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    Clinical Trial Results:
    Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Effects of EP547 in Subjects with Cholestatic Pruritus Due to Primary Biliary Cholangitis or Primary Sclerosing Cholangitis

    Summary
    EudraCT number
    		 2021-002526-25
    Trial protocol
    		 FR   ES  
    Global end of trial date
    05 Sep 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    31 Jul 2025
    First version publication date
    31 Jul 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    EP-547-201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Escient Pharmaceuticals
    Sponsor organisation address
    10578 Science Center Drive, Suite 250, San Diego, United States, 92121
    Public contact
    Kristin Taylor, Sr VP, Head of Clinical Development, Escient Pharmaceuticals, 1 858 6178220, clinicaltrials@escientpharma.com
    Scientific contact
    Kristin Taylor, Sr VP, Head of Clinical Development, Escient Pharmaceuticals, 1 858 6178220, clinicaltrials@escientpharma.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
    05 Sep 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Sep 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This study was conducted to assess the efficacy of EP547 compared to placebo on pruritus as assessed by the Worst Itch Numeric Rating Scale (WI-NRS).
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles of Good Clinical Practice, according to the International Council for Harmonisation Guidelines.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 Nov 2022
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 34
    Country: Number of subjects enrolled
    Canada: 6
    Country: Number of subjects enrolled
    United Kingdom: 8
    Country: Number of subjects enrolled
    Belgium: 4
    Country: Number of subjects enrolled
    France: 3
    Country: Number of subjects enrolled
    Spain: 3
    Country: Number of subjects enrolled
    Israel: 2
    Country: Number of subjects enrolled
    Netherlands: 1
    Worldwide total number of subjects
    61
    EEA total number of subjects
    11
    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)
    53
    From 65 to 84 years
    8
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Participants were enrolled at 29 study sites across the United States, United Kingdom, France, Spain, Canada, Israel, Belgium, and the Netherlands.

    Period 1
    Period 1 title
    DB Treatment Period (Weeks 1-6)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Data analyst

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo 100 mg QD; EP547 100 mg QD
    Arm description
    		 Participants were randomized to receive oral placebo 100 mg QD for 6 weeks in the Double-Blind (DB) Treatment Period. Participants who completed the Double-Blind Treatment Period and were still receiving study drug switched to oral EP547 100 mg QD for 6 weeks in the Open-Label Extension Period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    25 mg tablets

    Investigational medicinal product name
    EP547
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    25 mg tablets

    Arm title
    		 EP547 100 mg QD; EP547 100 mg QD
    Arm description
    		 Participants were randomized to receive oral EP547 100 milligrams (mg) once daily (QD) for 6 weeks in the Double-Blind Treatment Period. Participants who completed the Double-Blind Treatment Period and were still receiving study drug received oral EP547 100 mg QD for an additional 6 weeks in the Open-Label Extension Period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    EP547
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    25 mg tablets

    Number of subjects in period 1
    		Placebo 100 mg QD; EP547 100 mg QD EP547 100 mg QD; EP547 100 mg QD
    Started
    30
    31
    Completed
    29
    29
    Not completed
    1
    2
         Consent withdrawn by subject
    -
    1
         Protocol deviation
    1
    1
    Period 2
    Period 2 title
    Open-label Extension Period (Weeks 7-12)
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo 100 mg QD; EP547 100 mg QD
    Arm description
    		 Participants were randomized to receive oral placebo 100 mg QD for 6 weeks in the Double-Blind (DB) Treatment Period. Participants who completed the Double-Blind Treatment Period and were still receiving study drug switched to oral EP547 100 mg QD for 6 weeks in the Open-Label Extension Period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    25 mg tablets

    Arm title
    		 EP547 100 mg QD; EP547 100 mg QD
    Arm description
    		 Participants were randomized to receive oral EP547 100 milligrams (mg) once daily (QD) for 6 weeks in the Double-Blind Treatment Period. Participants who completed the Double-Blind Treatment Period and were still receiving study drug received oral EP547 100 mg QD for an additional 6 weeks in the Open-Label Extension Period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    EP547
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    25 mg tablets

    Number of subjects in period 2
    		Placebo 100 mg QD; EP547 100 mg QD EP547 100 mg QD; EP547 100 mg QD
    Started
    29
    29
    Completed
    29
    29

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo 100 mg QD; EP547 100 mg QD
    Reporting group description
    		 Participants were randomized to receive oral placebo 100 mg QD for 6 weeks in the Double-Blind (DB) Treatment Period. Participants who completed the Double-Blind Treatment Period and were still receiving study drug switched to oral EP547 100 mg QD for 6 weeks in the Open-Label Extension Period.

