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    Clinical Trial Results:
    An 8-week, dose ranging, open label, randomized, Phase 2 study with a 44-week extension, to evaluate the safety and efficacy of MBX-8025 in subjects with Primary Biliary Cholangitis (PBC) and an inadequate response to or intolerance to ursodeoxycholic acid (UDCA).

    Summary
    EudraCT number
    		 2016-002996-91
    Trial protocol
    		 DE   GB  
    Global end of trial date
    08 Jul 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Jan 2021
    First version publication date
    04 Jan 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CB8025-21629
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02955602
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    CymaBay Therapeutics, Inc.
    Sponsor organisation address
    7575 Gateway Blvd, Suite 110, Newark, United States, 94560
    Public contact
    Mary Standen, CymaBay Therapeutics, Inc., 001 5102938800, mstanden@cymabay.com
    Scientific contact
    Alexandra (Sasha) Steinberg, CymaBay Therapeutics, Inc., 001 5102938800, asteinberg@cymabay.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
    30 Jul 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Jul 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the safety and efficacy of seladelpar 2 mg, 5 mg and 10 mg over 8 weeks of treatment in subjects of primary biliary cholangitis (PBC) as measured by the mean percent change from baseline in serum alkaline phosphatase (ALP) levels. After completion of the 8-week initial treatment period, subjects entered a 44-week open-label extension period for a total of up to 52 weeks of treatment. During the extension period subjects took seladelpar orally once daily for up to 52 weeks. The 2 mg group was started in order to define the lower dose range for efficacy after review of initial treatment period results for the 5 mg and the 10 mg groups.
    Protection of trial subjects
    The study was conducted in accordance with the Declaration of Helsinki and its revisions and the International Conference on Harmonisation (ICH) Harmonized Tripartite Guideline for Good Clinical Practice (GCP). The study was also in compliance with the applicable local regulatory requirements and laws of each country in which the study was conducted, as well as with any applicable guidelines.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Nov 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 20
    Country: Number of subjects enrolled
    United States: 82
    Country: Number of subjects enrolled
    Canada: 6
    Country: Number of subjects enrolled
    Germany: 11
    Worldwide total number of subjects
    119
    EEA total number of subjects
    31
    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
    29
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 33 sites in the Canada, Germany, United Kingdom, and United States between 28 November 2016 and 08 July 2019.

    Pre-assignment
    Screening details
    		 A total of 192 subjects were screened of which 121 subjects randomized (2 subjects were not treated) into study and 71 were screen failures. Subjects were randomized to the 5 and 10 mg treatment groups for entry to the 8-week initial treatment period study, while those in the 2 mg treatment group entered after being sequentially assigned their dose

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Seladelpar 2 mg
    Arm description
    		 Subjects received two seladelpar 1 mg capsules orally once daily for 8 weeks with a 44-week extension period. Dose up-titration for efficacy reasons could be made after 12 weeks of treatment up to 10 mg.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Seladelpar
    Investigational medicinal product code
    Other name
    MBX-8025
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Seladelpar capsules taken once a day (QD) orally in initial treatment period and dose adjusted as necessary in the extension period. Dose up-titration up to 10 mg for efficacy reasons could be made after 12 weeks of treatment.

    Arm title
    		 Seladelpar 5 mg
    Arm description
    		 Subjects were randomized to receive one seladelpar 5 mg capsule orally once daily for 8 weeks with a 44-week extension period. Dose up-titration to 10 mg for efficacy reasons could be made after 12 weeks of treatment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Seladelpar
    Investigational medicinal product code
    Other name
    MBX-8025
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Seladelpar capsules taken QD orally in initial treatment period and dose adjusted as necessary in the extension period. Dose up-titration for efficacy reasons could be made after 12 weeks of treatment to up to 10 mg.

    Arm title
    		 Seladelpar 10 mg
    Arm description
    		 Subjects were randomized to receive one seladelpar 10 mg capsule orally once daily for 8 weeks with a 44-week extension period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Seladelpar
    Investigational medicinal product code
    Other name
    MBX-8025
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Seladelpar capsules taken QD orally in initial treatment period and dose adjusted as necessary in the extension period

    Number of subjects in period 1
    		Seladelpar 2 mg Seladelpar 5 mg Seladelpar 10 mg
    Started
    11
    53
    55
    Completed
    10
    46
    49
    Not completed
    1
    7
    6
         Consent withdrawn by subject
    1
    3
    2
         Adverse event, non-fatal
    -
    3
    -
         Study entry with violation of protocol
    -
    -
    3
         Confirmed Paget's Disease
    -
    1
    -
         Lost to follow-up
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Seladelpar 2 mg
    Reporting group description
    		 Subjects received two seladelpar 1 mg capsules orally once daily for 8 weeks with a 44-week extension period. Dose up-titration for efficacy reasons could be made after 12 weeks of treatment up to 10 mg.

    Reporting group title
    Seladelpar 5 mg
    Reporting group description
    		 Subjects were randomized to receive one seladelpar 5 mg capsule orally once daily for 8 weeks with a 44-week extension period. Dose up-titration to 10 mg for efficacy reasons could be made after 12 weeks of treatment.

    Reporting group title
    Seladelpar 10 mg
    Reporting group description
    		 Subjects were randomized to receive one seladelpar 10 mg capsule orally once daily for 8 weeks with a 44-week extension period.

