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    Clinical Trial Results:
    A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Tolerability of Entospletinib, a Selective SYK Inhibitor, in Combination with Systemic Corticosteroids as First-Line Therapy in Subjects with Chronic Graft Versus Host Disease (cGVHD)

    Summary
    EudraCT number
    		 2015-004572-30
    Trial protocol
    		 GB   ES   FR  
    Global end of trial date
    06 Mar 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Dec 2018
    First version publication date
    21 Dec 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GS-US-406-1840
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02701634
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Gilead Sciences
    Sponsor organisation address
    333 Lakeside Drive, Foster City, CA, United States, 94404
    Public contact
    Gilead Clinical Study Information Center, Gilead Sciences, GileadClinicalTrials@gilead.com
    Scientific contact
    Gilead Clinical Study Information Center, Gilead Sciences, GileadClinicalTrials@gilead.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
    06 Mar 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 Dec 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Mar 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the effect of entospletinib (ENTO) on the best overall response rate in adults with chronic graft versus host disease (cGVHD) who are currently receiving systemic corticosteroids as part of first-line therapy for cGVHD.
    Protection of trial subjects
    The protocol and consent/assent forms were submitted by each investigator to a duly constituted Independent Ethics Committee (IEC) or Institutional Review Board (IRB) for review and approval before study initiation. All revisions to the consent/assent forms (if applicable) after initial IEC/IRB approval were submitted by the investigator to the IEC/IRB for review and approval before implementation in accordance with regulatory requirements. This study was conducted in accordance with recognized international scientific and ethical standards, including but not limited to the International Conference on Harmonization guideline for Good Clinical Practice (ICH GCP) and the original principles embodied in the Declaration of Helsinki.
    Background therapy
    		 Participants were receiving systemic corticosteroids as first-line therapy for cGVHD.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 May 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 5
    Country: Number of subjects enrolled
    France: 8
    Country: Number of subjects enrolled
    Spain: 17
    Country: Number of subjects enrolled
    Germany: 11
    Country: Number of subjects enrolled
    United States: 21
    Country: Number of subjects enrolled
    Korea, Republic of: 3
    Country: Number of subjects enrolled
    Canada: 1
    Worldwide total number of subjects
    66
    EEA total number of subjects
    41
    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)
    49
    From 65 to 84 years
    17
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled at study sites in Europe, Asia, Canada, and United States. The first participant was screened on 27 May 2016. The last study visit occurred on 06 Mar 2018.

    Pre-assignment
    Screening details
    		 89 participants were screened.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 ENTO
    Arm description
    		 ENTO for 48 weeks in combination with systemic corticosteroids as first-line therapy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Entospletinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    400 mg or 200 mg administered twice daily

    Arm title
    		 Placebo
    Arm description
    		 Placebo to match entospletinib for 48 weeks in combination with systemic corticosteroids as first-line therapy.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered twice daily

    Number of subjects in period 1
    		ENTO Placebo
    Started
    33
    33
    Completed
    1
    2
    Not completed
    32
    31
         Withdrew Consent
    6
    7
         Study terminated by Sponsor
    15
    17
         Randomized but not treated
    1
    -
         Death
    1
    -
         Investigator's Discretion
    7
    4
         Adverse Events
    2
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    ENTO
    Reporting group description
    		 ENTO for 48 weeks in combination with systemic corticosteroids as first-line therapy.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo to match entospletinib for 48 weeks in combination with systemic corticosteroids as first-line therapy.

    Reporting group values
    		 ENTO Placebo Total
    Number of subjects
    		 33 33 66
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 51 ( 11.9 ) 58 ( 11.4 ) -
    Gender categorical
    Units: Subjects
        Female
    		 14 13 27
        Male
    		 19 20 39
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 1 2 3
        Not Hispanic or Latino
    		 27 28 55
        Not Permitted
    		 5 3 8
    Race
    Units: Subjects
        Asian
    		 3 1 4
        Black
    		 1 0 1
        White
    		 23 29 52
        Other
    		 2 0 2
        Not Permitted
    		 4 3 7

    End points

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    End points reporting groups
    Reporting group title
    ENTO
    Reporting group description
    		 ENTO for 48 weeks in combination with systemic corticosteroids as first-line therapy.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo to match entospletinib for 48 weeks in combination with systemic corticosteroids as first-line therapy.

