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    Clinical Trial Results:
    A Phase 2a, Randomized, Double-Blind, Multicenter, Placebo Controlled Study to Assess the Safety, Tolerability, Pharmacokinetics, and Efficacy of EYP001a in Patients With Nonalcoholic Steatohepatitis

    Summary
    EudraCT number
    2018-003119-22
    Trial protocol
    BE   FR   GB  
    Global end of trial date
    06 Jul 2021

    Results information
    Results version number
    v1(current)
    This version publication date
    15 Dec 2022
    First version publication date
    15 Dec 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    EYP001-202
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03812029
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Enyo Pharma SA
    Sponsor organisation address
    60 avenue Rockefeller, Lyon, France, 69008
    Public contact
    Chief Medical Officer, ENYO Pharma SA, 33 437 700 219, ps@enyopharma.com
    Scientific contact
    Chief Medical Officer, ENYO Pharma SA, 33 437 700 219, ps@enyopharma.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 Jul 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Jun 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Jul 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to determine the efficacy and safety profiles of EYP001a versus placebo on liver fat content (LFC) from baseline to Week 12 in patients with NASH.
    Protection of trial subjects
    The Clinical Study Protocol (CSP), informed consent documents, and any other appropriate study-related documents were reviewed and approved by an IEC/IRB.
    Background therapy
    Vonafexor is an agonist of the FXR, a key regulator of bile, lipid, and glucose metabolism, currently under clinical investigation as a new therapy for a functional cure of chronic HBV infection. In an experimental rodent model of NASH, vonafexor analogue has been shown to reduce liver steatosis, inflammation, apoptosis, and fibrosis. Moreover, bile acid activation of the FXR improved the histological features of NASH in patients with noncirrhotic NASH. The purpose of this Phase 2a study was to assess the effects of vonafexor compared with placebo on markers of LFC, inflammation, and fibrosis with respect to safety, tolerability, PK, PD, and lipid/metabolic profiles in subjects with a NASH diagnosis compatible with Stage F2 to F3 fibrosis.
    Evidence for comparator
    Placebo.
    Actual start date of recruitment
    30 Jan 2019
    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
    Puerto Rico: 3
    Country: Number of subjects enrolled
    United Kingdom: 5
    Country: Number of subjects enrolled
    Belgium: 3
    Country: Number of subjects enrolled
    France: 16
    Country: Number of subjects enrolled
    United States: 93
    Worldwide total number of subjects
    120
    EEA total number of subjects
    19
    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)
    90
    From 65 to 84 years
    30
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Males, females aged 18y or older provided informed consent and with a suspected diagnosis of NASH with fibrosis (non invasive testing) or a documented biopsy of Stage F2 to F3 liver fibrosis were enrolled in this study. Part A planned to randomize 24 subjects and 24 were randomized. Part B planned to randomize 90 subjects and 96 were randomized.

    Pre-assignment
    Screening details
    Following sequence of screening procedures were applied to each patient who signs an informed consent form: eligibility based on clinical and biological inclusion and exclusion criteria; eligibility based on FibroScan criteria; confirmation of eligibility based on MRI-PDFF results. Screening was up to 12 weeks prior to Day 1.

    Period 1
    Period 1 title
    Part A and B (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Part A Placebo
    Arm description
    Part A Placebo
    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
    Placebo twice a day

    Arm title
    Part A EYP001a pooled
    Arm description
    Part A EYP001a pooled 100mg BID, 200mg QD and 400mg QD
    Arm type
    Experimental

    Investigational medicinal product name
    EYP001a
    Investigational medicinal product code
    EYP001a
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    EYP001a once or twice a day according to treatment arms

    Arm title
    Part B Placebo
    Arm description
    Part B Placebo
    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
    Placebo once a day

    Arm title
    Part B EYP001a 100mg
    Arm description
    Part B EYP001a 100mg
    Arm type
    Experimental

    Investigational medicinal product name
    EYP001a
    Investigational medicinal product code
    EYP001a
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    EYP001a once a day

