes
    		 5 5
    Type of steroid
    Units: Subjects
        IV Methylprednisolone
    		 1 1
        None
    		 1 1
        Prednisolone
    		 12 12
    Prednisolone Dose
    Units: Subjects
        0.63 mg/kg
    		 1 1
        1 mg/kg
    		 9 9
        2 mg/kg
    		 1 1
        unknown
    		 3 3
    Methylprednisolone Dose
    Units: Subjects
        2 mg/kg
    		 14 14
    Patient come off immune suppression
    Units: Subjects
        yes
    		 4 4
        no
    		 10 10
    Immunosuppressive Agent
    Units: Subjects
        Ciclosporin
    		 9 9
        Tacrolimus
    		 2 2
        none
    		 3 3
    Medical conditions
    Units: Subjects
        No
    		 8 8
        yes
    		 6 6
    Diabetes
    Units: Subjects
        Yes
    		 4 4
        no
    		 10 10
    CardiacProblem
    Units: Subjects
        yes
    		 3 3
        no
    		 11 11
    Asthma
    Units: Subjects
        yes
    		 2 2
        No
    		 12 12
    Lung Disease
    Units: Subjects
        yes
    		 3 3
        no
    		 11 11
    Subject analysis sets

    Subject analysis set title
    mITT
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The population for analysis is defined as modified-intention-to-treat (mITT). This includes only evaluable patients and a patient becomes evaluable when they have completed one cycle of treatment.

    Subject analysis sets values
    		 mITT
    Number of subjects
    14
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    12
        From 65-84 years
    2
    Age continuous
    Units: years
        median (standard deviation)
    ( )
    Gender categorical
    Units: Subjects
        Male
    14
    Progression of Chronic GvHD on 1 mg/kg/day prednisolone over 2 weeks.
    Units: Subjects
        No
    14
    Stable Chronic GvHD on ≥ 0.5mg/kg/day prednisolone over 4 weeks
    Units: Subjects
        No
    14
    Inability to taper prednisolone below 0.5mg/kg/day without recurrence of clinical manifestations.
    Units: Subjects
        No
    4
        Yes
    11
    Inability to tolerate first line therapy (eg steroid myopathy, calcineurin inhibitor-induced renal t
    Units: Subjects
        No
    12
        yes
    3
    Progressive, recurrent or delayed-onset Acute GvHD
    Units: Subjects
        no
    10
        yes
    5
    Type of steroid
    Units: Subjects
        IV Methylprednisolone
    1
        None
    1
        Prednisolone
    13
    Prednisolone Dose
    Units: Subjects
        0.63 mg/kg
    1
        1 mg/kg
    9
        2 mg/kg
    1
        unknown
    3
    Methylprednisolone Dose
    Units: Subjects
        2 mg/kg
    1
    Patient come off immune suppression
    Units: Subjects
        yes
    4
        no
    11
    Immunosuppressive Agent
    Units: Subjects
        Ciclosporin
    9
        Tacrolimus
    2
        none
    3
    Medical conditions
    Units: Subjects
        No
    9
        yes
    6
    Diabetes
    Units: Subjects
        Yes
    4
        no
    10
    CardiacProblem
    Units: Subjects
        yes
    3
        no
    11
    Asthma
    Units: Subjects
        yes
    2
        No
    12
    Lung Disease
    Units: Subjects
        yes
    3
        no
    11

    End points

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    End points reporting groups
    Reporting group title
    Registered patients
    Reporting group description
    		 Patients will receive treatment with 36mg/m2 of azacitidine of days 1-5 of each cycle. Each cycle will last 28 days. Azacitidine may be administered via subcutaneous injection or intravenously to avoid potential complications of administering subcutaneously if the patient has extensive skin cGvHD. If a patient starts treatment with azacitidine being administered intravenously but subsequently can tolerate subcutaneous injection then the method of administration can be changed. This also applies if the patient starts on subcutaneous injection but can no longer tolerate this, the administration can be changed to intravenous. Patients will receive 6 cycles of azacitidine treatment. Patients may continue beyond 6 cycles (maximum of 10) if clinical benefit is observed.

    Subject analysis set title
    mITT
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The population for analysis is defined as modified-intention-to-treat (mITT). This includes only evaluable patients and a patient becomes evaluable when they have completed one cycle of treatment.

