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    Clinical Trial Results:
    A Double-Blind, Randomized, Placebo-Controlled Clinical Trial to Assess the Efficacy and Safety of Oral GKT137831 in Patients with Primary Biliary Cholangitis Receiving Ursodeoxycholic Acid and with Persistently Elevated Alkaline Phosphatase

    Summary
    EudraCT number
    		 2016-004599-23
    Trial protocol
    		 BE   GB   ES   GR   DE   IT  
    Global end of trial date
    08 Apr 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Mar 2022
    First version publication date
    01 Mar 2022
    Other versions
    Summary report(s)
    		 Synopsis 07Feb20

    Trial information

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    Trial identification
    Sponsor protocol code
    GSN000300
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03226067
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Genkyotex SA
    Sponsor organisation address
    16 Ch des Aulx, Plan-les-Ouates, Switzerland, 1228
    Public contact
    Richard Philipson, MD (CMO, Calliditas), Genkyotex SA, +46 8 411 3005, richard.philipson@calliditas.com
    Scientific contact
    Richard Philipson, MD (CMO, Calliditas), Genkyotex SA, +46 8 411 3005, richard.philipson@calliditas.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
    07 Feb 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    08 Apr 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Apr 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of oral GKT137831 in comparison with placebo, in subjects with PBC receiving UDCA and with persistently elevated Alkaline Phosphatase (ALP).
    Protection of trial subjects
    Independent safety monitoring board
    Background therapy
    		 UDCA
    Evidence for comparator
    		 N/A
    Actual start date of recruitment
    15 Jun 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 6
    Country: Number of subjects enrolled
    United Kingdom: 16
    Country: Number of subjects enrolled
    Belgium: 14
    Country: Number of subjects enrolled
    Germany: 7
    Country: Number of subjects enrolled
    Greece: 10
    Country: Number of subjects enrolled
    Canada: 6
    Country: Number of subjects enrolled
    Israel: 13
    Country: Number of subjects enrolled
    Italy: 12
    Country: Number of subjects enrolled
    United States: 27
    Worldwide total number of subjects
    111
    EEA total number of subjects
    65
    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)
    91
    From 65 to 84 years
    20
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 First subject enrolled: 06-Sep-2017 Last subject completed: 08-Apr-2019

    Pre-assignment
    Screening details
    		 Male or female subjects aged 18-80 years with primary biliary cholangitis receiving a stable dose of UDCA and with persistently elevated ALP, who met all the inclusion criteria and none of the exclusion criteria.

    Period 1
    Period 1 title
    Treatment (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    This is a double-blind study: the Sponsor, subjects, investigator staff, persons performing the assessments and data reviewers and statisticians will remain blinded to the identity of the study treatments. The identity of the study treatments will be concealed by the use of IMPs which are all identical in packaging, labeling, schedule of administration, appearance and odor. Randomization data will be kept strictly confidential, and will be accessible only to authorized personnel.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 GKT137831 400 mg OD
    Arm description
    		 GKT137831 400 mg once daily dosing
    Arm type
    		 Experimental

    Investigational medicinal product name
    Setanaxib
    Investigational medicinal product code
    GKT137831
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    70 capsules of 100 mg GKT137831 and/or matching placebo per bottle. Subjects self-administered IMP (4 capsules) twice daily once in the morning and once in the evening (aiming for a period of at least 10 hours between doses) with meals or up to 30 minutes after eating a meal.

    Arm title
    		 GKT137831 400 mg BID
    Arm description
    		 GKT137831 400 mg twice daily dosing
    Arm type
    		 Experimental

    Investigational medicinal product name
    Setanaxib
    Investigational medicinal product code
    GKT137831
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    70 capsules of 100 mg GKT137831 per bottle. Subjects self-administered IMP (4 capsules) twice daily once in the morning and once in the evening (aiming for a period of at least 10 hours between doses) with meals or up to 30 minutes after eating a meal.