    Primary: Best Overall Response Rate

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    End point title
    		 Best Overall Response Rate
    End point description
    Best overall response rate by 24 weeks was defined as the proportion of participants who achieved a complete or partial overall response as assessed by the NIH cGVHD Activity Assessment (NCAA) within 24 weeks, in the setting of add-on therapy to systemic corticosteroids as part of first-line therapy for cGVHD. ITT Analysis Set included all participants who were randomized into the study. Data was analyzed according to treatment randomized.
    End point type
    Primary
    End point timeframe
    Up to 24 weeks
    End point values
    		 ENTO Placebo
    Number of subjects analysed
    33
    33
    Units: Percentage of participants
        number (not applicable)
    72.7
    72.7
    Statistical analysis title
    		 Statistical Anaysis
    Comparison groups
    ENTO v Placebo
    Number of subjects included in analysis
    66
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.99 [1]
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [1] - P-value was calculated using the stratified Cochran-Mantel-Haenszel Chi-square test.

    Secondary: Change From Baseline in the Skin Domain of the Lee Symptom Scale (LSS) at 24 Weeks

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    End point title
    		 Change From Baseline in the Skin Domain of the Lee Symptom Scale (LSS) at 24 Weeks
    End point description
    The LSS is a patient-reported questionnaire used to measure symptom burden. Each of the LSS subscales ranged between 0 and 100, with higher scores indicating more severe symptoms. A decrease from baseline value correlates with improvement in clinical outcome. Participants in the ITT Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 24
    End point values
    		 ENTO Placebo
    Number of subjects analysed
    32
    32
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (ENTO: N = 32; Placebo: N = 32)
    15.0 ( 21.92 )
    19.8 ( 22.34 )
        Change at Week 24 (ENTO: N = 9; Placebo: N = 9)
    -3.3 ( 10.31 )
    -9.4 ( 14.24 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in the Mouth Domain of the LSS at 24 Weeks

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    End point title
    		 Change From Baseline in the Mouth Domain of the LSS at 24 Weeks
    End point description
    The LSS is a patient-reported questionnaire used to measure symptom burden. Each of the LSS subscales ranged between 0 and 100, with higher scores indicating more severe symptoms. A decrease from baseline value correlates with improvement in clinical outcome. Participants in the ITT Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 24
    End point values
    		 ENTO Placebo
    Number of subjects analysed
    32
    32
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (ENTO: N = 32; Placebo: N = 32)
    15.2 ( 18.17 )
    16.8 ( 21.21 )
        Change at Week 24 (ENTO: N = 9; Placebo: N = 9)
    -4.2 ( 16.54 )
    -1.4 ( 25.34 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in the Eyes Domain of the LSS at 24 Weeks

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    End point title
    		 Change From Baseline in the Eyes Domain of the LSS at 24 Weeks
    End point description
    The LSS is a patient-reported questionnaire used to measure symptom burden. Each of the LSS subscales ranged between 0 and 100, with higher scores indicating more severe symptoms. A decrease from baseline value correlates with improvement in clinical outcome. Participants in the ITT Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 24
    End point values
    		 ENTO Placebo
    Number of subjects analysed
    32
    32
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (ENTO: N = 32; Placebo: N = 32)
    29.4 ( 27.52 )
    21.4 ( 24.22 )
        Change at Week 24 (ENTO: N = 9, Placebo: N = 9)
    10.2 ( 21.56 )
    -1.4 ( 31.32 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in the Total Score of the LSS at 24 Weeks

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    End point title
    		 Change From Baseline in the Total Score of the LSS at 24 Weeks
    End point description
    The LSS is a patient-reported questionnaire used to measure symptom burden. Each of the LSS subscales ranged between 0 and 100, with higher scores indicating more severe symptoms. The total score was calculated by taking the average of the subscale scores. A decrease from baseline value correlates with improvement in clinical outcome. Participants in the ITT Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 24
    End point values
    		 ENTO Placebo
    Number of subjects analysed
    32
    32
    Units: score on a scale
    arithmetic mean (standard deviation)
        Baseline (ENTO: N = 32; Placebo: N = 32)
    16.0 ( 9.74 )
    14.7 ( 8.51 )
        Change at Week 24 (ENTO: N = 9; Placebo: N = 9)
    -0.5 ( 8.35 )
    -5.4 ( 8.54 )
    No statistical analyses for this end point