    Reporting group title
    EP547 100 mg QD; EP547 100 mg QD
    Reporting group description
    		 Participants were randomized to receive oral EP547 100 milligrams (mg) once daily (QD) for 6 weeks in the Double-Blind Treatment Period. Participants who completed the Double-Blind Treatment Period and were still receiving study drug received oral EP547 100 mg QD for an additional 6 weeks in the Open-Label Extension Period.

    Reporting group values
    		 Placebo 100 mg QD; EP547 100 mg QD EP547 100 mg QD; EP547 100 mg QD Total
    Number of subjects
    		 30 31 61
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 27 26 53
        From 65-84 years
    		 3 5 8
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 50.6 ( 12.99 ) 51.6 ( 12.88 ) -
    Sex: Female, Male
    Units: participants
        Female
    		 24 24 48
        Male
    		 6 7 13
    Race/Ethnicity, Customized
    Units: Subjects
        Asian
    		 0 1 1
        Black or African American
    		 3 3 6
        White
    		 26 25 51
        Asian/White
    		 1 0 1
        American Indian or Alaska Native/White
    		 0 1 1
        North African (Morocco)
    		 0 1 1
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 4 6 10
        Not Hispanic or Latino
    		 25 24 49
        Unknown or Not Reported
    		 1 1 2

    End points

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    End points reporting groups
    Reporting group title
    Placebo 100 mg QD; EP547 100 mg QD
    Reporting group description
    		 Participants were randomized to receive oral placebo 100 mg QD for 6 weeks in the Double-Blind (DB) Treatment Period. Participants who completed the Double-Blind Treatment Period and were still receiving study drug switched to oral EP547 100 mg QD for 6 weeks in the Open-Label Extension Period.

    Reporting group title
    EP547 100 mg QD; EP547 100 mg QD
    Reporting group description
    		 Participants were randomized to receive oral EP547 100 milligrams (mg) once daily (QD) for 6 weeks in the Double-Blind Treatment Period. Participants who completed the Double-Blind Treatment Period and were still receiving study drug received oral EP547 100 mg QD for an additional 6 weeks in the Open-Label Extension Period.
    Reporting group title
    Placebo 100 mg QD; EP547 100 mg QD
    Reporting group description
    		 Participants were randomized to receive oral placebo 100 mg QD for 6 weeks in the Double-Blind (DB) Treatment Period. Participants who completed the Double-Blind Treatment Period and were still receiving study drug switched to oral EP547 100 mg QD for 6 weeks in the Open-Label Extension Period.

    Reporting group title
    EP547 100 mg QD; EP547 100 mg QD
    Reporting group description
    		 Participants were randomized to receive oral EP547 100 milligrams (mg) once daily (QD) for 6 weeks in the Double-Blind Treatment Period. Participants who completed the Double-Blind Treatment Period and were still receiving study drug received oral EP547 100 mg QD for an additional 6 weeks in the Open-Label Extension Period.

    Primary: Change from Baseline in the Worst Itch Numeric Rating Scale (WI-NRS) score up to Week 6

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    End point title
    		 Change from Baseline in the Worst Itch Numeric Rating Scale (WI-NRS) score up to Week 6
    End point description
    Participants were asked to rate the severity of their worst level of itching in the past 24 hours using the daily WI-NRS, an 11-point scale ranging from 0 (no itching) to 10 (worst itching imaginable). Itching severity scores collected via the WI-NRS have been categorized in the as mild (<4), moderate (≥4 to <7), or severe (≥7). The average WI-NRS score using the daily values from the week before the first dose of study drug (including the WI-NRS score captured on Study Day 1 of dosing) served as the Baseline score. A weekly score was determined based on the average of all available daily scores of the week. Change from Baseline was calculated as the post-Baseline score minus the Baseline score. Full Analysis Set: all participants who were randomized and took at least 1 dose of randomized study drug. Participants were analyzed according to randomized treatment assignment. Only participants with available data were analyzed. MMRM=mixed effects model for repeated measures.
    End point type
    Primary
    End point timeframe
    Baseline; up to Week 6
    End point values
    		 Placebo 100 mg QD; EP547 100 mg QD EP547 100 mg QD; EP547 100 mg QD
    Number of subjects analysed
    27 [1]
    30 [2]
    Units: scores on a scale
        least squares mean (standard error)
    -2.20 ( 0.445 )
    -1.75 ( 0.430 )
    Notes
    [1] - Full Analysis Set
    [2] - Full Analysis Set
    Statistical analysis title
    		 EP547:Placebo Based on MMRM
    Comparison groups
    Placebo 100 mg QD; EP547 100 mg QD v EP547 100 mg QD; EP547 100 mg QD
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.4577
    Method
    		 MMRM
    Parameter type
    		 Least square mean difference (LSMD)
    Point estimate
    0.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.77
         upper limit
    		 1.68
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.609