    Arm title
    Part B EYP001a 200mg
    Arm description
    Part B EYP001a 200mg
    Arm type
    Experimental

    Investigational medicinal product name
    EYP001a
    Investigational medicinal product code
    EYP001a
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    EYP001a once a day

    Number of subjects in period 1
    Part A Placebo Part A EYP001a pooled Part B Placebo Part B EYP001a 100mg Part B EYP001a 200mg
    Started
    7
    17
    32
    31
    33
    Completed
    5
    7
    32
    25
    23
    Not completed
    2
    10
    0
    6
    10
         Stopping rules
    -
    1
    -
    -
    -
         Consent withdrawn by subject
    1
    -
    -
    2
    2
         Adverse event, non-fatal
    -
    9
    -
    3
    5
         Lost to follow-up
    -
    -
    -
    -
    3
         Protocol deviation
    1
    -
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part A Placebo
    Reporting group description
    Part A Placebo

    Reporting group title
    Part A EYP001a pooled
    Reporting group description
    Part A EYP001a pooled 100mg BID, 200mg QD and 400mg QD

    Reporting group title
    Part B Placebo
    Reporting group description
    Part B Placebo

    Reporting group title
    Part B EYP001a 100mg
    Reporting group description
    Part B EYP001a 100mg

    Reporting group title
    Part B EYP001a 200mg
    Reporting group description
    Part B EYP001a 200mg

    Reporting group values
    Part A Placebo Part A EYP001a pooled Part B Placebo Part B EYP001a 100mg Part B EYP001a 200mg Total
    Number of subjects
    7 17 32 31 33 120
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    48.7 ± 18.4 56.1 ± 8.9 57.3 ± 10.3 58.1 ± 13.7 54.0 ± 11.9 -
    Gender categorical
    Units: Subjects
        Female
    2 14 18 14 21 69
        Male
    5 3 14 17 12 51
    Ethnicity
    Units: Subjects
        Hispanic or latino
    2 5 6 8 10 31
        Not Hispanic or latino
    5 12 26 23 23 89
    Race
    Units: Subjects
        American Indian or Alaska native
    0 0 0 0 1 1
        Asian
    0 0 0 0 0 0
        Black or African American
    0 1 3 2 1 7
        Native hawaiian or other pacific islander
    0 0 0 0 0 0
        White
    7 16 29 26 31 109
        Other
    0 0 0 3 0 3
    Height
    Units: cm
        arithmetic mean (standard deviation)
    169.0 ± 7.4 163.2 ± 9.9 168.1 ± 9.8 167.1 ± 8.5 166.8 ± 10.1 -
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    112.4 ± 32.6 103.4 ± 25.4 97.5 ± 18.3 95.8 ± 14.0 98.8 ± 18.4 -
    BMI
    Units: kg/m2
        arithmetic mean (standard deviation)
    39.3 ± 10.2 38.8 ± 9.0 34.3 ± 4.3 34.3 ± 4.1 35.4 ± 5.1 -
    Waist circumference
    Units: cm
        arithmetic mean (standard deviation)
    128.9 ± 31.5 116.1 ± 16.0 112.6 ± 13.0 111.4 ± 8.6 114.1 ± 11.8 -

    End points

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    End points reporting groups
    Reporting group title
    Part A Placebo
    Reporting group description
    Part A Placebo

    Reporting group title
    Part A EYP001a pooled
    Reporting group description
    Part A EYP001a pooled 100mg BID, 200mg QD and 400mg QD

    Reporting group title
    Part B Placebo
    Reporting group description
    Part B Placebo

    Reporting group title
    Part B EYP001a 100mg
    Reporting group description
    Part B EYP001a 100mg

    Reporting group title
    Part B EYP001a 200mg
    Reporting group description
    Part B EYP001a 200mg