    Arm title
    		 Placebo
    Arm description
    		 Placebo twice daily administration
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Placebo
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    70 capsules of placebo per bottle. Subjects self administered placebo (4 capsules) once in the morning and once in the evening (aiming for a period of at least 10 hours between doses) with meals or up to 30 minutes after eating a meal.

    Number of subjects in period 1
    		GKT137831 400 mg OD GKT137831 400 mg BID Placebo
    Started
    38
    36
    37
    Completed
    35
    32
    37
    Not completed
    3
    4
    0
         Physician decision
    1
    -
    -
         Consent withdrawn by subject
    -
    1
    -
         Adverse event, non-fatal
    -
    2
    -
         Administrative reasons
    1
    1
    -
         Change in UDCA dose
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    GKT137831 400 mg OD
    Reporting group description
    		 GKT137831 400 mg once daily dosing

    Reporting group title
    GKT137831 400 mg BID
    Reporting group description
    		 GKT137831 400 mg twice daily dosing

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo twice daily administration

    Reporting group values
    		 GKT137831 400 mg OD GKT137831 400 mg BID Placebo Total
    Number of subjects
    		 38 36 37 111
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 31 30 30 91
        From 65-84 years
    		 7 6 7 20
        85 years and over
    		 0 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 30 34 35 99
        Male
    		 8 2 2 12
    Subject analysis sets

    Subject analysis set title
    ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The Intent-to-Treat (ITT) population included all subjects randomly allocated to a treatment arm who received at least one dose of setanaxib or placebo. All 111 randomized subjects were included in the ITT population.

    Subject analysis set title
    Safety analysis
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety population included all subjects who received at least one dose of setanaxib or placebo, (irrespective of whether they were randomly allocated to a treatment arm) and had at least one safety assessment. All 111 randomized subjects were included in the Safety population.

    Subject analysis sets values
    		 ITT Safety analysis
    Number of subjects
    111
    111
    Age categorical
    Units: Subjects
        In utero
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
        Newborns (0-27 days)
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
        Children (2-11 years)
    0
    0
        Adolescents (12-17 years)
    0
    0
        Adults (18-64 years)
    91
    91
        From 65-84 years
    20
    20
        85 years and over
    0
    0
    Age continuous
    Units:
        
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
    99
    99
        Male
    12
    12

    End points

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    End points reporting groups
    Reporting group title
    GKT137831 400 mg OD
    Reporting group description
    		 GKT137831 400 mg once daily dosing

    Reporting group title
    GKT137831 400 mg BID
    Reporting group description
    		 GKT137831 400 mg twice daily dosing

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo twice daily administration

    Subject analysis set title
    ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The Intent-to-Treat (ITT) population included all subjects randomly allocated to a treatment arm who received at least one dose of setanaxib or placebo. All 111 randomized subjects were included in the ITT population.

    Subject analysis set title
    Safety analysis
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety population included all subjects who received at least one dose of setanaxib or placebo, (irrespective of whether they were randomly allocated to a treatment arm) and had at least one safety assessment. All 111 randomized subjects were included in the Safety population.

    Primary: Percent change from baseline to Week 24 in serum GGT

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    End point title
    		 Percent change from baseline to Week 24 in serum GGT
    End point description
    End point type
    Primary
    End point timeframe
    Week 24
    End point values
    		 GKT137831 400 mg OD GKT137831 400 mg BID Placebo ITT
    Number of subjects analysed
    37
    30
    35
    102
    Units: U/L
        arithmetic mean (standard deviation)
    -4.9 ( 59.58 )
    -19 ( 28.89 )
    -8.4 ( 21.45 )
    -10.2 ( 41.16 )
    Statistical analysis title
    		 Analysis of Percent Change in serum GGT (W24)
    Statistical analysis description
    Analysis of Percent Change from Baseline to Week 24 Visit in Serum GGT (ITT Population)
    Comparison groups
    Placebo v GKT137831 400 mg BID v GKT137831 400 mg OD
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 < 0.04695 [2]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard deviation
    Notes
    [1] - The % change from baseline to W24 visit in serum GGT will be analyzed using ANCOVA with the allocated treatment & disease severity at baseline as fixed effects & the serum GGT baseline value as a continuous covariate. The LSM estimate of the difference between each dose of GKT137831 and placebo alongside the 95% CI will be calculated. Given 2 doses of GKT137831 are tested versus placebo, the 97.5% CI of the LSM of the difference between each dose of GKT137831 and placebo will also be calculated.
    [2] - statistical significance following Hochberg adjustment for multiple testing: the highest p-value is considered statistically significant if it is <0.04695 and the lowest p-value is considered statistically significant if it is <0.023475