    Primary: Best overall response

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    End point title
    		 Best overall response
    End point description
    Best overall response (complete or partial) (GvHD) within 6 cycles of trial treatment as defined by modified National Institutes of Health (NIH) Consensus Response Criteria
    End point type
    Primary
    End point timeframe
    Within 6 cycles of treatment
    End point values
    		 Registered patients mITT
    Number of subjects analysed
    14
    14
    Units: integer
        Overall Response (CR/PR)
    7
    7
        Complete Response (CR)
    1
    1
        Partial Response (PR)
    6
    6
        No Response (NR)
    7
    7
    Statistical analysis title
    		 Overall Response
    Comparison groups
    Registered patients v mITT
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 proportion
    Point estimate
    50
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 23
         upper limit
    		 77
    Statistical analysis title
    		 Complete Response
    Comparison groups
    Registered patients v mITT
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 proportion
    Point estimate
    7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 34
    Statistical analysis title
    		 Partial Response
    Comparison groups
    Registered patients v mITT
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 proportion
    Point estimate
    43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 18
         upper limit
    		 71
    Statistical analysis title
    		 No Response
    Comparison groups
    Registered patients v mITT
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 proportion
    Point estimate
    50
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 23
         upper limit
    		 77

    Primary: Tolerability of azacitidine

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    End point title
    		 Tolerability of azacitidine
    End point description
    Tolerability of azacitidine defined as the absence of grade 3 or 4 clinically relevant and drug related adverse events (AEs) resulting in stopping treatment early including treatment related deaths within 6 cycles of trial treatment
    End point type
    Primary
    End point timeframe
    Within 6 cycles of treatment
    End point values
    		 Registered patients mITT
    Number of subjects analysed
    14
    14
    Units: integer
    13
    13
    Statistical analysis title
    		 Tolerability of azacitidine
    Comparison groups
    Registered patients v mITT
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 proportion
    Point estimate
    93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 66
         upper limit
    		 100

    Secondary: Best overall response

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    End point title
    		 Best overall response
    End point description
    Best overall response (complete or partial) (GvHD) between registration and 6 months post end of trial treatment as defined by modified National Institutes of Health (NIH) Consensus Response Criteria
    End point type
    Secondary
    End point timeframe
    Between registration and 6 months post end of trial treatment
    End point values
    		 Registered patients mITT
    Number of subjects analysed
    14
    14
    Units: integer
        Overall Response (CR/PR)
    8
    8
        Complete Response (CR)
    5
    5
        Partial Response (PR)
    3
    3
        No Response (NR)
    6
    6
    Statistical analysis title
    		 Overall Response
    Comparison groups
    Registered patients v mITT
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 proportion
    Point estimate
    57
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 29
         upper limit
    		 82
    Statistical analysis title
    		 Complete Response
    Comparison groups
    Registered patients v mITT
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 proportion
    Point estimate
    36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 13
         upper limit
    		 65
    Statistical analysis title
    		 Partial Response
    Comparison groups
    Registered patients v mITT
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 proportion
    Point estimate
    21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 5
         upper limit
    		 51
    Statistical analysis title
    		 No Response
    Comparison groups
    Registered patients v mITT
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 proportion
    Point estimate
    43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 18
         upper limit
    		 71

    Secondary: Best organ level response

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    End point title
    		 Best organ level response
    End point description
    Best organ level response (GvHD) between registration and 6 months post end of trial treatment as determined by the incremental improvement and changes in individual organ systems involved in cGvHD according to modified NIH Consensus Response Criteria.
    End point type
    Secondary
    End point timeframe
    Between registration and 6 months post end of trial treatment
    End point values
    		 Registered patients mITT
    Number of subjects analysed
    14
    14
    Units: integer
        Complete Response
    4
    4
        Partial Response
    4
    4
        Organ Progression
    2
    2
        No Response
    4
    4
    Statistical analysis title
    		 Complete Response
    Comparison groups
    Registered patients v mITT
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 proportion
    Point estimate
    29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 8
         upper limit
    		 58
    Statistical analysis title
    		 Partial Response
    Comparison groups
    Registered patients v mITT
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 proportion
    Point estimate
    29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 8
         upper limit
    		 58
    Statistical analysis title
    		 Organ Progression
    Comparison groups
    Registered patients v mITT
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 proportion
    Point estimate
    14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2
         upper limit
    		 43
    Statistical analysis title
    		 No Response
    Comparison groups
    Registered patients v mITT
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 proportion
    Point estimate
    29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 8
         upper limit
    		 58

    Secondary: Duration of response

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    End point title
    		 Duration of response
    End point description
    The median duration of response is presented. 95% confidence interval is also presented but the upper limit cannot be estimated due to small numbers.
    End point type
    Secondary
    End point timeframe
    This will be measured from date of response to date of progression or date last seen for patients who do not progress during the trial
    End point values
    		 Registered patients mITT
    Number of subjects analysed
    14
    8
    Units: time
        number (confidence interval 95%)
    4.7 (1.0 to 5)
    4.7 (1 to 5)
    No statistical analyses for this end point