    Primary: Liver Fat Content

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    End point title
    Liver Fat Content
    End point description
    Change from baseline to D84
    End point type
    Primary
    End point timeframe
    From baseline to D84
    End point values
    Part A Placebo Part A EYP001a pooled Part B Placebo Part B EYP001a 100mg Part B EYP001a 200mg
    Number of subjects analysed
    5
    12
    32
    28
    28
    Units: percent
        least squares mean (confidence interval 95%)
    3.9 (-2.5 to 10.4)
    -4.7 (-8.5 to -0.9)
    -2.3 (-4.0 to -0.6)
    -6.3 (-8.1 to -4.5)
    -5.4 (-7.2 to -3.6)
    Statistical analysis title
    Analysis of change from baseline in LFC
    Comparison groups
    Part B EYP001a 100mg v Part B Placebo v Part B EYP001a 200mg v Part A EYP001a pooled v Part A Placebo
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.05
    Method
    ANCOVA
    Confidence interval

    Secondary: glomerular filtration rate part A

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    End point title
    glomerular filtration rate part A [1]
    End point description
    Change from baseline to D84
    End point type
    Secondary
    End point timeframe
    From baseline to D84
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Other arms are reported in a separate endpoint.
    End point values
    Part A Placebo Part A EYP001a pooled
    Number of subjects analysed
    7
    17
    Units: mL/min/1.73m2
        geometric mean (standard deviation)
    -4 ± 18.4
    -11.3 ± 12.5
    No statistical analyses for this end point

    Secondary: Analyse of % change from baseline Liver Fat Content

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    End point title
    Analyse of % change from baseline Liver Fat Content
    End point description
    % change from baseline to D84
    End point type
    Secondary
    End point timeframe
    From baseline to D84
    End point values
    Part A Placebo Part A EYP001a pooled Part B Placebo Part B EYP001a 100mg Part B EYP001a 200mg
    Number of subjects analysed
    5
    12
    32
    28
    28
    Units: percent
        least squares mean (confidence interval 95%)
    11.7 (-28.5 to 51.9)
    -25.0 (-48.4 to -1.5)
    -10.5 (-19.0 to -2.0)
    -30.4 (-39.4 to -21.3)
    -25.3 (-34.3 to -16.2)
    Statistical analysis title
    Analysis of % change from baseline in LFC
    Comparison groups
    Part B Placebo v Part B EYP001a 100mg v Part B EYP001a 200mg v Part A EYP001a pooled v Part A Placebo
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.05
    Method
    ANCOVA
    Confidence interval

    Secondary: Analyse of change from baseline in CT1

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    End point title
    Analyse of change from baseline in CT1
    End point description
    Change from baseline to D84
    End point type
    Secondary
    End point timeframe
    From baseline to D84
    End point values
    Part A Placebo Part A EYP001a pooled Part B Placebo Part B EYP001a 100mg Part B EYP001a 200mg
    Number of subjects analysed
    5
    12
    32
    28
    28
    Units: msec
        least squares mean (confidence interval 95%)
    35.0 (-27.0 to 97.0)
    -58.2 (-98.7 to -17.8)
    -9.9 (-38.5 to 18.7)
    -80.2 (-110.6 to -49.8)
    -71.8 (-100.4 to -43.2)
    Statistical analysis title
    Analysis of change from baseline in CT1
    Comparison groups
    Part B Placebo v Part B EYP001a 100mg v Part B EYP001a 200mg v Part A Placebo v Part A EYP001a pooled
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.05
    Method
    ANCOVA
    Confidence interval