    Secondary: Absolute and percent change in serum GGT from baseline to each assessment

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    End point title
    		 Absolute and percent change in serum GGT from baseline to each assessment
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to Weeks 2, 6, 12, 18, 24
    End point values
    		 GKT137831 400 mg OD GKT137831 400 mg BID Placebo ITT
    Number of subjects analysed
    38
    35
    37
    110
    Units: U/L
    arithmetic mean (standard deviation)
        Absolute change W2
    -14.3 ( 112.66 )
    -48.5 ( 61.83 )
    -11.2 ( 45.96 )
    -24.2 ( 80.49 )
        Absolute change W6
    -22.2 ( 76.68 )
    -53.5 ( 67.57 )
    -17.9 ( 59.01 )
    -30.7 ( 69.42 )
        Absolute change W12
    -3.9 ( 115.13 )
    -50.6 ( 74.7 )
    -8.6 ( 70.11 )
    -20.1 ( 91.18 )
        Absolute change W18
    -19.2 ( 134.32 )
    -37.9 ( 93.88 )
    -4.5 ( 79.81 )
    -19.9 ( 105.83 )
        Absolute change W24
    -17.9 ( 117.62 )
    -43.6 ( 62.22 )
    -10.7 ( 78.2 )
    -23 ( 91.05 )
        Percent change W2
    -7 ( 25.08 )
    -17 ( 17.25 )
    -6.2 ( 13.04 )
    -9.9 ( 19.66 )
        Percent change W6
    -11.8 ( 21.59 )
    -22 ( 23.4 )
    -7.5 ( 16.89 )
    -13.6 ( 21.44 )
        Percent change W12
    1.7 ( 66.84 )
    -18.6 ( 27.44 )
    -5.5 ( 19.44 )
    -7.1 ( 44.23 )
        Percent change W18
    -4.5 ( 69.65 )
    -18.7 ( 28.55 )
    -5.2 ( 22.79 )
    -9.1 ( 46.23 )
        Percent change W24
    -4.9 ( 59.58 )
    -19.0 ( 28.89 )
    -8.4 ( 21.45 )
    -10.2 ( 41.16 )
    No statistical analyses for this end point

    Secondary: Absolute and percent change in serum ALP from baseline to each assessment

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    End point title
    		 Absolute and percent change in serum ALP from baseline to each assessment
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to Weeks 2, 6, 12, 18 and 24
    End point values
    		 GKT137831 400 mg OD GKT137831 400 mg BID Placebo ITT
    Number of subjects analysed
    38
    35
    37
    110
    Units: U/L
    arithmetic mean (standard deviation)
        Absolute change W2
    -19.8 ( 35.95 )
    -45.9 ( 75.75 )
    -17 ( 44.4 )
    -27.2 ( 55.19 )
        Absolute change W6
    -27.3 ( 44.13 )
    -58.6 ( 63.88 )
    -14.5 ( 59.72 )
    -32.9 ( 58.74 )
        Absolute change W12
    -15.3 ( 67.79 )
    -53 ( 66.51 )
    -7.1 ( 52.75 )
    -24.3 ( 65.14 )
        Absolute change W18
    -27.6 ( 62.54 )
    -53.2 ( 80.01 )
    -6 ( 50.15 )
    -28 ( 66.90 )
        Absolute change W24
    -32.5 ( 65.3 )
    -45.2 ( 84.41 )
    -12.4 ( 53.48 )
    -29.4 ( 68.60 )
        Percent change W2
    -5.5 ( 10.95 )
    -13.0 ( 12.71 )
    -3.6 ( 11.51 )
    -7.2 ( 12.29 )
        Percent change W6
    -8.6 ( 13.42 )
    -16.3 ( 13.32 )
    -1.4 ( 15.19 )
    -8.6 ( 15.14 )
        Percent change W12
    -3.9 ( 22.17 )
    -14.6 ( 17.89 )
    -0.6 ( 16.41 )
    -6.1 ( 19.77 )
        Percent change W18
    -7.8 ( 21.68 )
    -15.8 ( 21.42 )
    -0.5 ( 15.66 )
    -7.7 ( 20.50 )
        Percent change W24
    -9.7 ( 21.1 )
    -12.9 ( 19.55 )
    -3.1 ( 15.99 )
    -8.4 ( 19.26 )
    No statistical analyses for this end point