    Secondary: Change from Baseline in the 5-D Itch Scale total score at Week 6

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    End point title
    		 Change from Baseline in the 5-D Itch Scale total score at Week 6
    End point description
    The 5-D Itch Scale is a multidimensional (degree, duration, direction, disability, distribution) questionnaire measuring changes in pruritis. The duration, degree, and direction domain scores range from 1 (no pruritus) to 5 (most severe pruritus). The disability domain includes 4 items assessing itching impact on daily activities: sleep, leisure/social activities, housework/errands, and work/school. Disability domain score=highest score on any of the 4 categories (1 [no pruritis] to 5 [most severe pruritis]). For the distribution domain, 16 body parts are listed to determine the distribution of itching over the last 2 weeks; the number of affected body parts is tallied (potential sum=0-16); the sum is sorted into 5 thresholds: 0-2 is assigned a score of 1; 3-5, a score of 2; 6-10, a score of 3; 11-13, a score of 4; 14-16, a score of 5. Higher scores indicate more severe pruritis. The 5 domain scores are summed to get a total 5-D score: 5 (no pruritus) to 25 (most severe pruritus).
    End point type
    Secondary
    End point timeframe
    Baseline; Week 6
    End point values
    		 Placebo 100 mg QD; EP547 100 mg QD EP547 100 mg QD; EP547 100 mg QD
    Number of subjects analysed
    27 [3]
    25 [4]
    Units: scores on a scale
        least squares mean (standard error)
    -3.7 ( 0.78 )
    -3.8 ( 0.82 )
    Notes
    [3] - Full Analysis Set. Only participants with available data were analyzed.
    [4] - Full Analysis Set. Only participants with available data were analyzed.
    No statistical analyses for this end point

    Secondary: Percentage of participants with improvement in pruritus as defined by Patient Global Impression of Change (PGI-C) at Week 6

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    End point title
    		 Percentage of participants with improvement in pruritus as defined by Patient Global Impression of Change (PGI-C) at Week 6
    End point description
    Participants were asked to rate their impression of overall change in pruritus in the past 7 days compared to before they started taking study drug using the PGI-C, a 7-point scale ranging from “much improved” to “much worse,” with higher scores indicating less improvement in pruritus. Participants that reported a change in their itch of "minimally improved" or better were considered to be responders in terms of "improvement in pruritus." Exact binomial (Clopper-Pearson) confidence intervals have been reported.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 6
    End point values
    		 Placebo 100 mg QD; EP547 100 mg QD EP547 100 mg QD; EP547 100 mg QD
    Number of subjects analysed
    27 [5]
    28 [6]
    Units: percentage of participants
        number (confidence interval 95%)
    55.6 (35.3 to 74.5)
    60.7 (40.6 to 78.5)
    Notes
    [5] - Full Analysis Set. Only participants with available data were analyzed.
    [6] - Full Analysis Set. Only participants with available data were analyzed.
    No statistical analyses for this end point

    Secondary: Percentage of participants with a reduction in WI-NRS score ≥2 from Baseline at Week 6

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    End point title
    		 Percentage of participants with a reduction in WI-NRS score ≥2 from Baseline at Week 6
    End point description
    Participants were asked to rate the severity of their worst level of itching in the past 24 hours using the daily WI-NRS, an 11-point scale ranging from 0 (no itching) to 10 (worst itching imaginable). Itching severity scores collected via the WI-NRS have been categorized in the as mild (<4), moderate (≥4 to <7), or severe (≥7). The average WI-NRS score using the daily values from the week before the first dose of study drug (including the WI-NRS score captured on Study Day 1 of dosing) served as the Baseline score. A weekly score was determined based on the average of all available daily scores of the week. Exact binomial (Clopper-Pearson) confidence intervals have been reported.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 6
    End point values
    		 Placebo 100 mg QD; EP547 100 mg QD EP547 100 mg QD; EP547 100 mg QD
    Number of subjects analysed
    28 [7]
    28 [8]
    Units: percentage of participants
        number (confidence interval 95%)
    44.4 (25.5 to 64.7)
    35.7 (18.6 to 55.9)
    Notes
    [7] - Full Analysis Set. Only participants with available data were analyzed
    [8] - Full Analysis Set. Only participants with available data were analyzed
    No statistical analyses for this end point

    Secondary: Percentage of participants with improvement in pruritus severity from Baseline as defined by change in Patient Global Impress of Severity (PGI-S) at Week 6