    Secondary: Duration of Response

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    End point title
    		 Duration of Response
    End point description
    Duration of response was defined as the time from the documentation of best overall response rate to the documentation of progressive disease. Note that flare was not considered as progressive disease in this analysis. Participants in the ITT Analysis Set were analyzed. '99999' here represents 'Not reached'.
    End point type
    Secondary
    End point timeframe
    Up to 48 weeks
    End point values
    		 ENTO Placebo
    Number of subjects analysed
    33
    33
    Units: weeks
        median (confidence interval 95%)
    26.3 (9.1 to 44.3)
    32.0 (8.1 to 99999)
    Statistical analysis title
    		 Statistical Anaysis 1
    Comparison groups
    ENTO v Placebo
    Number of subjects included in analysis
    66
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.67
    Method
    		 Logrank
    Confidence interval

    Secondary: Percentage of Participants Who Achieve at Least 50% Reduction in Systemic Corticosteroid Dose Relative to Baseline

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    End point title
    		 Percentage of Participants Who Achieve at Least 50% Reduction in Systemic Corticosteroid Dose Relative to Baseline
    End point description
    The percentage reduction was calculated as (systemic corticosteroid dose post baseline - baseline systemic corticosteroid dose) / baseline systemic corticosteroid dose. Participants in the ITT Analysis Set were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Up to 48 weeks
    End point values
    		 ENTO Placebo
    Number of subjects analysed
    33
    33
    Units: Percentage of participants
        number (not applicable)
    72.7
    63.6
    Statistical analysis title
    		 Statistical Anaysis 1
    Comparison groups
    ENTO v Placebo
    Number of subjects included in analysis
    66
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.33 [2]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [2] - P-value was calculated using the two sample proportion t-test.

    Secondary: Percentage of Participants Who Initiate Second-Line Therapy for cGVHD

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    End point title
    		 Percentage of Participants Who Initiate Second-Line Therapy for cGVHD
    End point description
    Second-line therapy for cGVHD was defined as receiving any therapy besides systemic corticosteroids or study drug for the treatment of cGVHD. Inhaled and topical steroids are not considered second-line therapy. Participants in the ITT Analysis Set were analyzed.
    End point type
    Secondary
    End point timeframe
    Up to 48 weeks
    End point values
    		 ENTO Placebo
    Number of subjects analysed
    33
    33
    Units: Percentage of participants
        number (not applicable)
    9.1
    15.2
    Statistical analysis title
    		 Statistical Anaysis 1
    Comparison groups
    ENTO v Placebo
    Number of subjects included in analysis
    66
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.49 [3]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [3] - P-value was calculated using the two sample proportion t-test.

    Secondary: Failure-Free Survival

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    End point title
    		 Failure-Free Survival
    End point description
    Failure-free survival was defined as the time from randomization to the earliest of first documentation of systemic therapy change, nonrelapse mortality, or recurrent malignancy. Participants in the ITT Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Up to 48 weeks
    End point values
    		 ENTO Placebo
    Number of subjects analysed
    20
    20
    Units: Days
        median (confidence interval 95%)
    99.0 (57.0 to 214.0)
    85.0 (56.0 to 254.0)
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    ENTO v Placebo
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 = 0.8 [5]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.55
         upper limit
    		 2.18
    Notes
    [4] - Hazard ratio was estimated from Cox regression model adjusted for treatment and stratified for disease severity and usage of calcineurin inhibitor or mycophenolate mofetil (MMF).
    [5] - P-value was calculated using the log-rank test and stratified for disease severity and usage of calcineurin inhibit or MMF.