    Reporting group values
    		 Seladelpar 2 mg Seladelpar 5 mg Seladelpar 10 mg Total
    Number of subjects
    		 11 53 55 119
    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)
    		 8 41 41 90
        From 65-84 years
    		 3 12 14 29
        85 years and over
    		 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 55.2 ± 9.6 57.5 ± 8.1 57.4 ± 9.7 -
    Gender categorical
    Units: Subjects
        Female
    		 11 51 50 112
        Male
    		 0 2 5 7
    Race
    Units: Subjects
        White
    		 10 50 49 109
        Black or African-American
    		 0 1 3 4
        Asian
    		 0 2 1 3
        American Indian or Alaska native
    		 0 0 1 1
        Native Hawaiian or other Pacific Islander
    		 0 0 0 0
        Other
    		 1 0 0 1
        Multiple
    		 0 0 1 1

    End points

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    End points reporting groups
    Reporting group title
    Seladelpar 2 mg
    Reporting group description
    		 Subjects received two seladelpar 1 mg capsules orally once daily for 8 weeks with a 44-week extension period. Dose up-titration for efficacy reasons could be made after 12 weeks of treatment up to 10 mg.

    Reporting group title
    Seladelpar 5 mg
    Reporting group description
    		 Subjects were randomized to receive one seladelpar 5 mg capsule orally once daily for 8 weeks with a 44-week extension period. Dose up-titration to 10 mg for efficacy reasons could be made after 12 weeks of treatment.

    Reporting group title
    Seladelpar 10 mg
    Reporting group description
    		 Subjects were randomized to receive one seladelpar 10 mg capsule orally once daily for 8 weeks with a 44-week extension period.

    Primary: Relative Change from Baseline in Serum Alkaline Phosphatase (ALP) Levels at Week 8 (Endpoint)

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    End point title
    		 Relative Change from Baseline in Serum Alkaline Phosphatase (ALP) Levels at Week 8 (Endpoint)
    End point description
    Relative change from baseline is in serum ALP levels at Week 8 (endpoint). The modified Intent-to-Treat (mITT) analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment. n, denotes number of subjects evaluable for the respective timepoints
    End point type
    Primary
    End point timeframe
    Week 8 (Endpoint)
    End point values
    		 Seladelpar 2 mg Seladelpar 5 mg Seladelpar 10 mg
    Number of subjects analysed
    11
    49
    52
    Units: Percent Change
    arithmetic mean (standard deviation)
        Percent change (n= 11, 47, 51)
    -26.06 ± 9.15
    -33.38 ± 17.81
    -41.42 ± 13.05
    Statistical analysis title
    		 Statistical Analysis 1, 5 mg vs 2 mg
    Statistical analysis description
    The analyses will assess the change from baseline in each treatment group and will assess the hypothesis that there are no differences in the percent change in ALP serum level between seladelpar 2 mg and 5 mg treatment groups after 8 weeks of treatment
    Comparison groups
    Seladelpar 2 mg v Seladelpar 5 mg
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.2242
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Statistical Analysis 2, 2 mg vs 10 mg
    Statistical analysis description
    The analyses will assess the change from baseline in each treatment group and will assess the hypothesis that there are no differences in the percent change in ALP serum level between seladelpar 2 mg and 10 mg treatment groups after 8 weeks of treatment.
    Comparison groups
    Seladelpar 2 mg v Seladelpar 10 mg
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.0021
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Statistical Analysis 3, 5 mg vs 10 mg
    Statistical analysis description
    The analyses will assess the change from baseline in each treatment group and will assess the hypothesis that there are no differences in the percent change in ALP serum level between seladelpar 5 mg and 10 mg treatment groups after 8 weeks of treatment.
    Comparison groups
    Seladelpar 5 mg v Seladelpar 10 mg
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.0024
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Absolute Change in Serum Alkaline Phosphatase (ALP) Levels from Baseline to Weeks 12 and 52 (Endpoint)

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    End point title
    		 Absolute Change in Serum Alkaline Phosphatase (ALP) Levels from Baseline to Weeks 12 and 52 (Endpoint)
    End point description
    Absolute change in ALP from baseline to Weeks 12 and 52 The mITT analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment. n, denotes number of subjects evaluable for the respective timepoints
    End point type
    Secondary
    End point timeframe
    Weeks 12 and 52 (Endpoint)
    End point values
    		 Seladelpar 2 mg Seladelpar 5 mg Seladelpar 10 mg
    Number of subjects analysed
    11
    49
    52
    Units: Absolute Change
    arithmetic mean (standard deviation)
        Absolute Change at Week 12 (n= 11, 46, 49)
    -68.318 ± 63.276
    -135.902 ± 150.954
    -127.867 ± 60.284
        Absolute Change at Week 52 (n= 10, 42, 48)
    -101.150 ± 107.956
    -158.310 ± 143.668
    -133.760 ± 76.151
    No statistical analyses for this end point

    Secondary: Relative Change from Baseline in Serum Alkaline Phosphatase (ALP) Levels at Weeks 12 and 52 (Endpoint)