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    End point title
    		 Percentage of participants with improvement in pruritus severity from Baseline as defined by change in Patient Global Impress of Severity (PGI-S) at Week 6
    End point description
    Participants were asked to rate the severity of their pruritus in the past 7 days using the PGI-S, a 4-point scale ranging from “none” to “severe.” Participants that reported a positive shift in their categorical assessment of itch compared to their Baseline level (e.g., “severe” at Visit 2 [Day 1] with a shift to “moderate” at Visit 6 [Week 6]) were considered to be responders in terms of “improvement in pruritus." Exact binomial (Clopper-Pearson) confidence intervals have been reported.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 6
    End point values
    		 Placebo 100 mg QD; EP547 100 mg QD EP547 100 mg QD; EP547 100 mg QD
    Number of subjects analysed
    27 [9]
    28 [10]
    Units: percentage of participants
        number (confidence interval 95%)
    56.0 (34.9 to 75.6)
    52.0 (31.3 to 72.2)
    Notes
    [9] - Full Analysis Set. Only participants with available data were analyzed.
    [10] - Full Analysis Set. Only participants with available data were analyzed.
    No statistical analyses for this end point

    Secondary: Percentage of participants with a reduction in WI-NRS score ≥3 from Baseline at Week 6

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    End point title
    		 Percentage of participants with a reduction in WI-NRS score ≥3 from Baseline at Week 6
    End point description
    Participants were asked to rate the severity of their worst level of itching in the past 24 hours using the daily WI-NRS, an 11-point scale ranging from 0 (no itching) to 10 (worst itching imaginable). Itching severity scores collected via the WI-NRS have been categorized in the as mild (<4), moderate (≥4 to <7), or severe (≥7). The average WI-NRS score using the daily values from the week before the first dose of study drug (including the WI-NRS score captured on Study Day 1 of dosing) served as the Baseline score. A weekly score was determined based on the average of all available daily scores of the week. Exact binomial (Clopper-Pearson) confidence intervals have been reported.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 6
    End point values
    		 Placebo 100 mg QD; EP547 100 mg QD EP547 100 mg QD; EP547 100 mg QD
    Number of subjects analysed
    28 [11]
    28 [12]
    Units: percentage of participants
        number (confidence interval 95%)
    37.0 (19.4 to 57.6)
    25.0 (10.7 to 44.9)
    Notes
    [11] - Full Analysis Set. Only participants with available data were analyzed.
    [12] - Full Analysis Set. Only participants with available data were analyzed.
    No statistical analyses for this end point

    Secondary: Percentage of participants with a reduction in WI-NRS score ≥4 from Baseline at Week 6

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    End point title
    		 Percentage of participants with a reduction in WI-NRS score ≥4 from Baseline at Week 6
    End point description
    Participants were asked to rate the severity of their worst level of itching in the past 24 hours using the daily WI-NRS, an 11-point scale ranging from 0 (no itching) to 10 (worst itching imaginable). Itching severity scores collected via the WI-NRS have been categorized in the as mild (<4), moderate (≥4 to <7), or severe (≥7). The average WI-NRS score using the daily values from the week before the first dose of study drug (including the WI-NRS score captured on Study Day 1 of dosing) served as the Baseline score. A weekly score was determined based on the average of all available daily scores of the week. Exact binomial (Clopper-Pearson) confidence intervals have been reported.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 6
    End point values
    		 Placebo 100 mg QD; EP547 100 mg QD EP547 100 mg QD; EP547 100 mg QD
    Number of subjects analysed
    28 [13]
    28 [14]
    Units: percentage of participants
        number (confidence interval 95%)
    37.0 (19.4 to 57.6)
    17.9 (6.1 to 36.9)
    Notes
    [13] - Full Analysis Set. Only participants with available data were analyzed.
    [14] - Full Analysis Set. Only participants with available data were analyzed.
    No statistical analyses for this end point

    Secondary: Percentage of participants with a WI-NRS score <4 at Week 6

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    End point title
    		 Percentage of participants with a WI-NRS score <4 at Week 6
    End point description
    Participants were asked to rate the severity of their worst level of itching in the past 24 hours using the daily WI-NRS, an 11-point scale ranging from 0 (no itching) to 10 (worst itching imaginable). Itching severity scores collected via the WI-NRS have been categorized in the as mild (<4), moderate (≥4 to <7), or severe (≥7). The average WI-NRS score using the daily values from the week before the first dose of study drug (including the WI-NRS score captured on Study Day 1 of dosing) served as the Baseline score. A weekly score was determined based on the average of all available daily scores of the week. Exact binomial (Clopper-Pearson) confidence intervals have been reported.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 6
    End point values
    		 Placebo 100 mg QD; EP547 100 mg QD EP547 100 mg QD; EP547 100 mg QD
    Number of subjects analysed
    28 [15]
    28 [16]
    Units: percentage of participants
        number (confidence interval 95%)
    42.9 (24.5 to 62.8)
    35.7 (18.6 to 55.9)
    Notes
    [15] - Full Analysis Set. Only participants with available data were analyzed.
    [16] - Full Analysis Set. Only participants with available data were analyzed.
    No statistical analyses for this end point