    Secondary: ALT

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    End point title
    ALT
    End point description
    Analysis change from baseline to D84 One patient in VONA-200QD arm part B excluded because experienced a serious transaminase increase due to previously undiagnosed auto-immune hepatitis.
    End point type
    Secondary
    End point timeframe
    From baseline to D84
    End point values
    Part A Placebo Part A EYP001a pooled Part B Placebo Part B EYP001a 100mg Part B EYP001a 200mg
    Number of subjects analysed
    7
    17
    32
    31
    32
    Units: U/L
        least squares mean (confidence interval 95%)
    -4.1 (-27.5 to 19.3)
    17.7 (1.9 to 33.5)
    -11.7 (-18.9 to -4.6)
    -16.3 (-24.1 to -8.4)
    -7.5 (-15.3 to 0.4)
    Statistical analysis title
    Analysis of change from baseline in ALT
    Comparison groups
    Part B Placebo v Part B EYP001a 100mg v Part B EYP001a 200mg v Part A Placebo v Part A EYP001a pooled
    Number of subjects included in analysis
    119
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.05
    Method
    Mixed models analysis
    Confidence interval

    Secondary: Gamma GT

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    End point title
    Gamma GT
    End point description
    Analysis change from baseline to D84
    End point type
    Secondary
    End point timeframe
    From baseline to D84
    End point values
    Part A Placebo Part A EYP001a pooled Part B Placebo Part B EYP001a 100mg Part B EYP001a 200mg
    Number of subjects analysed
    7
    17
    32
    31
    33
    Units: U/L
        least squares mean (confidence interval 95%)
    3.7 (-7.8 to 15.2)
    -25.2 (-34.2 to -16.3)
    -3.9 (-9.9 to 2.2)
    -40.6 (-47.1 to -34.0)
    -34.1 (-40.6 to -27.7)
    Statistical analysis title
    Analysis of change from baseline in GGT
    Comparison groups
    Part B Placebo v Part B EYP001a 100mg v Part B EYP001a 200mg v Part A Placebo v Part A EYP001a pooled
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.05
    Method
    Mixed models analysis
    Confidence interval

    Secondary: Body weight

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    End point title
    Body weight
    End point description
    Analysis change from baseline to D84
    End point type
    Secondary
    End point timeframe
    From baseline to D84
    End point values
    Part A Placebo Part A EYP001a pooled Part B Placebo Part B EYP001a 100mg Part B EYP001a 200mg
    Number of subjects analysed
    7
    17
    32
    31
    33
    Units: kg
        least squares mean (confidence interval 95%)
    1.2 (-1.0 to 3.4)
    -2.2 (-3.7 to -0.7)
    -0.1 (-1.0 to 0.9)
    -1.7 (-2.7 to -0.7)
    -2.5 (-3.5 to -1.5)
    Statistical analysis title
    Analysis of change from baseline in body weight
    Comparison groups
    Part B Placebo v Part B EYP001a 100mg v Part B EYP001a 200mg v Part A Placebo v Part A EYP001a pooled
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.05
    Method
    Mixed models analysis
    Confidence interval

    Secondary: Waist circumference

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    End point title
    Waist circumference
    End point description
    Analysis change from baseline to D84
    End point type
    Secondary
    End point timeframe
    From baseline to D84
    End point values
    Part A Placebo Part A EYP001a pooled Part B Placebo Part B EYP001a 100mg Part B EYP001a 200mg
    Number of subjects analysed
    7
    17
    32
    31
    33
    Units: cm
        least squares mean (confidence interval 95%)
    -1.8 (-5.0 to 1.4)
    -2.9 (-5.0 to -0.7)
    0.1 (-1.2 to 1.3)
    -1.2 (-2.6 to 0.1)
    -2.2 (-3.6 to -0.9)
    Statistical analysis title
    Analysis change from baseline waist circumference
    Comparison groups
    Part B Placebo v Part B EYP001a 100mg v Part B EYP001a 200mg v Part A Placebo v Part A EYP001a pooled
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.05
    Method
    Mixed models analysis
    Confidence interval