    Secondary: Absolute and Percent Change in Serum Conjugated Bilirubin from Baseline to Each Assessment

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    End point title
    		 Absolute and Percent Change in Serum Conjugated Bilirubin from Baseline to Each Assessment
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to Week 2,6,12,18 and 24
    End point values
    		 GKT137831 400 mg OD GKT137831 400 mg BID Placebo ITT
    Number of subjects analysed
    32
    27
    32
    91
    Units: μmol/L
    arithmetic mean (standard deviation)
        Absolute change W2
    0.0 ( 1.32 )
    0.3 ( 1.61 )
    -0.1 ( 1.4 )
    0.1 ( 1.43 )
        Absolute change W6
    -0.3 ( 1.14 )
    0.5 ( 2.06 )
    -0.3 ( 1.29 )
    -0.0 ( 1.56 )
        Absolute change W12
    0.8 ( 1.97 )
    0.4 ( 1.28 )
    -0.1 ( 1.55 )
    0.3 ( 1.66 )
        Absolute change W18
    0.5 ( 2.10 )
    0.6 ( 1.78 )
    -0.0 ( 1.91 )
    0.3 ( 1.94 )
        Absolute change W24
    1.1 ( 3.44 )
    1.1 ( 1.76 )
    0.3 ( 2.57 )
    0.8 ( 2.70 )
        Percent change W2
    0.9 ( 16.81 )
    5.2 ( 22.79 )
    1.3 ( 28.11 )
    2.3 ( 22.91 )
        Percent change W6
    -3.4 ( 18.7 )
    6.3 ( 29.4 )
    -3.5 ( 17.99 )
    -0.4 ( 22.61 )
        Percent change W12
    9.4 ( 27.14 )
    4.8 ( 18.55 )
    -0.7 ( 20.81 )
    4.5 ( 22.76 )
        Percent change W18
    6.0 ( 28.16 )
    8.9 ( 19.34 )
    1.8 ( 25.98 )
    5.2 ( 24.99 )
        Percent change W24
    12.7 ( 36.35 )
    16.1 ( 24.85 )
    6.4 ( 32.90 )
    11.4 ( 31.85 )
    No statistical analyses for this end point

    Secondary: Absolute and Percent Change in Serum Total Bilirubin from Baseline to Each Assessment