    Secondary: Open-label Extension Period: Number of participants with any TEAE, any ≥Grade 3 TEAE, any related TEAE, and any TEAE that led to discontinuation of study drug

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    End point title
    		 Open-label Extension Period: Number of participants with any TEAE, any ≥Grade 3 TEAE, any related TEAE, and any TEAE that led to discontinuation of study drug
    End point description
    An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable or unintended sign (including a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product. TEAEs are AEs with an onset after the first dose of study drug or existing events that worsened after the first dose during the study. TEAEs were graded for severity (mild [Grade 1], moderate [Grade 2], severe [Grade 3], life threatening [Grade 4], death [Grade 5]) using CTCAE, version 5.0. The investigator assessed whether the TEAEs were related or unrelated to the study drug. Analysis was conducted in the Open-label Extension Analysis Set, comprised of all participants who completed the Double-Blind Treatment Period and received at least 1 dose of study drug in the Open-Label Extension Period.
    End point type
    Secondary
    End point timeframe
    from the beginning of Week 7 up to Week 12
    End point values
    		 Placebo 100 mg QD; EP547 100 mg QD EP547 100 mg QD; EP547 100 mg QD
    Number of subjects analysed
    29 [17]
    29 [18]
    Units: participants
        Any TEAE
    16
    15
        Any ≥Grade 3 TEAE
    2
    0
        Any related TEAE
    5
    2
        Any TEAE that led to discontinuation of study drug
    0
    0
    Notes
    [17] - Open-label Extension Analysis Set
    [18] - Open-label Extension Analysis Set
    No statistical analyses for this end point

    Secondary: Double-blind Treatment Period: Number of participants with any treatment-emergent adverse event (TEAE), any ≥Grade 3 TEAE, any related TEAE, and any TEAE that led to discontinuation of study drug

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    End point title
    		 Double-blind Treatment Period: Number of participants with any treatment-emergent adverse event (TEAE), any ≥Grade 3 TEAE, any related TEAE, and any TEAE that led to discontinuation of study drug
    End point description
    An adverse event (AE) is any untoward medical occurrence in a participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable or unintended sign (including a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product. TEAEs are AEs with an onset after the first dose of study drug or existing events that worsened after the first dose during the study. TEAEs were graded for severity (mild [Grade 1], moderate [Grade 2], severe [Grade 3], life threatening [Grade 4], death [Grade 5]) using Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. The investigator assessed whether the TEAEs were related or unrelated to the study drug. Safety Analysis Set: all participants who were randomized and took at least 1 dose of randomized study drug.
    End point type
    Secondary
    End point timeframe
    up to the end of Week 6
    End point values
    		 Placebo 100 mg QD; EP547 100 mg QD EP547 100 mg QD; EP547 100 mg QD
    Number of subjects analysed
    30 [19]
    31 [20]
    Units: participants
        Any TEAE
    15
    18
        Any ≥Grade 3 TEAE
    0
    0
        Any related TEAE
    5
    5
        Any TEAE that led to discontinuation of study drug
    0
    0
    Notes
    [19] - Safety Analysis Set. Analysis was based on the treatment actually received.
    [20] - Safety Analysis Set. Analysis was based on the treatment actually received.
    No statistical analyses for this end point

    Secondary: Double-blind Treatment Period: Number of participants with any serious TEAE, any ≥Grade 3 serious TEAE, any related serious TEAE, and any serious TEAE that led to discontinuation (discon) of study drug

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    End point title
    		 Double-blind Treatment Period: Number of participants with any serious TEAE, any ≥Grade 3 serious TEAE, any related serious TEAE, and any serious TEAE that led to discontinuation (discon) of study drug
    End point description
    TEAEs are AEs with an onset after the first dose of study drug or existing events that worsened after the first dose during the study. A serious TEAE is any untoward medical occurrence, that at any dose: results in death; is life threatening; requires hospital admission or prolongs hospitalization; results in persistent or significant disability or incapacity; is a congenital anomaly/birth defect; or is a medically significant event that, based on appropriate medical judgment, may jeopardize the participant and may require medical or surgical intervention to prevent one of the previously listed outcomes. Serious TEAEs were graded for severity (mild [Grade 1], moderate [Grade 2], severe [Grade 3], life threatening [Grade 4], death [Grade 5]) using CTCAE, version 5.0. The investigator assessed whether the serious TEAEs were related or unrelated to the study drug.
    End point type
    Secondary
    End point timeframe
    up to the end of Week 6
    End point values
    		 Placebo 100 mg QD; EP547 100 mg QD EP547 100 mg QD; EP547 100 mg QD
    Number of subjects analysed
    30 [21]
    31 [22]
    Units: participants
        Any serious TEAE
    0
    0
        Any ≥Grade 3 serious TEAE
    0
    0
        Any related serious TEAE
    0
    0
        Any serious TEAE that led to discon of study drug
    0
    0
    Notes
    [21] - Safety Analysis Set
    [22] - Safety Analysis Set
    No statistical analyses for this end point