    Secondary: Waist to hip ratio part B

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    End point title
    Waist to hip ratio part B [2]
    End point description
    Analysis change from baseline to D84
    End point type
    Secondary
    End point timeframe
    From baseline to D84
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Other arms are reported in a separate endpoint.
    End point values
    Part B Placebo Part B EYP001a 100mg Part B EYP001a 200mg
    Number of subjects analysed
    32
    31
    33
    Units: ratio
        least squares mean (confidence interval 95%)
    0.014 (0.001 to 0.026)
    -0.017 (-0.031 to -0.003)
    -0.010 (-0.024 to 0.004)
    Statistical analysis title
    Analysis change from baseline waist hip ratio
    Comparison groups
    Part B Placebo v Part B EYP001a 100mg v Part B EYP001a 200mg
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.05
    Method
    Mixed models analysis
    Confidence interval

    Secondary: glomerular filtration rate part B

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    End point title
    glomerular filtration rate part B [3]
    End point description
    End point type
    Secondary
    End point timeframe
    Change from baseline to D84
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Other arms are reported in a separate endpoint.
    End point values
    Part B Placebo Part B EYP001a 100mg Part B EYP001a 200mg
    Number of subjects analysed
    32
    31
    33
    Units: mL/min/1.73m2
        least squares mean (confidence interval 95%)
    -2.7 (-6.6 to 1.2)
    6.2 (1.9 to 10.2)
    3.2 (-1.2 to 7.7)
    Statistical analysis title
    Analysis of change from baseline in eGFR
    Comparison groups
    Part B Placebo v Part B EYP001a 100mg v Part B EYP001a 200mg
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.05
    Method
    ANCOVA
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    After the first dose of study drug until D96
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    22
    Reporting groups
    Reporting group title
    Part A Placebo
    Reporting group description
    Part A Placebo - treatment emergent AE

    Reporting group title
    Part A EYP001a pooled
    Reporting group description
    Part A EYP001a pooled - treatment emergent AE

    Reporting group title
    Part B Placebo
    Reporting group description
    Part B Placebo - treatment emergent AE

    Reporting group title
    Part B EYP001a 100mg
    Reporting group description
    Part B EYP001a 100mg - treatment emergent AE

    Reporting group title
    Part B EYP001a 200mg
    Reporting group description
    Part B EYP001a 200mg - treatment emergent AE