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    End point title
    		 Relative Change from Baseline in Serum Alkaline Phosphatase (ALP) Levels at Weeks 12 and 52 (Endpoint)
    End point description
    Mean percent change in ALP from baseline to Weeks 12 and 52 (Endpoint) The mITT analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment. n, denotes number of subjects evaluable for the respective timepoints
    End point type
    Secondary
    End point timeframe
    Weeks 12 and 52 (Endpoint)
    End point values
    		 Seladelpar 2 mg Seladelpar 5 mg Seladelpar 10 mg
    Number of subjects analysed
    11
    49
    52
    Units: Percent Change
    arithmetic mean (standard deviation)
        Percent Change at Week 12 (n= 11, 47, 51)
    -22.56 ± 13.92
    -34.49 ± 20.62
    -43.20 ± 12.39
        Percent Change at Week 52 (n= 11, 45, 49)
    -32.72 ± 22.48
    -40.09 ± 24.23
    -44.19 ± 15.52
    Statistical analysis title
    		 Statistical Analysis 1, 5 mg vs 2 mg (12 weeks)
    Statistical analysis description
    The analyses will assess the percent change from baseline in each treatment group and will assess the hypothesis that there are no differences in the percent change in ALP serum level between seladelpar 2 mg and 5 mg treatment groups after 12 weeks of treatment.
    Comparison groups
    Seladelpar 2 mg v Seladelpar 5 mg
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.0493
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Statistical Analysis 2, 2 mg vs 10 mg (12 weeks)
    Statistical analysis description
    The analyses will assess the percent change from baseline in each treatment group and will assess the hypothesis that there are no differences in the percent change in ALP serum level between seladelpar 2 mg and 10 mg treatment groups after 12 weeks of treatment.
    Comparison groups
    Seladelpar 10 mg v Seladelpar 2 mg
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.0003
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Statistical Analysis 3, 5 mg vs 10 mg (12 weeks)
    Statistical analysis description
    The analyses will assess the percent change from baseline in each treatment group and will assess the hypothesis that there are no differences in the percent change in ALP serum level between seladelpar 5 mg vs 10 mg treatment groups after 12 weeks of treatment.
    Comparison groups
    Seladelpar 5 mg v Seladelpar 10 mg
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.0053
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Statistical Analysis 4, 2 mg vs 5 mg (52 weeks)
    Statistical analysis description
    The analyses will assess the percent change from baseline in each treatment group and will assess the hypothesis that there are no differences in the percent change in ALP serum level between seladelpar 2 mg and 5 mg treatment groups after 52 weeks of treatment.
    Comparison groups
    Seladelpar 2 mg v Seladelpar 5 mg
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.3466
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Statistical Analysis 5, 2 mg vs 10 mg (52 weeks)
    Statistical analysis description
    The analyses will assess the percent change from baseline in each treatment group and will assess the hypothesis that there are no differences in the percent change in ALP serum level between seladelpar 2 mg vs 10 mg treatment groups after 52 weeks of treatment.
    Comparison groups
    Seladelpar 2 mg v Seladelpar 10 mg
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.0949
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Statistical Analysis 6, 5 mg vs 10 mg (52 weeks)
    Statistical analysis description
    The analyses will assess the percent change from baseline in each treatment group and will assess the hypothesis that there are no differences in the percent change in ALP serum level between seladelpar 5 mg vs 10 mg treatment groups after 52 weeks of treatment.
    Comparison groups
    Seladelpar 5 mg v Seladelpar 10 mg
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.251
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Percentage of Subjects with Response Defined by Composite Risk Scores (ALP< 1.67 x Upper Limit of Normal [ULN] at Endpoint, Total Bilirubin [BIL] Within Normal Limits at Endpoint, and Greater Than Equal To [≥] 15% ALP Reduction from Baseline to Endpoint

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    End point title
    		 Percentage of Subjects with Response Defined by Composite Risk Scores (ALP< 1.67 x Upper Limit of Normal [ULN] at Endpoint, Total Bilirubin [BIL] Within Normal Limits at Endpoint, and Greater Than Equal To [≥] 15% ALP Reduction from Baseline to Endpoint
    End point description
    Reporting was done for percentage of subjects with response defined by Composite Risk Scores (ALP Less than [<] 1.67 x ULN at endpoint, Total BIL within normal limits at endpoint, and ≥15% ALP reduction from baseline to Endpoint). The mITT analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment. The mITT analysis was performed in a manner similar to primary endpoint. n, denotes number of subjects evaluable for the respective timepoints
    End point type
    Secondary
    End point timeframe
    12 Weeks and 52 Weeks
    End point values
    		 Seladelpar 2 mg Seladelpar 5 mg Seladelpar 10 mg
    Number of subjects analysed
    11
    49
    52
    Units: Percentage of subjects
    number (not applicable)
        Week 12 (n= 11, 47, 51)
    45.5
    48.9
    66.7
        Week 52 (n= 11, 45, 49)
    63.6
    53.3
    67.3
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Response Based on PARIS I Risk Score at Weeks 12 and 52 (Endpoint)

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    End point title
    		 Percentage of Subjects with Response Based on PARIS I Risk Score at Weeks 12 and 52 (Endpoint)
    End point description
    Percentage of subjects with response based on Paris I risk score was defined as ALP less than or equal to (≤) 3x ULN and aspartate aminotransferase (AST) less than or equal to (≤) 2 x ULN and Total Bilirubin ≤ 1 mg/dL. The mITT analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment. n, denotes number of subjects evaluable for the respective timepoints
    End point type
    Secondary
    End point timeframe
    At Weeks 12, 52 (Endpoint)
    End point values
    		 Seladelpar 2 mg Seladelpar 5 mg Seladelpar 10 mg
    Number of subjects analysed
    11
    49
    52
    Units: Percentage of subjects
    number (not applicable)
        Week 12 (n=9, 35, 37)
    81.8
    76.1
    75.5
        Week 52 (n=9, 34, 38)
    90
    81.0
    79.2
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Response Based on PARIS II Risk Score at Weeks 12 and 52 (Endpoint)

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    End point title
    		 Percentage of Subjects with Response Based on PARIS II Risk Score at Weeks 12 and 52 (Endpoint)
    End point description
    Percentage of subjects with response based on Paris II risk score was defined as ALP≤1.5xULN and AST≤1.5xULN and Total Bilirubin ≤ 1 mg/dL. The mITT analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment. n, denotes number of subjects evaluable for the respective timepoints
    End point type
    Secondary
    End point timeframe
    At Weeks 12 and 52 (Endpoint)
    End point values
    		 Seladelpar 2 mg Seladelpar 5 mg Seladelpar 10 mg
    Number of subjects analysed
    11
    49
    52
    Units: Percentage of subjects
    number (not applicable)
        Week 12 (n=4, 17, 29)
    36.4
    37.0
    59.2
        Week 52 (n=5, 23, 29)
    50.0
    54.8
    60.4
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Response Based on Toronto I Risk Score at Weeks 12 and 52 (Endpoint)