    Secondary: Open-label Extension Period: Number of participants with any serious TEAE, any ≥Grade 3 serious TEAE, any related serious TEAE, and any serious TEAE that led to discontinuation of study drug

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    End point title
    		 Open-label Extension Period: Number of participants with any serious TEAE, any ≥Grade 3 serious TEAE, any related serious TEAE, and any serious TEAE that led to discontinuation of study drug
    End point description
    TEAEs are AEs with an onset after the first dose of study drug or existing events that worsened after the first dose during the study. A serious TEAE is any untoward medical occurrence, that at any dose: results in death; is life threatening; requires hospital admission or prolongs hospitalization; results in persistent or significant disability or incapacity; is a congenital anomaly/birth defect; or is a medically significant event that, based on appropriate medical judgment, may jeopardize the participant and may require medical or surgical intervention to prevent one of the previously listed outcomes. Serious TEAEs were graded for severity (mild [Grade 1], moderate [Grade 2], severe [Grade 3], life threatening [Grade 4], death [Grade 5]) using CTCAE, version 5.0. The investigator assessed whether the serious TEAEs were related or unrelated to the study drug.
    End point type
    Secondary
    End point timeframe
    from the beginning of Week 7 up to Week 12
    End point values
    		 Placebo 100 mg QD; EP547 100 mg QD EP547 100 mg QD; EP547 100 mg QD
    Number of subjects analysed
    29 [23]
    29 [24]
    Units: participants
        Any serious TEAE
    1
    0
        Any ≥Grade 3 serious TEAE
    1
    0
        Any related serious TEAE
    0
    0
        Any serious TEAE that led to discon of study drug
    0
    0
    Notes
    [23] - Open-label Extension Analysis Set
    [24] - Open-label Extension Analysis Set
    No statistical analyses for this end point

    Secondary: Double-blind Treatment Period: Number of participants with any treatment-emergent (TE) adverse event of special interest (AESI), any ≥Grade 3 TE AESI, any related TE AESI, and any TE AESI that led to discontinuation of study drug

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    End point title
    		 Double-blind Treatment Period: Number of participants with any treatment-emergent (TE) adverse event of special interest (AESI), any ≥Grade 3 TE AESI, any related TE AESI, and any TE AESI that led to discontinuation of study drug
    End point description
    An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. TEAEs are AEs with an onset after the first dose of study drug or existing events that worsened after the first dose during the study. AESI were considered to be any clinically meaningful new, worsening from Baseline, or abnormal laboratory findings or symptoms suggestive of acute kidney injury (AKI) (e.g., “blood urea increased” or “protein urine present” AEs as identified by the Standardized Medical Dictionary for Regulatory Activities [MedDRA] Query [SMQ] “Acute renal failure”). TE AESIs were graded for severity (mild [Grade 1], moderate [Grade 2], severe [Grade 3], life threatening [Grade 4], death [Grade 5]) using CTCAE, version 5.0. The investigator assessed whether the AE AESIs were related or unrelated to the study drug.
    End point type
    Secondary
    End point timeframe
    up to the end of Week 6
    End point values
    		 Placebo 100 mg QD; EP547 100 mg QD EP547 100 mg QD; EP547 100 mg QD
    Number of subjects analysed
    30 [25]
    31 [26]
    Units: participants
        Any treatment-emergent (TE) AESI
    0
    0
        Any ≥Grade 3 TE AESI
    0
    0
        Any related TE AESI
    0
    0
        Any TE AESI that led to discon of study drug
    0
    0
    Notes
    [25] - Safety Analysis Set
    [26] - Safety Analysis Set
    No statistical analyses for this end point

    Secondary: Open-label Extension Period: Number of participants with any treatment-emergent (TE) AESI, any ≥Grade 3 TE AESI, any related TE AESI, and any TE AESI that led to discontinuation of study drug