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    End point title
    		 Absolute and Percent Change in Serum Total Bilirubin from Baseline to Each Assessment
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to Week 2,6,12,18,24
    End point values
    		 GKT137831 400 mg OD GKT137831 400 mg BID Placebo ITT
    Number of subjects analysed
    38
    35
    37
    110
    Units: μmol/L
    arithmetic mean (standard deviation)
        Absolute change W2
    -0.2 ( 2.51 )
    0.1 ( 2.76 )
    -0.4 ( 3.75 )
    -0.2 ( 3.03 )
        Absolute change W6
    -0.5 ( 2.35 )
    0.5 ( 3.39 )
    -0.5 ( 3.29 )
    -0.1 ( 3.05 )
        Absolute change W12
    0.6 ( 3.35 )
    0.1 ( 2.69 )
    0.0 ( 2.21 )
    0.2 ( 2.79 )
        Absolute change W18
    0.1 ( 3.22 )
    0.5 ( 2.82 )
    -0.1 ( 3.81 )
    0.1 ( 3.30 )
        Absolute change W24
    0.5 ( 3.77 )
    1.2 ( 2.71 )
    0.7 ( 3.23 )
    0.8 ( 3.28 )
        Percent change W2
    -0.6 ( 23.62 )
    5.3 ( 32.42 )
    3.3 ( 39.98 )
    2.6 ( 32.42 )
        Percent change W6
    -1.6 ( 21.94 )
    8.8 ( 41.19 )
    0.1 ( 34.6 )
    2.3 ( 33.38 )
        Percent change W12
    5.7 ( 32.99 )
    7.7 ( 37.53 )
    3.1 ( 22.39 )
    5.5 ( 3.21 )
        Percent change W18
    1.7 ( 28.34 )
    9.6 ( 32.56 )
    4.1 ( 29.50 )
    4.9 ( 29.97 )
        Percent change W24
    5.4 ( 29.77 )
    14.5 ( 31.60 )
    10.5 ( 32.27 )
    9.8 ( 31.10 )
    No statistical analyses for this end point

    Secondary: Absolute and Percent Change from Baseline to Week 24 in Liver Stiffness

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    End point title
    		 Absolute and Percent Change from Baseline to Week 24 in Liver Stiffness
    End point description
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 GKT137831 400 mg OD GKT137831 400 mg BID Placebo ITT
    Number of subjects analysed
    33
    26
    32
    91
    Units: kPa
    arithmetic mean (standard deviation)
        Absolute change W24
    -0.5 ( 5.24 )
    -0.3 ( 2.65 )
    0.7 ( 3.63 )
    -0.0 ( 4.06 )
        Percent change W24
    3.3 ( 34.95 )
    7.9 ( 43.68 )
    10.1 ( 33.11 )
    7.0 ( 36.75 )
    No statistical analyses for this end point

    Secondary: Absolute and Percent Change from Baseline to Week 24 in Liver Stiffness by Subgroup (≥9.6 kPa) of Baseline Liver Stiffness Values

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    End point title
    		 Absolute and Percent Change from Baseline to Week 24 in Liver Stiffness by Subgroup (≥9.6 kPa) of Baseline Liver Stiffness Values
    End point description
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 GKT137831 400 mg OD GKT137831 400 mg BID Placebo ITT
    Number of subjects analysed
    14
    9
    16
    39
    Units: kPa
    arithmetic mean (standard deviation)
        Absolute change W24
    -1.9 ( 7.49 )
    -2.1 ( 2.43 )
    0.4 ( 4.65 )
    -1.0 ( 5.51 )
        Percent change W24
    -5.3 ( 35.10 )
    -16.1 ( 20.71 )
    4.2 ( 30.09 )
    -3.9 ( 30.54 )
    No statistical analyses for this end point

    Secondary: Percent Change in Serum Levels of Collagen Fragments Indicative of Collagen Formation and Degradation, from Baseline to Weeks 12 and 24