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    End point title
    		 Percentage of Subjects with Response Based on Toronto I Risk Score at Weeks 12 and 52 (Endpoint)
    End point description
    Percentage of subjects with response based on Toronto I risk score defined as ALP ≤ 1.67 x ULN. The mITT analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment. n, denotes number of subjects evaluable for the respective timepoints
    End point type
    Secondary
    End point timeframe
    At Weeks 12 and 52 (Endpoint)
    End point values
    		 Seladelpar 2 mg Seladelpar 5 mg Seladelpar 10 mg
    Number of subjects analysed
    11
    49
    52
    Units: Percentage of subjects
    number (not applicable)
        Week 12 (n=7, 24, 40)
    63.6
    51.1
    78.4
        Week 52 (n=7, 26, 35)
    63.6
    57.8
    71.4
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Response Based on Barcelona Risk Score at Weeks 12 and 52 (Endpoint)

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    End point title
    		 Percentage of Subjects with Response Based on Barcelona Risk Score at Weeks 12 and 52 (Endpoint)
    End point description
    Percentage of subjects with response based on Barcelona risk scores was defined as Normalization of ALP or a Decrease of ALP ≥ 40%. The mITT analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment. . n, denotes number of subjects evaluable for the respective timepoints
    End point type
    Secondary
    End point timeframe
    At Weeks 12 and 52 (Endpoint)
    End point values
    		 Seladelpar 2 mg Seladelpar 5 mg Seladelpar 10 mg
    Number of subjects analysed
    11
    49
    52
    Units: Percentage of subjects
    number (not applicable)
        Week 12 (n=1, 20, 32)
    9.1
    42.6
    62.7
        Week 52 (n=5, 30, 32)
    45.5
    66.7
    65.3
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Response Based on Rotterdam Risk Score at Weeks 12 and 52 (Endpoint)

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    End point title
    		 Percentage of Subjects with Response Based on Rotterdam Risk Score at Weeks 12 and 52 (Endpoint)
    End point description
    Percentage of subjects with response based on Rotterdam risk scores was defined in terms of populations of early stage (normal Total Bilirubin and normal Albumin), moderately advanced stage (either abnormal Albumin or abnormal Total Bilirubin), and advanced stages (both abnormal Albumin and abnormal Total Bilirubin). The mITT analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment. n, denotes number of subjects evaluable for the respective timepoints
    End point type
    Secondary
    End point timeframe
    At Weeks 12 and 52 (Endpoint)
    End point values
    		 Seladelpar 2 mg Seladelpar 5 mg Seladelpar 10 mg
    Number of subjects analysed
    11
    49
    52
    Units: Percentage of subjects
    number (not applicable)
        Early Stage (12 Weeks, n=11, 36, 42)
    100
    82.6
    81.6
        Early Stage (52 weeks, n=10, 36, 42)
    100
    85.7
    87.5
        Moderately Advanced Stage (12 weeks, n=0, 7, 9)
    0
    15.2
    18.4
        Moderately Advanced Stage (52 weeks, n=0, 3, 5)
    0
    7.1
    18.4
        Advanced Stage (12 weeks, n=0, 1, 0)
    0
    2.2
    0
        Advanced Stage (52 weeks, n=0, 3, 1)
    0
    7.1
    2.1
    No statistical analyses for this end point

    Secondary: Change from Baseline in Total bilirubin (TB) Levels at Weeks 12 and 52 (Endpoint)

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    End point title
    		 Change from Baseline in Total bilirubin (TB) Levels at Weeks 12 and 52 (Endpoint)
    End point description
    Change from baseline in TB levels at endpoint is being reported. The mITT analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment. n, denotes number of subjects evaluable for the respective timepoints
    End point type
    Secondary
    End point timeframe
    Weeks 12 and 52 (Endpoint)
    End point values
    		 Seladelpar 2 mg Seladelpar 5 mg Seladelpar 10 mg
    Number of subjects analysed
    11
    49
    52
    Units: mg/dL
    arithmetic mean (standard deviation)
        Week 12 (n= 11, 46, 49)
    -0.010 ± 0.121
    -0.055 ± 0.161
    -0.067 ± 0.199
        Week 52 (n= 10, 42, 48)
    0.002 ± 0.152
    -0.028 ± 0.263
    -0.068 ± 0.190
    No statistical analyses for this end point

    Secondary: Change from Baseline in Aspartate Aminotransferase (AST) Levels at Weeks 12 and 52 (Endpoint)

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    End point title
    		 Change from Baseline in Aspartate Aminotransferase (AST) Levels at Weeks 12 and 52 (Endpoint)
    End point description
    Change from baseline in AST levels at endpoint was reported. The mITT analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment. n, denotes number of subjects evaluable for the respective timepoints
    End point type
    Secondary
    End point timeframe
    Weeks 12, 52 (Endpoint)
    End point values
    		 Seladelpar 2 mg Seladelpar 5 mg Seladelpar 10 mg
    Number of subjects analysed
    11
    49
    52
    Units: U/L
    arithmetic mean (standard deviation)
        Week 12 (n= 11, 46, 49)
    -2.50 ± 16.72
    -1.13 ± 24.28
    -3.35 ± 10.55
        Week 52 (n= 10, 42, 48)
    -7.05 ± 10.50
    -6.18 ± 13.98
    -6.14 ± 9.18
    No statistical analyses for this end point

    Secondary: Change from Baseline in Alanine Aminotransferase (ALT) Levels at Weeks 12 and 52 (Endpoint)

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    End point title
    		 Change from Baseline in Alanine Aminotransferase (ALT) Levels at Weeks 12 and 52 (Endpoint)
    End point description
    Change from baseline in ALT levels at endpoint was reported. The mITT analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment. n, denotes number of subjects evaluable for the respective timepoints
    End point type
    Secondary
    End point timeframe
    Weeks 12 and 52 (Endpoint)
    End point values
    		 Seladelpar 2 mg Seladelpar 5 mg Seladelpar 10 mg
    Number of subjects analysed
    11
    49
    52
    Units: U/L
    arithmetic mean (standard deviation)
        Week 12 (n= 11, 46, 49)
    -5.59 ± 16.07
    -10.48 ± 21.41
    -10.87 ± 20.25
        Week 52 (n= 10, 42, 48)
    -14.30 ± 25.12
    -17.29 ± 17.46
    -15.32 ± 13.89
    No statistical analyses for this end point