    Serious adverse events
    Part A Placebo Part A EYP001a pooled Part B Placebo Part B EYP001a 100mg Part B EYP001a 200mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 32 (3.13%)
    1 / 31 (3.23%)
    2 / 33 (6.06%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Investigations
    Transaminases increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina unstable
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory failure
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Part A Placebo Part A EYP001a pooled Part B Placebo Part B EYP001a 100mg Part B EYP001a 200mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 7 (57.14%)
    16 / 17 (94.12%)
    22 / 32 (68.75%)
    25 / 31 (80.65%)
    30 / 33 (90.91%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    2 / 32 (6.25%)
    1 / 31 (3.23%)
    1 / 33 (3.03%)
         occurrences all number
    0
    0
    2
    1
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 17 (5.88%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    1
    1
    1
    0
    0
    Adverse drug reaction
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Pain
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 17 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    0
    0
    1
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Anxiety
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Depression
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    0
    0
    0
    2
    Insomnia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    0
    0
    0
    3
    Investigations
    Low density lipoprotein increased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    Transaminases increased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    1
    0
    0
    2
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    2 / 32 (6.25%)
    1 / 31 (3.23%)
    0 / 33 (0.00%)
         occurrences all number
    0
    0
    2
    1
    0
    Injury, poisoning and procedural complications
    Skin abrasion
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 17 (5.88%)
    1 / 32 (3.13%)
    0 / 31 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    1
    1
    1
    0
    0
    Electric shock
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 17 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Foot fracture
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Post-traumatic pain
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 17 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Limb injury
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    3 / 33 (9.09%)
         occurrences all number
    0
    0
    0
    0
    3
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 17 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Atrial fibrillation
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 32 (0.00%)
    2 / 31 (6.45%)
    0 / 33 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Nervous system disorders
    Paraesthesia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    0
    0
    1
    Headache
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    4 / 32 (12.50%)
    3 / 31 (9.68%)
    2 / 33 (6.06%)
         occurrences all number
    0
    0
    6
    4
    2
    Eye disorders
    Vision blurred
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 17 (11.76%)
    2 / 32 (6.25%)
    0 / 31 (0.00%)
    5 / 33 (15.15%)
         occurrences all number
    0
    2
    2
    0
    5
    Vomiting
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 17 (11.76%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    2
    0
    0
    2
    Abdominal pain
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    0
    0
    2
    Abdominal rigidity
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    0
    0
    1
    Constipation
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 17 (0.00%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
    1 / 33 (3.03%)
         occurrences all number
    1
    0
    0
    1
    1
    Diarrhoea
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
    4 / 33 (12.12%)
         occurrences all number
    0
    1
    0
    1
    5
    Toothache
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    3 / 32 (9.38%)
    0 / 31 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    0
    3
    0
    0
    Hepatobiliary disorders
    Hepatic cyst
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    0 / 7 (0.00%)
    16 / 17 (94.12%)
    4 / 32 (12.50%)
    19 / 31 (61.29%)
    22 / 33 (66.67%)
         occurrences all number
    0
    22
    4
    29
    36
    Hyperhidrosis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 32 (0.00%)
    1 / 31 (3.23%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    Rash macular
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Rash pruritic
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Skin lesion
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    0
    0
    0
    2
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Renal cyst
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Infections and infestations
    Gastroenteritis viral
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 17 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    2 / 32 (6.25%)
    1 / 31 (3.23%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    2
    1
    1
    COVID-19
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 32 (0.00%)
    2 / 31 (6.45%)
    1 / 33 (3.03%)
         occurrences all number
    0
    0
    0
    2
    2
    Metabolism and nutrition disorders
    Diabetes mellitus inadequate control
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 17 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 32 (3.13%)
    2 / 31 (6.45%)
    1 / 33 (3.03%)
         occurrences all number
    0
    0
    1
    2
    1
    Hypercholesterolaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 32 (0.00%)
    0 / 31 (0.00%)
    3 / 33 (9.09%)
         occurrences all number
    0
    0
    0
    0
    4
    Hyperlipidaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 32 (0.00%)
    2 / 31 (6.45%)
    0 / 33 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Nov 2018
    Consolidated and signed version of the draft sent to FDA
    11 Jan 2019
    Eligibility criteria restricted (reduced allowable variability in baseline ALT and AST). Version incorporating outcome of discussions with FDA during the IND review period.
    28 May 2019
    Eligibility criteria expanded (increased allowable variability in baseline ALT, AST, ALP, and total bilirubin). Increased Screening Period (increased from 60 days to 12 weeks). Centra lab reference ranges for ALT, AST, and ALP updated. Following correspondence on May 3, 2019 from ENYO to FDA regarding the high SF rate, and FDA’s advice letter dated May 9, 2019 in which FDA provided recommended protocol modifications to improve the SF rate.
    24 Mar 2020
    Following DSMC-review of the unblinded Part A data and unscheduled interim analysis of Part A data (presented in Section 10), the following changes to study conduct were implemented: Eligibility criteria restricted: − Subjects with a BMI >45 kg/m2 were excluded. − eGFR exclusion criteria decreased from <60 mL/min/1.73 m2 to <50 mL/min/1.73 m2. Changes to study design: − Reduction in the number of subjects to be enrolled in Part B (reduced from 136 to 90 subjects). − Removal of the vonafexor 400 mg QD treatment group from Part B. − Dosing strategy for vonafexor a 200 mg QD in Part B updated to a step-up strategy (100 mg QD for the first 2 weeks of treatment, followed by an uptitration to 200 mg QD) to address the pruritus-related tolerance issues observed in the unblinded Part A data. − The Clinical Safety Monitoring Plan updated to ensure, in Part B, the DSMC were promptly notified for further review if any subjects experience ALT, AST, or bilirubin elevations 2×baseline values. − Removal of inhouse 24-hour PK monitoring.

    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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