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    End point title
    		 Percent Change in Serum Levels of Collagen Fragments Indicative of Collagen Formation and Degradation, from Baseline to Weeks 12 and 24
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12 and Week 24
    End point values
    		 GKT137831 400 mg OD GKT137831 400 mg BID Placebo ITT
    Number of subjects analysed
    38
    33
    34
    105
    Units: ng/mL
    arithmetic mean (standard deviation)
        Percent change ProC3 W12
    -2.58 ( 21.09 )
    -1.31 ( 18.23 )
    3.64 ( 27.86 )
    -0.16 ( 22.71 )
        Percent change ProC3 W24
    -3.6 ( 22.54 )
    0.69 ( 18.17 )
    3.10 ( 20.78 )
    -0.01 ( 20.70 )
        Percent change ProC5 W12
    1.17 ( 20.56 )
    -6.65 ( 22.99 )
    0.35 ( 22.52 )
    -1.51 ( 22.03 )
        Percent change ProC5 W24
    2.26 ( 30.36 )
    -3.27 ( 37.35 )
    -0.51 ( 37.78 )
    -0.34 ( 34.88 )
        Percent change C3M W12
    -0.63 ( 15.03 )
    -3.06 ( 17.73 )
    1.31 ( 20.17 )
    -0.74 ( 17.58 )
        Percent change C3M W24
    -0.93 ( 15.29 )
    0.17 ( 30.10 )
    -1.06 ( 23.88 )
    -0.65 ( 23.19 )
        Percent change C4M W12
    1.59 ( 15.76 )
    -4.82 ( 18.97 )
    3.19 ( 20.80 )
    0.14 ( 18.64 )
        Percent C4M W24
    -4.43 ( 17.72 )
    3.33 ( 37.63 )
    0.73 ( 21.55 )
    -0.35 ( 26.21 )
        Percent change BGM W12
    -0.13 ( 14.91 )
    -4.30 ( 18.81 )
    -0.12 ( 23.07 )
    -1.41 ( 18.99 )
        Percent change BGM W24
    1.19 ( 17.15 )
    2.18 ( 29.14 )
    3.77 ( 25.89 )
    2.38 ( 24.03 )
    No statistical analyses for this end point

    Secondary: Absolute and Percent Change in Pruritis Visual Analogue Scale (VAS) Scores from baseline to weeks 12 and 24

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    End point title
    		 Absolute and Percent Change in Pruritis Visual Analogue Scale (VAS) Scores from baseline to weeks 12 and 24
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12 and week 24
    End point values
    		 GKT137831 400 mg OD GKT137831 400 mg BID Placebo ITT
    Number of subjects analysed
    38
    34
    37
    109
    Units: score
    arithmetic mean (standard deviation)
        Absolute change W12
    -0.1 ( 3.1 )
    0.3 ( 2.33 )
    0.5 ( 1.79 )
    0.2 ( 2.47 )
        Absolute change W24
    -1.0 ( 2.32 )
    0.1 ( 2.3 )
    0.7 ( 1.83 )
    -0.1 ( 2.26 )
        Percent change W12
    -35.1 ( 46.13 )
    -11.7 ( 73.87 )
    26.1 ( 79.35 )
    -8.3 ( 70.68 )
        Percent change W24
    -36.9 ( 58.6 )
    -0.3 ( 92.71 )
    27.3 ( 72.88 )
    -5.6 ( 78.38 )
    No statistical analyses for this end point

    Secondary: Absolute and Percent Change from Baseline to Weeks 12 and 24 in PBC-40 Domain Scores