    Secondary: Change from Baseline in Gamma-glutamyl Transferase (GGT) Levels at Weeks 12 and 52 (Endpoint)

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    End point title
    		 Change from Baseline in Gamma-glutamyl Transferase (GGT) Levels at Weeks 12 and 52 (Endpoint)
    End point description
    Change from baseline in GGT levels at endpoint was reported. The mITT analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment. n, denotes number of subjects evaluable for the respective timepoints
    End point type
    Secondary
    End point timeframe
    Weeks 12 and 52 (Endpoint)
    End point values
    		 Seladelpar 2 mg Seladelpar 5 mg Seladelpar 10 mg
    Number of subjects analysed
    11
    49
    52
    Units: U/L
    arithmetic mean (standard deviation)
        Week 12 (n= 11, 46, 49)
    -43.68 ± 56.87
    -75.35 ± 87.57
    -80.82 ± 109.06
        Week 52 (n= 10, 42, 48)
    -78.60 ± 81.59
    -91.37 ± 102.23
    -88.08 ± 122.14
    No statistical analyses for this end point

    Secondary: Change from Baseline in Model for End-stage Liver Disease (MELD) score at Weeks 12 and 52 (Endpoint)

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    End point title
    		 Change from Baseline in Model for End-stage Liver Disease (MELD) score at Weeks 12 and 52 (Endpoint)
    End point description
    The prognostic model for estimating disease severity and survival was utilized for subjects by assessing the Model for End-stage Liver Disease (MELD) score. To calculate the MELD score, samples for creatinine, bilirubin, international normalized ratio (INR), and sodium values were taken as specified in assessment schedule. The MELD scores were calculated as per following formulae: MELD(i) score = 10×(0.957×ln[creatinine, mg/dL]+0.378×ln[bilirubin, mg/dL]+1.120×ln[INR] + 0.643). If MELD(i) is less than or equal to 11 then MELD score = MELD(i). If MELD(i) is greater than 11 then MELD score = MELD(i) + (1.32 *(137 - (Na)) – (0.033*MELD(i)*(137 – Na)) The mITT analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment. mITT, included population; n, denotes number of subjects evaluable for the respective timepoints
    End point type
    Secondary
    End point timeframe
    Weeks 12 and 52 (Endpoint)
    End point values
    		 Seladelpar 2 mg Seladelpar 5 mg Seladelpar 10 mg
    Number of subjects analysed
    11
    49
    52
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Week 12 (n= 11, 46, 48)
    -0.3 ± 1.6
    0.1 ± 1.2
    0.1 ± 1.0
        Week 52 (n= 10, 42, 48)
    -0.7 ± 1.6
    0.3 ± 1.1
    0.2 ± 1.2
    No statistical analyses for this end point

    Secondary: Change from Baseline in Global PBC Study Group (GLOBE) score at Weeks 12 and 52 (Endpoint)

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    End point title
    		 Change from Baseline in Global PBC Study Group (GLOBE) score at Weeks 12 and 52 (Endpoint)
    End point description
    The Global PBC Study Group (GLOBE) score was assessed using the validated tool to accurately stratify patients into high- and low- risk for liver transplantation or death at 12 months of ursodeoxycholic acid (UDCA) treatment. Samples for bilirubin, ALP, albumin, and platelet count determination were used as per specifications to calculate the GLOBE score. Formula used : (0.044378×age+0.93982×ln[total bilirubin/ULN]+[0.335648×ln(alkaline phosphatase/ULN)]-2.266708×albumin /LLN-0.002581×platelet count per 109/L)+1.216865. The modified Intent-to-Treat (mITT) analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment. mITT, included population; n, denotes number of subjects evaluable for the respective timepoints
    End point type
    Secondary
    End point timeframe
    Weeks 12 and 52 (Endpoint)
    End point values
    		 Seladelpar 2 mg Seladelpar 5 mg Seladelpar 10 mg
    Number of subjects analysed
    11
    53
    55
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Week 12 (n= 10, 43, 46)
    -0.079 ± 0.260
    -0.292 ± 0.304
    -0.346 ± 0.269
        Week 52 (n= 9, 37, 43)
    -0.180 ± 0.217
    -0.271 ± 0.354
    -0.404 ± 0.298
    No statistical analyses for this end point

    Secondary: Risk as Assessed by United Kingdom-Primary Biliary Cholangitis (UK-PBC) Score at Weeks 12 and 52 (Endpoint)