    Secondary: Percentage of Participants Who Experience Any Treatment-Emergent Adverse Events (AEs)

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    End point title
    		 Percentage of Participants Who Experience Any Treatment-Emergent Adverse Events (AEs)
    End point description
    Treatment-emergent adverse events are defined as 1 or both of the following: 1) any AEs with an onset on or after study drug or placebo start date and no later than earlier of 30 days after permanent discontinuation of study drug or placebo, 2) any AEs leading to premature discontinuation of study drug or placebo. Safety Analysis Set included all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
    End point type
    Secondary
    End point timeframe
    Up to 48 weeks plus 30 days
    End point values
    		 ENTO Placebo
    Number of subjects analysed
    32
    33
    Units: Percentage of participants
        number (not applicable)
    96.9
    97.0
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Permanently Discontinued Any Study Drug Due to an Adverse Event

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    End point title
    		 Percentage of Participants Who Permanently Discontinued Any Study Drug Due to an Adverse Event
    End point description
    Participants in the Safety Analysis Set were analyzed.
    End point type
    Secondary
    End point timeframe
    Up to 48 weeks plus 30 days
    End point values
    		 ENTO Placebo
    Number of subjects analysed
    32
    33
    Units: Percentage of participants
        number (not applicable)
    12.5
    12.1
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Experienced Treatment-Emergent Graded Laboratory Abnormalities

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    End point title
    		 Percentage of Participants Who Experienced Treatment-Emergent Graded Laboratory Abnormalities
    End point description
    Participants in the Safety Analysis Set were analyzed.
    End point type
    Secondary
    End point timeframe
    Up to 48 weeks plus 30 days
    End point values
    		 ENTO Placebo
    Number of subjects analysed
    32
    33
    Units: Percentage of participants
        number (not applicable)
    100.0
    100.0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks)
    Adverse event reporting additional description
    Safety Analysis Set included all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    ENTO
    Reporting group description
    		 ENTO for 48 weeks in combination with systemic corticosteroids as first-line therapy.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo to match entospletinib for 48 weeks in combination with systemic corticosteroids as first-line therapy.