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    End point title
    		 Absolute and Percent Change from Baseline to Weeks 12 and 24 in PBC-40 Domain Scores
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to week 12 and week 24
    End point values
    		 GKT137831 400 mg OD GKT137831 400 mg BID Placebo ITT
    Number of subjects analysed
    38
    34
    37
    109
    Units: Score
    arithmetic mean (standard deviation)
        Absolute change Symptoms W12
    -0.4 ( 3.34 )
    -0.9 ( 3.19 )
    -0.2 ( 3.52 )
    -0.5 ( 3.34 )
        Absolute change symptoms W24
    0.1 ( 3.46 )
    -1.4 ( 4.23 )
    -0.3 ( 3.10 )
    -0.5 ( 3.6 )
        Absolute change Itch W12
    -0.2 ( 2.61 )
    0.6 ( 2.69 )
    0.4 ( 2.79 )
    0.2 ( 2.69 )
        Absolute change Itch W24
    -0.4 ( 3.22 )
    0.1 ( 2.83 )
    0.1 ( 2.85 )
    -0.1 ( 2.96 )
        Absolute change Fatigue W12
    -1.8 ( 5.76 )
    -3.2 ( 8.25 )
    0.6 ( 4.91 )
    -1.4 ( 6.53 )
        Absolute change Fatigue W24
    -0.8 ( 6.31 )
    -3.6 ( 7.32 )
    0.6 ( 5.35 )
    -1.1 ( 6.47 )
        Absolute change Cognitive W12
    -0.1 ( 5.02 )
    -2.4 ( 5.68 )
    1.0 ( 4.35 )
    -0.4 ( 5.17 )
        Absolute change cognitive W24
    0.8 ( 4.67 )
    -1.4 ( 5.34 )
    0.3 ( 3.67 )
    0.0 ( 4.61 )
        Absolute change Emotional W12
    -0.5 ( 2.09 )
    -1.8 ( 3.2 )
    0.4 ( 2.35 )
    -0.6 ( 2.68 )
        Absolute change Emotional W24
    -0.3 ( 2.6 )
    -2.0 ( 3.0 )
    0.4 ( 1.78 )
    -0.5 ( 2.65 )
        Absolute change Social W12
    0.6 ( 4.69 )
    -2.1 ( 5.24 )
    2.0 ( 5.43 )
    0.2 ( 5.34 )
        Absolute change Social W24
    0.8 ( 5.08 )
    -2.2 ( 4.93 )
    1.7 ( 5.01 )
    0.2 ( 5.22 )
        Percent change Symptoms W12
    -2.8 ( 24.68 )
    -2.7 ( 24.48 )
    3.1 ( 37.21 )
    -0.8 ( 29.34 )
        Percent change Symptoms W24
    1.1 ( 25.27 )
    -3.7 ( 25.19 )
    1.1 ( 35.03 )
    -0.3 ( 28.84 )
        Percent change Itch W12
    -5.6 ( 62.92 )
    -9.2 ( 43.43 )
    -2.5 ( 48.47 )
    -5.5 ( 52.28 )
        Percent change Itch W24
    -11.4 ( 52.75 )
    -9.5 ( 41.83 )
    -6.8 ( 40.62 )
    -9.2 ( 45.18 )
        Percent change Fatigue W12
    -3.4 ( 21.11 )
    -6.8 ( 26.51 )
    3.4 ( 20.45 )
    -2.1 ( 22.91 )
        Percent change Fatigue W24
    0.3 ( 24.89 )
    -9.9 ( 19.81 )
    2.4 ( 23.07 )
    -2.0 ( 23.24 )
        Percent change Cognitive W12
    6.1 ( 56.79 )
    -9.5 ( 32.14 )
    11.7 ( 51.28 )
    3.1 ( 48.71 )
        Percent change Cognitive W24
    16.0 ( 62.27 )
    -1.9 ( 40.79 )
    5.2 ( 46.11 )
    7.0 ( 51.23 )
        Percent change Emotional W12
    -1.2 ( 35.5 )
    -12.8 ( 33.88 )
    8.7 ( 45.99 )
    -1.5 ( 39.53 )
        Percent change Emotional W24
    4.9 ( 54.41 )
    -16.9 ( 26.85 )
    8.7 ( 34.49 )
    -0.1 ( 42.16 )
        Percent change Social W12
    4.8 ( 24.14 )
    -6.2 ( 21.65 )
    13.9 ( 40.03 )
    4.5 ( 30.72 )
        Percent change Social W24
    8.1 ( 27.94 )
    -7.7 ( 18.38 )
    9.3 ( 28.53 )
    3.9 ( 26.59 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From ICF signature until 4 weeks after the last study drug administration.
    Adverse event reporting additional description
    Treatment-emergent AEs
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    GKT137831 400 mg OD
    Reporting group description
    		 GKT137831 400 mg once daily dosing

    Reporting group title
    GKT137831 400 mg BID
    Reporting group description
    		 GKT137831 400 mg twice daily dosing

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo twice daily administration