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    End point title
    		 Risk as Assessed by United Kingdom-Primary Biliary Cholangitis (UK-PBC) Score at Weeks 12 and 52 (Endpoint)
    End point description
    The UK-PBC Risk Score at endpoint is defined by the mean percentage risk that a PBC patient treated with ursodeoxycholic acid (UDCA) would develop liver failure requiring liver transplantation in 5, 10 and 15 years from diagnosis. Formula used for UK-PBC risk score = 1- 0.982 ^EXP(0.0287854*(AP12 x ULN-1.722136304) - 0.0422873*(((TA12 xULN/10)^-1) - 8.675729006) + 1.4199 * (LN(BIL12 x ULN/10)+2.709607778)-1.960303*(Albumin x LLN-1.17673001)-0.4161954*(Platelet x LLN-1.873564875)). Where, Baseline survivor function = 0.982, 0.941, and 0.893 for 5 years, 10 years and 15 years respectively. AP12, TA12 and BIL12 refers to the AP, transaminases (ALT, AST), and total bilirubin assessments, respectively. The modified Intent-to-Treat (mITT) analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment. mITT, included population; n, denotes number of subjects evaluable for timepoint
    End point type
    Secondary
    End point timeframe
    Weeks 12 and 52 (Endpoint)
    End point values
    		 Seladelpar 2 mg Seladelpar 5 mg Seladelpar 10 mg
    Number of subjects analysed
    11
    49
    52
    Units: Units on a scale
    arithmetic mean (standard deviation)
        5 years (week 12, n= 11, 44, 48)
    1.3929 ± 0.6976
    2.2553 ± 2.5145
    1.8124 ± 1.7267
        5 years (week 52, n= 10, 40, 47)
    1.3145 ± 0.7704
    2.3485 ± 3.4325
    1.7244 ± 1.6121
        10 years (week 12, n= 11, 44, 48)
    4.5705 ± 2.2479
    7.1229 ± 7.4904
    5.8293 ± 5.3605
        10 years (week 52, n= 10, 40, 47)
    4.3128 ± 2.4649
    7.2322 ± 9.5794
    5.5607 ± 5.0092
        15 years (week 12, n= 11, 44, 48)
    8.3008 ± 3.9932
    12.4002 ± 12.1785
    10.3469 ± 9.1269
        15 years (week 52, n= 10, 40, 47)
    7.8325 ± 4.3413
    12.3028 ± 14.5701
    9.9008 ± 8.5396
    No statistical analyses for this end point

    Secondary: Change from Baseline in Pruritus as Assessed by Visual Analogue Scale (VAS) Total Score at Weeks 12 and 52 (Endpoint)

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    End point title
    		 Change from Baseline in Pruritus as Assessed by Visual Analogue Scale (VAS) Total Score at Weeks 12 and 52 (Endpoint)
    End point description
    VAS is the commonly used graphic tool for self-reporting of pruritus intensity in patients. VAS is a simple to use, validated, reliable and widely applicable too that does not determine the impact of pruritus to quality of life. It comprises of a 100-mm horizontal line labelled as “no symptom” on left end and “worst imaginable symptom” on right end. Based on the intensity of the itch patient is instructed to draw a vertical line on the horizontal scale having a range [VAS values (unit: mm) ranging from 0 to 100, where 0 represents “no itching” and 100 “worst possible itching”]. The modified Intent-to-Treat (mITT) analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment. mITT, included population; n, denotes number of subjects evaluable for the respective timepoints
    End point type
    Secondary
    End point timeframe
    Weeks 12 and 52 (Endpoint)
    End point values
    		 Seladelpar 2 mg Seladelpar 5 mg Seladelpar 10 mg
    Number of subjects analysed
    11
    49
    52
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Week 12 (n= 11, 45, 49)
    -3.7 ± 6.4
    -5.5 ± 25.0
    -12.3 ± 22.3
        Week 52 (n= 10, 42, 48)
    -3.3 ± 11.7
    -9.6 ± 22.5
    -16.5 ± 23.0
    No statistical analyses for this end point

    Secondary: Change from Baseline in Primary Biliary Cholangitis-40 (PBC-40) Quality of Life Questionnaire Scores at Weeks 12 and 52 (Endpoint)

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    End point title
    		 Change from Baseline in Primary Biliary Cholangitis-40 (PBC-40) Quality of Life Questionnaire Scores at Weeks 12 and 52 (Endpoint)
    End point description
    The PBC-40 QoL questionnaire is a disease-specific health-related tool developed for measuring the psychometric profile in PBC patients. It has 10 domains and a 43 questions relevant to PBC, including Cognitive, Social, Emotional Function, Fatigue, Itch, and Other Symptoms. Questions in domains: 1) digestion and diet (questions 1-3); 2) experiences (questions 4-7); 3) itching (questions 8-10); 4) fatigue (questions 11-18); 5) effort and planning (questions 19-21); 6) memory and concentration (questions 22-27); 7) affects to you as person (questions 28-33); 8) affects to your social life (questions 34-37); 9) overall impact on your life (questions 38-40); 10) general health and well-being (questions A-C). Within a domain, items are scored from 1 to 5 and the individual item scores are summed to give a total domain score. High scores represent high impact and low scores low impact of PBC on QoL. mITT, included population; n, number of subjects evaluable at respective timepoint
    End point type
    Secondary
    End point timeframe
    Weeks 12 and 52 (Endpoint)
    End point values
    		 Seladelpar 2 mg Seladelpar 5 mg Seladelpar 10 mg
    Number of subjects analysed
    11
    49
    52
    Units: Units on a scale
    arithmetic mean (standard deviation)
        General Symptoms
    1.9 ± 2.7
    -0.7 ± 5.1
    -0.5 ± 3.6
        Itch
    -0.4 ± 2.0
    -0.5 ± 3.4
    -0.8 ± 3.1
        Fatigue
    -1.5 ± 6.1
    -2.1 ± 10.4
    -3.0 ± 5.2
        Cognitive Function
    -0.9 ± 2.4
    -0.6 ± 5.7
    -0.7 ± 2.8
        Social
    0.8 ± 2.8
    -0.5 ± 7.9
    -1.0 ± 6.3
        Emotional
    -0.9 ± 1.6
    -1.0 ± 2.6
    -0.8 ± 2.1
        General Symptoms, Week 12 (n= 11, 45, 49)
    1.9 ± 2.7
    -0.7 ± 5.1
    -0.5 ± 3.6
        General Symptoms, Week 52 (n= 10, 42, 48)
    0.3 ± 2.4
    -1.4 ± 4.4
    -0.1 ± 4.4
        Itch, Week 12 (n= 11, 45, 49)
    -0.4 ± 2.0
    -0.5 ± 3.4
    -0.8 ± 3.1
        Itch, Week 52 (n= 10, 42, 48)
    0.4 ± 2.7
    -1.3 ± 3.2
    -1.4 ± 3.7
        Fatigue, Week 12 (n= 11, 45, 49)
    -1.5 ± 6.1
    -2.1 ± 10.4
    -3.0 ± 5.2
        Fatigue, Week 52 (n= 10, 42, 48)
    -1.2 ± 7.8
    -3.0 ± 8.5
    -3.4 ± 6.3
        Cognitive Function, Week 12 (n= 11, 45, 49)
    -0.9 ± 2.4
    -0.6 ± 5.7
    -0.7 ± 2.8
        Cognitive Function, Week 52 (n= 10, 42, 48)
    -0.7 ± 7.6
    -1.4 ± 5.3
    -0.6 ± 2.5
        Social, Week 12 (n= 11, 44, 49)
    0.8 ± 2.8
    -0.5 ± 7.9
    -1.0 ± 6.3
        Social, Week 52 (n= 10, 42, 48)
    -3.3 ± 5.2
    -1.6 ± 7.2
    -1.6 ± 6.2
        Emotional, Week 12 (n= 11, 44, 48)
    -0.9 ± 1.6
    -1.0 ± 2.6
    -0.8 ± 2.1
        Emotional, Week 52 (n= 10, 42, 47)
    -2.1 ± 2.3
    -1.3 ± 2.7
    0.9 ± 2.1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to week 56
    Adverse event reporting additional description
    Adverse events
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Seladelpar 2 mg
    Reporting group description
    		 Subjects received seladelpar 2 milligram (mg) capsules orally once daily for 8 weeks with a 44-week extension period. Subjects entered the 44-week extension on their assigned dose. The dose was up-titrated after safety and efficacy data review of the first 8 weeks of treatment. During the extension, a subject's dose may have been re-adjusted for safety or efficacy reasons. The 2 mg group was started after safety and efficacy review of the 5 mg and the 10 mg groups was completed.