    Serious adverse events
    		 ENTO Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    15 / 32 (46.88%)
    11 / 33 (33.33%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    1
    0
    Investigations
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical condition abnormal
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute leukaemia
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chloroma
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Wound dehiscence
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Coronary artery disease
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Disease recurrence
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 32 (3.13%)
    2 / 33 (6.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal haemorrhage
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Interstitial lung disease
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Obliterative bronchiolitis
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 33 (3.03%)
         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
    0 / 32 (0.00%)
    1 / 33 (3.03%)
         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
    Myositis
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    3 / 32 (9.38%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 32 (3.13%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 32 (3.13%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    H1N1 influenza
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Listeriosis
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis media acute
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 33 (3.03%)
         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 / 32 (3.13%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 ENTO Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    31 / 32 (96.88%)
    30 / 33 (90.91%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 32 (9.38%)
    1 / 33 (3.03%)
         occurrences all number
    3
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    8 / 32 (25.00%)
    4 / 33 (12.12%)
         occurrences all number
    8
    5
    Oedema peripheral
         subjects affected / exposed
    5 / 32 (15.63%)
    6 / 33 (18.18%)
         occurrences all number
    6
    6
    Asthenia
         subjects affected / exposed
    3 / 32 (9.38%)
    3 / 33 (9.09%)
         occurrences all number
    3
    3
    Pyrexia
         subjects affected / exposed
    5 / 32 (15.63%)
    1 / 33 (3.03%)
         occurrences all number
    7
    3
    Chest pain
         subjects affected / exposed
    1 / 32 (3.13%)
    2 / 33 (6.06%)
         occurrences all number
    1
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 32 (12.50%)
    7 / 33 (21.21%)
         occurrences all number
    4
    7
    Dyspnoea
         subjects affected / exposed
    2 / 32 (6.25%)
    1 / 33 (3.03%)
         occurrences all number
    2
    1
    Nasal congestion
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    2 / 32 (6.25%)
    2 / 33 (6.06%)
         occurrences all number
    2
    2
    Anxiety
         subjects affected / exposed
    2 / 32 (6.25%)
    1 / 33 (3.03%)
         occurrences all number
    2
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    4 / 32 (12.50%)
    5 / 33 (15.15%)
         occurrences all number
    4
    7
    Aspartate aminotransferase increased
         subjects affected / exposed
    4 / 32 (12.50%)
    4 / 33 (12.12%)
         occurrences all number
    5
    4
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    5 / 32 (15.63%)
    1 / 33 (3.03%)
         occurrences all number
    5
    2
    Blood alkaline phosphatase increased
         subjects affected / exposed
    3 / 32 (9.38%)
    1 / 33 (3.03%)
         occurrences all number
    3
    1
    Platelet count decreased
         subjects affected / exposed
    0 / 32 (0.00%)
    4 / 33 (12.12%)
         occurrences all number
    0
    13
    Neutrophil count decreased
         subjects affected / exposed
    2 / 32 (6.25%)
    1 / 33 (3.03%)
         occurrences all number
    2
    6
    Weight increased
         subjects affected / exposed
    1 / 32 (3.13%)
    2 / 33 (6.06%)
         occurrences all number
    1
    2
    Amylase increased
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 32 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    2
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    Neuropathy peripheral
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    Paraesthesia
         subjects affected / exposed
    0 / 32 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 32 (12.50%)
    4 / 33 (12.12%)
         occurrences all number
    7
    7
    Thrombocytopenia
         subjects affected / exposed
    2 / 32 (6.25%)
    3 / 33 (9.09%)
         occurrences all number
    2
    3
    Neutropenia
         subjects affected / exposed
    2 / 32 (6.25%)
    2 / 33 (6.06%)
         occurrences all number
    2
    2
    Lymphopenia
         subjects affected / exposed
    1 / 32 (3.13%)
    2 / 33 (6.06%)
         occurrences all number
    1
    3
    Eye disorders
    Dry eye
         subjects affected / exposed
    4 / 32 (12.50%)
    1 / 33 (3.03%)
         occurrences all number
    4
    1
    Keratitis
         subjects affected / exposed
    0 / 32 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    2
    Vision blurred
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    5 / 32 (15.63%)
    4 / 33 (12.12%)
         occurrences all number
    7
    5
    Abdominal pain
         subjects affected / exposed
    3 / 32 (9.38%)
    5 / 33 (15.15%)
         occurrences all number
    3
    5
    Nausea
         subjects affected / exposed
    3 / 32 (9.38%)
    4 / 33 (12.12%)
         occurrences all number
    3
    4
    Vomiting
         subjects affected / exposed
    4 / 32 (12.50%)
    2 / 33 (6.06%)
         occurrences all number
    4
    2
    Constipation
         subjects affected / exposed
    2 / 32 (6.25%)
    3 / 33 (9.09%)
         occurrences all number
    2
    3
    Abdominal pain upper
         subjects affected / exposed
    3 / 32 (9.38%)
    0 / 33 (0.00%)
         occurrences all number
    3
    0
    Dry mouth
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    2 / 32 (6.25%)
    3 / 33 (9.09%)
         occurrences all number
    2
    3
    Rash
         subjects affected / exposed
    2 / 32 (6.25%)
    1 / 33 (3.03%)
         occurrences all number
    2
    1
    Rash maculo-papular
         subjects affected / exposed