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    End point title
    		 Open-label Extension Period: Number of participants with any treatment-emergent (TE) AESI, any ≥Grade 3 TE AESI, any related TE AESI, and any TE AESI that led to discontinuation of study drug
    End point description
    An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. TEAEs are AEs with an onset after the first dose of study drug or existing events that worsened after the first dose during the study. AESI were considered to be any clinically meaningful new, worsening from Baseline, or abnormal laboratory findings or symptoms suggestive of acute kidney injury (AKI) (e.g., “blood urea increased” or “protein urine present” AEs as identified by the Standardized Medical Dictionary for Regulatory Activities [MedDRA] Query [SMQ] “Acute renal failure”). TE AESIs were graded for severity (mild [Grade 1], moderate [Grade 2], severe [Grade 3], life threatening [Grade 4], death [Grade 5]) using CTCAE, version 5.0. The investigator assessed whether the AE AESIs were related or unrelated to the study drug.
    End point type
    Secondary
    End point timeframe
    from the beginning of Week 7 up to Week 12
    End point values
    		 Placebo 100 mg QD; EP547 100 mg QD EP547 100 mg QD; EP547 100 mg QD
    Number of subjects analysed
    29 [27]
    29 [28]
    Units: participants
        Any TE AESI
    0
    0
        Any ≥Grade 3 TE AESI
    0
    0
        Any related TE AESI
    0
    0
        Any TE AESI that led to discon of study drug
    0
    0
    Notes
    [27] - Open-label Extension Analysis Set
    [28] - Open-label Extension Analysis Set
    No statistical analyses for this end point

    Secondary: Number of participants with any clinically meaningful changes from Baseline in vital sign measurements

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    End point title
    		 Number of participants with any clinically meaningful changes from Baseline in vital sign measurements
    End point description
    Vital sign measurements included measurements for blood pressure, pulse rate, oxygen saturation, body temperature, and respiratory rate. The investigator determined if changes were clinically meaningful.
    End point type
    Secondary
    End point timeframe
    up to the end of Week 12
    End point values
    		 Placebo 100 mg QD; EP547 100 mg QD EP547 100 mg QD; EP547 100 mg QD
    Number of subjects analysed
    30 [29]
    31 [30]
    Units: participants
    0
    1
    Notes
    [29] - Safety Analysis Set
    [30] - Safety Analysis Set
    No statistical analyses for this end point

    Secondary: Number of participants with any clinically meaningful changes from Baseline in clinically meaningful in clinical laboratory test results

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    End point title
    		 Number of participants with any clinically meaningful changes from Baseline in clinically meaningful in clinical laboratory test results
    End point description
    Clinical laboratory test results included results for clinical hematology, chemistry, coagulation, and thyroid function parameters . The investigator determined if changes were clinically meaningful.
    End point type
    Secondary
    End point timeframe
    up to the end of Week 12
    End point values
    		 Placebo 100 mg QD; EP547 100 mg QD EP547 100 mg QD; EP547 100 mg QD
    Number of subjects analysed
    30 [31]
    31 [32]
    Units: participants
    3
    0
    Notes
    [31] - Safety Analysis Set
    [32] - Safety Analysis Set
    No statistical analyses for this end point

    Secondary: Number of participants with any clinically significant changes from Baseline in electrocardiogram (ECG) parameters

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    End point title
    		 Number of participants with any clinically significant changes from Baseline in electrocardiogram (ECG) parameters
    End point description
    ECG parameters included heart rate, RR interval, PR interval, QRS duration, or QT interval. The investigator determined if changes were clinically significant.
    End point type
    Secondary
    End point timeframe
    up to the end of Week 12
    End point values
    		 Placebo 100 mg QD; EP547 100 mg QD EP547 100 mg QD; EP547 100 mg QD
    Number of subjects analysed
    30 [33]
    31 [34]
    Units: participants
    0
    0
    Notes
    [33] - Safety Analysis Set
    [34] - Safety Analysis Set
    No statistical analyses for this end point