    Reporting group title
    Seladelpar 10 mg
    Reporting group description
    		 Subjects were randomized to receive seladelpar 10 milligram (mg) capsules orally once daily for 8 weeks with a 44-week extension period. Subjects entered the 44-week extension on their assigned dose. The dose was up- or down-titrated after safety and efficacy data review of the first 8 weeks of treatment. During the extension, a subject's dose may have been re-adjusted for safety or efficacy reasons.

    Reporting group title
    Seladelpar 5 mg
    Reporting group description
    		 Subjects were randomized to receive seladelpar 5 milligram (mg) capsules orally once daily for 8 weeks with a 44-week extension period. Subjects entered the 44-week extension on their assigned dose. The dose was up- or down-titrated after safety and efficacy data review of the first 8 weeks of treatment. During the extension, a subject's dose may have been re-adjusted for safety or efficacy reasons.

    Serious adverse events
    		 Seladelpar 2 mg Seladelpar 10 mg Seladelpar 5 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 11 (9.09%)
    5 / 55 (9.09%)
    8 / 53 (15.09%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Injury, poisoning and procedural complications
    Femoral neck fracture
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 55 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 55 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 55 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 55 (0.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 55 (1.82%)
    0 / 53 (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
    Atrial fibrillation
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 55 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 55 (1.82%)
    0 / 53 (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
    Pneumonia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 55 (1.82%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyonephrosis
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 55 (1.82%)
    0 / 53 (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
    Syncope
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 55 (1.82%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 55 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 55 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 55 (1.82%)
    0 / 53 (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
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 55 (0.00%)
    1 / 53 (1.89%)
         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
    		 Seladelpar 2 mg Seladelpar 10 mg Seladelpar 5 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    11 / 11 (100.00%)
    47 / 55 (85.45%)
    45 / 53 (84.91%)
    Injury, poisoning and procedural complications
    Diarrhoea
         subjects affected / exposed
    4 / 11 (36.36%)
    9 / 55 (16.36%)
    7 / 53 (13.21%)
         occurrences all number
    4
    9
    7
    Nausea
         subjects affected / exposed
    4 / 11 (36.36%)
    6 / 55 (10.91%)
    9 / 53 (16.98%)
         occurrences all number
    8
    6
    11
    Abdominal pain upper
         subjects affected / exposed
    3 / 11 (27.27%)
    5 / 55 (9.09%)
    7 / 53 (13.21%)
         occurrences all number
    3
    5
    8
    Vomiting
         subjects affected / exposed
    3 / 11 (27.27%)
    5 / 55 (9.09%)
    4 / 53 (7.55%)
         occurrences all number
    3
    5
    6
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 11 (9.09%)
    5 / 55 (9.09%)
    5 / 53 (9.43%)
         occurrences all number
    1
    5
    7
    Abdominal distension
         subjects affected / exposed
    2 / 11 (18.18%)
    4 / 55 (7.27%)
    4 / 53 (7.55%)
         occurrences all number
    2
    4
    4
    Abdominal pain
         subjects affected / exposed
    3 / 11 (27.27%)
    3 / 55 (5.45%)
    3 / 53 (5.66%)
         occurrences all number
    3
    3
    3
    Dry mouth
         subjects affected / exposed
    2 / 11 (18.18%)
    4 / 55 (7.27%)
    2 / 53 (3.77%)
         occurrences all number
    2
    4
    2
    Dyspepsia
         subjects affected / exposed
    3 / 11 (27.27%)
    1 / 55 (1.82%)
    2 / 53 (3.77%)
         occurrences all number
    3
    1
    4
    Urinary tract infection
         subjects affected / exposed
    1 / 11 (9.09%)
    8 / 55 (14.55%)
    8 / 53 (15.09%)
         occurrences all number
    2
    12
    11
    Nasopharyngitis
         subjects affected / exposed
    4 / 11 (36.36%)
    6 / 55 (10.91%)
    5 / 53 (9.43%)
         occurrences all number
    5
    9
    7
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 11 (9.09%)
    3 / 55 (5.45%)
    5 / 53 (9.43%)
         occurrences all number
    1
    3
    6
    Influenza
         subjects affected / exposed
    0 / 11 (0.00%)
    2 / 55 (3.64%)
    5 / 53 (9.43%)
         occurrences all number
    0
    2
    5
    Bronchitis
         subjects affected / exposed
    0 / 11 (0.00%)
    3 / 55 (5.45%)
    3 / 53 (5.66%)
         occurrences all number
    0
    3
    3
    Pruritus
         subjects affected / exposed
    6 / 11 (54.55%)
    12 / 55 (21.82%)
    11 / 53 (20.75%)
         occurrences all number
    9
    12
    13
    Arthralgia
         subjects affected / exposed
    1 / 11 (9.09%)
    7 / 55 (12.73%)
    6 / 53 (11.32%)
         occurrences all number
    1
    8
    6
    Back pain
         subjects affected / exposed
    3 / 11 (27.27%)
    3 / 55 (5.45%)
    5 / 53 (9.43%)
         occurrences all number
    3
    3
    5
    Myalgia
         subjects affected / exposed
    0 / 11 (0.00%)
    2 / 55 (3.64%)
    5 / 53 (9.43%)
         occurrences all number
    0
    2
    6
    Muscle spasms
         subjects affected / exposed
    1 / 11 (9.09%)
    2 / 55 (3.64%)
    3 / 53 (5.66%)
         occurrences all number
    1
    2
    6
    Musculoskeletal pain
         subjects affected / exposed
    1 / 11 (9.09%)
    4 / 55 (7.27%)
    1 / 53 (1.89%)
         occurrences all number
    1
    5
    1
    Fatigue
         subjects affected / exposed
    3 / 11 (27.27%)
    6 / 55 (10.91%)
    9 / 53 (16.98%)
         occurrences all number
    3
    6
    10
    Headache
         subjects affected / exposed
    2 / 11 (18.18%)
    3 / 55 (5.45%)
    6 / 53 (11.32%)
         occurrences all number
    5
    3
    9
    Dizziness
         subjects affected / exposed
    2 / 11 (18.18%)
    3 / 55 (5.45%)
    5 / 53 (9.43%)
         occurrences all number
    2
    3
    5
    Cough
         subjects affected / exposed
    2 / 11 (18.18%)
    3 / 55 (5.45%)
    4 / 53 (7.55%)
         occurrences all number
    2
    3
    4
    Oropharyngeal pain
         subjects affected / exposed
    2 / 11 (18.18%)
    4 / 55 (7.27%)
    1 / 53 (1.89%)
         occurrences all number
    2
    4
    2
    Dry eye
         subjects affected / exposed
    2 / 11 (18.18%)
    4 / 55 (7.27%)
    1 / 53 (1.89%)
         occurrences all number
    2
    4
    1