    2 / 32 (6.25%)
    1 / 33 (3.03%)
         occurrences all number
    2
    1
    Renal and urinary disorders
    Micturition disorder
         subjects affected / exposed
    0 / 32 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 32 (9.38%)
    3 / 33 (9.09%)
         occurrences all number
    3
    5
    Back pain
         subjects affected / exposed
    3 / 32 (9.38%)
    2 / 33 (6.06%)
         occurrences all number
    3
    2
    Muscular weakness
         subjects affected / exposed
    3 / 32 (9.38%)
    1 / 33 (3.03%)
         occurrences all number
    3
    1
    Myalgia
         subjects affected / exposed
    2 / 32 (6.25%)
    1 / 33 (3.03%)
         occurrences all number
    2
    1
    Musculoskeletal pain
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    Myositis
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    Pain in extremity
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    Infections and infestations
    Cytomegalovirus infection
         subjects affected / exposed
    3 / 32 (9.38%)
    4 / 33 (12.12%)
         occurrences all number
    3
    4
    Respiratory tract infection
         subjects affected / exposed
    3 / 32 (9.38%)
    4 / 33 (12.12%)
         occurrences all number
    3
    4
    Influenza
         subjects affected / exposed
    2 / 32 (6.25%)
    3 / 33 (9.09%)
         occurrences all number
    2
    3
    Nasopharyngitis
         subjects affected / exposed
    3 / 32 (9.38%)
    1 / 33 (3.03%)
         occurrences all number
    3
    1
    Oral candidiasis
         subjects affected / exposed
    3 / 32 (9.38%)
    1 / 33 (3.03%)
         occurrences all number
    3
    1
    Candida infection
         subjects affected / exposed
    0 / 32 (0.00%)
    3 / 33 (9.09%)
         occurrences all number
    0
    3
    Sinusitis
         subjects affected / exposed
    3 / 32 (9.38%)
    0 / 33 (0.00%)
         occurrences all number
    3
    0
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 32 (9.38%)
    0 / 33 (0.00%)
         occurrences all number
    3
    0
    Urinary tract infection
         subjects affected / exposed
    1 / 32 (3.13%)
    2 / 33 (6.06%)
         occurrences all number
    1
    2
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 32 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    3
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    5 / 32 (15.63%)
    4 / 33 (12.12%)
         occurrences all number
    5
    5
    Hypokalaemia
         subjects affected / exposed
    5 / 32 (15.63%)
    2 / 33 (6.06%)
         occurrences all number
    7
    7
    Decreased appetite
         subjects affected / exposed
    3 / 32 (9.38%)
    2 / 33 (6.06%)
         occurrences all number
    3
    3
    Hypertriglyceridaemia
         subjects affected / exposed
    1 / 32 (3.13%)
    4 / 33 (12.12%)
         occurrences all number
    1
    4
    Hypercholesterolaemia
         subjects affected / exposed
    2 / 32 (6.25%)
    2 / 33 (6.06%)
         occurrences all number
    2
    3
    Hypomagnesaemia
         subjects affected / exposed
    2 / 32 (6.25%)
    1 / 33 (3.03%)
         occurrences all number
    2
    1
    Hyponatraemia
         subjects affected / exposed
    1 / 32 (3.13%)
    2 / 33 (6.06%)
         occurrences all number
    1
    2
    Hypophosphataemia
         subjects affected / exposed
    1 / 32 (3.13%)
    2 / 33 (6.06%)
         occurrences all number
    1
    2
    Vitamin D deficiency
         subjects affected / exposed
    2 / 32 (6.25%)
    1 / 33 (3.03%)
         occurrences all number
    2
    1
    Hyperkalaemia
         subjects affected / exposed
    0 / 32 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 May 2016
    Provided rationale for open-label extension (OLE), clarified when subject participation could be discontinued, and other minor administrative updates.
    31 Aug 2016
    Updated text throughout to state frequency of assessments after week 72 in the open-label extension (OLE) are to be done every 12 weeks until Week 144, updated study schema and text in protocol to state there is a minimum of 14 days of co-administration of ENTO/Placebo with systemic corticosteroids, added minimum of one day and maximum of 21 days of systemic corticosteroids are allowed prior to first dose of ENTO/Placebo, modified Exclusion Criteria 1, uncontrolled infection for 4 weeks prior to Randomization instead of Screening, added a range of 0.90 to 1.10 mg/kg/day if 1.0 mg/kg/day of prednisone is not possible due to tablet formulation, ultimate goal of prednisone taper is for participants to completely discontinue prednisone, allowing use of standard of care pulmonary function tests (PFTs) done within the screening period, collection of smoking status, clarified local lab results may be used to diagnose liver cGVHD, modified language regarding specialists to allow flexibility for institutes who prefer to perform these assessments, clarified when walk test was required, and removed drug accountability requirement at non-dispensing visits.
    30 Jan 2017
    Updated the number of sites from approximately 30 to 65, updated inclusion criteria subjects must be able to start systemic corticosteroids at a dose of ≥ 0.5 mg/kg/day, added exclusion criteria for subjects unable to start systemic corticosteroids at a dose of ≥ 0.5 mg/kg/day, updated when first DMC will be held, updated tablet description language to include description of a new study drug lot in which tablets will be beige instead of blue, updated drug interaction study data and concomitant medication warnings, updated systemic corticosteroid tapering table to reflect example based on an initial dose of 1mg/kg/day, clarified guidance on CMV surveillance and holding of ENTO/Placebo while on antiviral therapy, made monitoring levels of tacrolimus, cyclosporine or MMF optional on Days 2 or 3, updated footnote “d” in the Schedule of Assessments and ‘Criteria for Discontinuation of Study Treatment’ section to reinforce sites should ask subjects to continue with study visits through Week 48 even if study drug is discontinued, and inserted a sentence at the end of Appendix 5 Form A for consistency with source.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    18 Dec 2017
    Gilead made a decision to terminate this study early based on lack of clinical response noted at the pre-specified interim futility analysis.
    -

    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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