    Serious adverse events
    		 GKT137831 400 mg OD GKT137831 400 mg BID Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 36 (2.78%)
    1 / 37 (2.70%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Injury, poisoning and procedural complications
    Multiple fractures
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 36 (2.78%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 36 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 GKT137831 400 mg OD GKT137831 400 mg BID Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    34 / 38 (89.47%)
    31 / 36 (86.11%)
    31 / 37 (83.78%)
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 36 (0.00%)
    2 / 37 (5.41%)
         occurrences all number
    0
    0
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 38 (13.16%)
    4 / 36 (11.11%)
    5 / 37 (13.51%)
         occurrences all number
    8
    4
    5
    Dizziness
         subjects affected / exposed
    4 / 38 (10.53%)
    2 / 36 (5.56%)
    1 / 37 (2.70%)
         occurrences all number
    5
    2
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 38 (2.63%)
    3 / 36 (8.33%)
    8 / 37 (21.62%)
         occurrences all number
    1
    3
    8
    Pyrexia
         subjects affected / exposed
    1 / 38 (2.63%)
    2 / 36 (5.56%)
    2 / 37 (5.41%)
         occurrences all number
    1
    2
    3
    Asthenia
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 36 (5.56%)
    0 / 37 (0.00%)
         occurrences all number
    0
    4
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    3 / 38 (7.89%)
    6 / 36 (16.67%)
    4 / 37 (10.81%)
         occurrences all number
    3
    7
    6
    Abdominal pain
         subjects affected / exposed
    3 / 38 (7.89%)
    3 / 36 (8.33%)
    0 / 37 (0.00%)
         occurrences all number
    4
    3
    0
    Abdominal pain upper
         subjects affected / exposed
    2 / 38 (5.26%)
    2 / 36 (5.56%)
    2 / 37 (5.41%)
         occurrences all number
    2
    2
    2
    Diarrhoea
         subjects affected / exposed
    1 / 38 (2.63%)
    2 / 36 (5.56%)
    3 / 37 (8.11%)
         occurrences all number
    1
    2
    5
    Constipation
         subjects affected / exposed
    1 / 38 (2.63%)
    3 / 36 (8.33%)
    1 / 37 (2.70%)
         occurrences all number
    1
    4
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    3 / 38 (7.89%)
    1 / 36 (2.78%)
    1 / 37 (2.70%)
         occurrences all number
    4
    1
    1
    Abdominal discomfort
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 36 (2.78%)
    2 / 37 (5.41%)
         occurrences all number
    1
    1
    2
    Dry mouth
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 36 (0.00%)
    1 / 37 (2.70%)
         occurrences all number
    2
    0
    1
    Abdominal distension
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 36 (5.56%)
    0 / 37 (0.00%)
         occurrences all number
    0
    2
    0
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    1 / 38 (2.63%)
    2 / 36 (5.56%)
    1 / 37 (2.70%)
         occurrences all number
    1
    2
    2
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    8 / 38 (21.05%)
    8 / 36 (22.22%)
    8 / 37 (21.62%)
         occurrences all number
    11
    10
    8
    Alopecia
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 36 (2.78%)
    2 / 37 (5.41%)
         occurrences all number
    0
    1
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 38 (5.26%)
    1 / 36 (2.78%)
    3 / 37 (8.11%)
         occurrences all number
    2
    1
    3
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    3 / 38 (7.89%)
    1 / 36 (2.78%)
    3 / 37 (8.11%)
         occurrences all number
    3
    1
    5
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 36 (5.56%)
    2 / 37 (5.41%)
         occurrences all number
    0
    2
    2
    Urinary tract infection
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 36 (5.56%)
    4 / 37 (10.81%)
         occurrences all number
    0
    2
    5
    Oral Herpes
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 36 (2.78%)
    2 / 37 (5.41%)
         occurrences all number
    0
    1
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 May 2017
    Amendment 1
    09 Nov 2017
    Amendment 2
    24 Jul 2018
    Amendment 3

    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
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