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Feb 2017
    •Enrollment in the 5 and 10 mg dose groups was changed from ~12 to ~18 subjects each. Subjects in the 2 mg (n ~ 6) and 20 mg (n ~ 12) dose groups were to be registered in the study. •Because of the level of activity observed in the 5 and 10 mg dose groups at Interim Analysis 1, the 2 mg dose group was added and the next highest dose was decreased from 25 mg to 20 mg to limit exposure to seladelpar. •Dose titration options for the extension period were changed from 5, 10, and 25 mg to 1, 2, 5, 10, 15, and 20 mg. •microRNA-122 was added as a biomarker of liver disease.
    25 Apr 2017
    •After Interim Analysis 2, the extension period was changed from 18 to 44 weeks, and the treatment period was extended from 26 to 52 weeks. The total study duration (8 weeks’ initial treatment + extension period + 4 weeks’ follow-up) was extended from 30 to 56 weeks. •An exclusion criterion was added: total bilirubin > ULN and albumin < LLN with the exception of subjects with Gilbert’s syndrome. Subjects with Gilbert’s syndrome were to be excluded if direct bilirubin was >ULN. •During the extension period, dose up-titration to above 10 mg could not be performed until interim analysis results were available and the 20 mg dose group was initiated. •Barcelona PBC response criteria were added to outcome measures. •Prohibited systemic steroids were specified as long term (>2 weeks). •Review of medical history was to include history of liver related symptoms. •Physical examinations were to include evaluation of liver related symptoms. •A post-dose adjustment visit was added for subjects whose dose was adjusted at any time during the extension period. •Prothrombin time was removed from laboratory evaluations. •Subjects who withdrew from the study could be replaced.
    17 Jul 2017
    •During the extension period, dose up-titration to above 10 mg was prohibited until interim analysis results were available. •The time for the second 24-hour PK determination was changed from after 2 weeks of treatment to after 12 weeks of treatment. •The size of the 2 mg dose group was changed from ~6 to up to 18 subjects, and the size of the 5 and 10 mg dose groups was changed from ~18 to ~49 subjects each. The size of the 20 mg dose group remained ~12 subjects. •The number of subjects undergoing 24-hour PK determinations was changed from ~3 to up to 6 subjects receiving 2 mg, from ~6 to up to 12 receiving 5 mg, from ~6 to up to 12 receiving 10 mg, and from ~6 to up to 12 receiving 20 mg. •Prohibited systemic steroids were specified as long term (>2 weeks). •Review of medical history was to include history of liver related symptoms. •Physical examinations were to include evaluation of liver related symptoms. •A post-dose adjustment visit was added for subjects whose dose was adjusted at any time during the extension period.
    20 Jul 2017
    •The 20 mg dose was removed. •Dose up-titration to 15 mg could take place only within 26 weeks of treatment. Beyond 26 weeks the highest dose was to be 10 mg. •The time for the second 24-hour PK determination was changed from after 2 weeks of treatment to after 12 weeks of treatment. •The size of the 2 mg dose group was changed from ~6 to up to 18 subjects, and the size of the 5 and 10 mg dose groups was changed from ~18 to ~49 subjects each. •The number of subjects undergoing 24-hour PK determinations was changed from ~3 to up to 6 subjects receiving 2 mg, from ~6 to up to 12 receiving 5 mg, and from ~6 to up to 12 receiving 10 mg.

    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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