    Secondary: Plasma concentration of EP547 and metabolites

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    End point title
    		 Plasma concentration of EP547 and metabolites
    End point description
    The lower level of quantitation = 0.01 micrograms per milliliter (µg/mL) for EP547 and 0.005 μg/mL for EP3583. Analysis was conducted in members of the Pharmcokinetic Set, comprised of all participants who received at least 1 dose of EP547 and provided adequate blood samples for bioanalysis.
    End point type
    Secondary
    End point timeframe
    predose and 1, 2, and 3 hours postdose on Day 1 and Week 3; predose on Weeks 1, 2, and 6
    End point values
    		 Placebo 100 mg QD; EP547 100 mg QD EP547 100 mg QD; EP547 100 mg QD
    Number of subjects analysed
    0 [35]
    31 [36]
    Units: nanograms per milliliter (ng/mL)
    geometric mean (geometric coefficient of variation)
        EP547: Day 1, 1 hour postdose, n=0, 30
    ( )
    2661.0 ( 159.42 )
        EP547: Day 1, 2 hours postdose, n=0, 30
    ( )
    5197.7 ( 93.75 )
        EP547: Day 1, 3 hours postdose, n=0, 30
    ( )
    5698.4 ( 75.27 )
        EP547: Week 1, predose, n=0, 30
    ( )
    6267.9 ( 51.54 )
        EP547: Week 2, predose, n=0, 29
    ( )
    5786.5 ( 56.27 )
        EP547: Week 3, predose, n=0, 29
    ( )
    6617.4 ( 49.06 )
        EP547: Week 3, 1 hour postdose, n=0, 29
    ( )
    11709.4 ( 39.25 )
        EP547: Week 3, 2 hours postdose, n=0, 29
    ( )
    12012.7 ( 30.98 )
        EP547: Week 3, 3 hours postdose, n=0, 28
    ( )
    11909.4 ( 49.76 )
        EP547: Week 6, predose, n=0, 28
    ( )
    4947.6 ( 91.61 )
        EP3583: Day 1, 1 hour postdose, n=0, 30
    ( )
    308.5 ( 160.23 )
        EP3583: : Day 1, 2 hours postdose, n=0, 30
    ( )
    796.1 ( 104.08 )
        EP3583: : Day 1, 3 hours postdose, n=0, 30
    ( )
    910.6 ( 90.22 )
        EP3583: Week 1, predose, n=0, 30
    ( )
    952.1 ( 56.10 )
        EP3583: Week 2, predose, n=0, 29
    ( )
    948.2 ( 61.73 )
        EP3583: Week 3, predose, n=0, 29
    ( )
    1028.9 ( 64.53 )
        EP3583: Week 3, 1 hour postdose, n=0, 29
    ( )
    1625.4 ( 54.57 )
        EP3583: Week 3, 2 hours postdose, n=0, 29
    ( )
    1898.0 ( 47.98 )
        EP3583: Week 3, 3 hours postdose, n=0, 28
    ( )
    1836.0 ( 62.20 )
        EP3583: Week 6, predose, n=0, 28
    ( )
    801.8 ( 103.25 )
    Notes
    [35] - Pharmokinetic Set
    [36] - Pharmokinetic Set
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    12 weeks
    Adverse event reporting additional description
    For participants who received placebo up to Week 6 and then switched to EP547, adverse events are presented by the treatment they were on at onset of the event.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants were randomized to receive oral placebo 100 mg QD for 6 weeks in the Double-Blind (DB) Treatment Period.

    Reporting group title
    EP547
    Reporting group description
    		 Participants received oral EP547 100 mg QD for 6 weeks in the Double-Blind Treatment Period. Participants who received placebo during the Double-Blind Treatment Period and completed the period received oral EP547 100 mg QD for an additional 6 weeks in the Open-Label Extension Period.

    Serious adverse events
    		 Placebo EP547
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 60 (1.67%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Gun shot wound
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo EP547
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 30 (23.33%)
    24 / 60 (40.00%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 30 (10.00%)
    6 / 60 (10.00%)
         occurrences all number
    3
    15
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 30 (0.00%)
    3 / 60 (5.00%)
         occurrences all number
    0
    3
    Abdominal pain
         subjects affected / exposed
    0 / 30 (0.00%)
    3 / 60 (5.00%)
         occurrences all number
    0
    3
    Abdominal pain upper
         subjects affected / exposed
    0 / 30 (0.00%)
    3 / 60 (5.00%)
         occurrences all number
    0
    4
    Diarrhoea
         subjects affected / exposed
    0 / 30 (0.00%)
    6 / 60 (10.00%)
         occurrences all number
    0
    6
    Nausea
         subjects affected / exposed
    1 / 30 (3.33%)
    3 / 60 (5.00%)
         occurrences all number
    1
    3
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    3 / 30 (10.00%)
    4 / 60 (6.67%)
         occurrences all number
    3
    5
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    0 / 30 (0.00%)
    6 / 60 (10.00%)
         occurrences all number
    0
    6
    Nasopharyngitis
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 60 (0.00%)
         occurrences all number
    2
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 30 (0.00%)
    4 / 60 (6.67%)
         occurrences all number
    0
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Nov 2021
    The primary purpose of the amendment was to implement changes to the study population, include additional safety monitoring, and incorporate operational changes.
    20 Apr 2022
    The primary purpose of the amendment was to increase opportunities for remote visits to ease participant burden associated with participating in this clinical study. Previously, participants were able to attend study visits at a physical study site as well as remotely (hybrid model) where allowed per regulatory/local requirements. This amendment introduced another option that allowed all visits to be conducted remotely at a virtual site (decentralized model) where allowed per regulatory/local requirements.
    02 Oct 2023
    The primary purpose of the amendment was to adjust the eligibility criteria for estimated glomerular filtration rate, change the contraceptive requirements, decrease the required duration of ursodeoxycholic acid treatment, expand the drug interaction information, and to revise the description of the primary endpoint analysis.

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

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

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