    Secondary: Reduction in corticosteroid dosage

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    End point title
    		 Reduction in corticosteroid dosage
    End point description
    End point type
    Secondary
    End point timeframe
    Percentage change from baseline in corticosteroid dosage at the end of six cycles of trial treatment will be presented along with the 95% confidence interval
    End point values
    		 Registered patients mITT
    Number of subjects analysed
    7
    7
    Units: integer
        End of 6 cycles
    7
    7
    Statistical analysis title
    		 End of 6 cycles
    Comparison groups
    Registered patients v mITT
    Number of subjects included in analysis
    14
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 proportion
    Point estimate
    72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 33
         upper limit
    		 100

    Secondary: Reduction in corticosteroid dosage

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    End point title
    		 Reduction in corticosteroid dosage
    End point description
    End point type
    Secondary
    End point timeframe
    Percentage change from baseline in corticosteroid dosage at 6 months post end of trial treatment will be presented along with the 95% confidence interval.
    End point values
    		 Registered patients mITT
    Number of subjects analysed
    11
    11
    Units: integer
        6 months post end of trial treatment
    11
    11
    Statistical analysis title
    		 6 months post end of trial treatment
    Comparison groups
    Registered patients v mITT
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 proportion
    Point estimate
    78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 56
         upper limit
    		 100

    Secondary: Quality of Life

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    End point title
    		 Quality of Life
    End point description
    FACT-BMT Total Score and Lee Symptom Total Score are presented
    End point type
    Secondary
    End point timeframe
    Between registration and 6 months post end of trial treatment
    End point values
    		 Registered patients mITT
    Number of subjects analysed
    14
    14
    Units: integer
        FACT-BMT Total Score
    14
    14
        Lee Symptom Total Score
    14
    14
    Statistical analysis title
    		 FACT-BMT Total Score
    Comparison groups
    Registered patients v mITT
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.006
    Method
    		 Mixed models analysis
    Parameter type
    		 coefficient
    Point estimate
    0.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.27
         upper limit
    		 1.61
    Statistical analysis title
    		 Lee Symptom Total Score
    Comparison groups
    Registered patients v mITT
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.199
    Method
    		 Mixed models analysis
    Parameter type
    		 coefficient
    Point estimate
    -0.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.8
         upper limit
    		 0.17

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Details of all AEs (except those listed above) were to be documented and reported from the date of commencement of protocol defined treatment until 28 days after the administration of the last treatment.
    Adverse event reporting additional description
    SAEs that were at least possibly related to azacitidine were reported in an expedited manner irrespective of how long after IMP administration the reaction occurred.
    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
    14 / 14 (100.00%)
         number of deaths (all causes)
    3
         number of deaths resulting from adverse events
    1
    Investigations
    Investigations
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Platelet count decreased
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Vascular disorders
    Vascular disorders
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Neuralgia
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Fever
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Diarrhea
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Vomiting
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnea
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Productive cough
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Confusion
         subjects affected / exposed
    3 / 14 (21.43%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    1 / 2
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorder
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Lung infection
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Sinusitis
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 1
         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
    14 / 14 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 14 (14.29%)
         occurrences all number
    2
    General disorders and administration site conditions
    Flu like symptoms
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Injection site reaction
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Multi-organ failure
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Dyspnea
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Epistaxis
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Restlessness
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    2 / 14 (14.29%)
         occurrences all number
    5
    Platelet count decreased
         subjects affected / exposed
    2 / 14 (14.29%)
         occurrences all number
    5
    White blood cell decreased
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    2
    Nervous system disorders
    Encephalopathy
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Lethargy
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Neuralgia
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Tremor
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Eye disorders
    Retinal vascular disorder
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Gastrointestinal disorders
    Diarrhea
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Gastroesophageal reflux disease
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Nausea
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Vomiting
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Pain of skin
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    3
    Pruritus
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Rash maculo-papular
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorder
         subjects affected / exposed
    2 / 14 (14.29%)
         occurrences all number
    2
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Chronic kidney disease
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    2
    Musculoskeletal and connective tissue disorders
    Flank pain
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorder
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    3
    Infections and infestations
    Bladder infection
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Lung infection
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Sepsis
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Sinusitis
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Hyperglycemia
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Hypocalcemia
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Hypokalemia
         subjects affected / exposed
    2 / 14 (14.29%)
         occurrences all number
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Dec 2016
    Change to the time point the first research sample is taken. Change to the route of administration of azacitidine from remaining consistent per patient throughout the trial to allowing the route to be changed during treatment. Update to NIH chronic GvHD assessment for Clinician use Update to lung function tests
    11 Jul 2017
    Clarification of permitted delays to treatment. Change to the lung function tests. Change to the units used to measure Liver total bilirubin in the NIH chronic GvHD assessment form. Clarification of statistical analysis of primary and secondary outcome measures, population for analysis and interim and final analysis, Addition of units for the baseline only values in the NIH chronic GvHD assessment form v3.0 17-Jan-2018.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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