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    Clinical Trial Results:
    A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Safety, Tolerability, and Efficacy of Cilofexor in Non-Cirrhotic Subjects With Primary Sclerosing Cholangitis

    Summary
    EudraCT number
    		 2019-000204-14
    Trial protocol
    		 FI   BE   AT   GB   DK   FR   ES   IT  
    Global end of trial date
    23 Dec 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 Dec 2023
    First version publication date
    16 Dec 2023
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    GS-US-428-4194
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03890120
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 jRCT2080224728: Japan Registry of Clinical Trials
    Sponsors
    Sponsor organisation name
    Gilead Sciences
    Sponsor organisation address
    333 Lakeside Drive, Foster City, CA, United States, 94404
    Public contact
    Gilead Clinical Study Information Center, Gilead Sciences, GileadClinicalTrials@gilead.com
    Scientific contact
    Gilead Clinical Study Information Center, Gilead Sciences, GileadClinicalTrials@gilead.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    23 Dec 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Nov 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Dec 2022
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate whether cilofexor reduces the risk of fibrosis progression among non-cirrhotic adults with primary sclerosing cholangitis (PSC).
    Protection of trial subjects
    The protocol and consent/assent forms were submitted by each investigator to a duly constituted Independent Ethics Committee (IEC) or Institutional Review Board (IRB) for review and approval before study initiation. All revisions to the consent/assent forms (if applicable) after initial IEC/IRB approval were submitted by the investigator to the IEC/IRB for review and approval before implementation in accordance with regulatory requirements. This study was conducted in accordance with recognized international scientific and ethical standards, including but not limited to the International Conference on Harmonization guideline for Good Clinical Practice (ICH GCP) and the original principles embodied in the Declaration of Helsinki.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 Mar 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 31
    Country: Number of subjects enrolled
    Austria: 4
    Country: Number of subjects enrolled
    Belgium: 6
    Country: Number of subjects enrolled
    Canada: 38
    Country: Number of subjects enrolled
    Denmark: 7
    Country: Number of subjects enrolled
    Finland: 19
    Country: Number of subjects enrolled
    France: 14
    Country: Number of subjects enrolled
    Germany: 18
    Country: Number of subjects enrolled
    Israel: 11
    Country: Number of subjects enrolled
    Italy: 23
    Country: Number of subjects enrolled
    Japan: 27
    Country: Number of subjects enrolled
    New Zealand: 6
    Country: Number of subjects enrolled
    Spain: 16
    Country: Number of subjects enrolled
    Switzerland: 6
    Country: Number of subjects enrolled
    United Kingdom: 19
    Country: Number of subjects enrolled
    United States: 174
    Worldwide total number of subjects
    419
    EEA total number of subjects
    107
    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)
    395
    From 65 to 84 years
    24
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Participants were enrolled at study sites in Europe, North America, Oceania, and Asia.

    Pre-assignment
    Screening details
    		 587 participants were screened.

    Period 1
    Period 1 title
    Blinded Treatment Phase (100.3 weeks)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cilofexor 100 mg (Blinded Phase)
    Arm description
    		 Participants received cilofexor 100 mg tablet, orally, once daily for up to 100.3 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cilofexor
    Investigational medicinal product code
    Other name
    GS-9674
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg tablet administered orally once daily for up to 100.3 weeks.

    Arm title
    		 Placebo (Blinded Phase)
    Arm description
    		 Participants received placebo to match cilofexor 100 mg tablet, orally, once daily for up to 98.1 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    placebo to match cilofexor 100 mg tablet administered orally once daily for up to 98.1 weeks.

    Number of subjects in period 1
    		Cilofexor 100 mg (Blinded Phase) Placebo (Blinded Phase)
    Started
    278
    141
    Completed
    123
    66
    Not completed
    155
    75
         Adverse event, non-fatal
    17
    7
         Death
    1
    -
         Pregnancy
    -
    1
         Study terminated by sponsor
    119
    57
         Non-compliance with study drug
    -
    1
         Withdrew consent
    12
    4
         Lost to follow-up
    4
    1
         Investigator's discretion
    1
    2
         Randomized but never treated
    1
    2
    Period 2
    Period 2 title
    Open-Label Extension Phase (45 weeks)
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cilofexor From Cilofexor 100 mg (OLE Phase)
    Arm description
    		 Participants who received cilofexor in blinded phase and had entered the open-label extension (OLE) phase received open-label cilofexor 100 mg tablet, orally, once daily for up to 44.7 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cilofexor
    Investigational medicinal product code
    Other name
    GS-9674
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg tablet administered orally once daily for up to 44.7 weeks.

    Arm title
    		 Cilofexor From Placebo (OLE Phase)
    Arm description
    		 Participants who received placebo in blinded phase and had entered the OLE phase received open-label cilofexor 100 mg tablet, orally, once daily for up to 45.0 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cilofexor
    Investigational medicinal product code
    Other name
    GS-9674
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg tablet administered orally once daily for up to 45.0 weeks.

    Number of subjects in period 2 [1]
    		Cilofexor From Cilofexor 100 mg (OLE Phase) Cilofexor From Placebo (OLE Phase)
    Started
    80
    45
    Completed
    0
    0
    Not completed
    80
    45
         Adverse event, non-fatal
    3
    1
         Study terminated by sponsor
    76
    42
         Withdrew consent
    1
    -
         Lost to follow-up
    -
    2
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Participants who consented to enter the OLE Phase and completed the Blinded Study Phase Week 96 with an evaluable biopsy (noncirrhotic F0, F1, F2, and F3) as determined by the central reader and Blinded Study Phase follow-up visit entered OLE Phase.

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Cilofexor 100 mg (Blinded Phase)
    Reporting group description
    		 Participants received cilofexor 100 mg tablet, orally, once daily for up to 100.3 weeks.

    Reporting group title
    Placebo (Blinded Phase)
    Reporting group description
    		 Participants received placebo to match cilofexor 100 mg tablet, orally, once daily for up to 98.1 weeks.

    Reporting group values
    		 Cilofexor 100 mg (Blinded Phase) Placebo (Blinded Phase) Total
    Number of subjects
    		 278 141 419
    Age categorical
    Units: Subjects
        18 – 64 Years
    		 260 135 395
        65 – 84 Years
    		 18 6 24
    Gender categorical
    Units: Subjects
        Female
    		 107 54 161
        Male
    		 171 87 258
    Race
    Units: Subjects
        White
    		 228 117 345
        Asian
    		 28 10 38
        Black or African American
    		 11 9 20
        Unknown or Not Reported
    		 6 5 11
        Other or More Than One Race
    		 5 0 5
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 11 3 14
        Not Hispanic or Latino
    		 259 132 391
        Unknown or Not Reported
    		 8 6 14
    Alkaline Phosphatase (ALP)
    Units: units per liter (U/L)
        arithmetic mean (standard deviation)
    		 ± ± -
    Aspartate Aminotransferase (AST)
    Units: U/L
        arithmetic mean (standard deviation)
    		 ± ± -
    Fasting Total Bile Acids
    Units: micromoles per liter (μmol/L)
        arithmetic mean (standard deviation)
    		 ± ± -
    Enhanced Liver Fibrosis (ELF™) Test Score
    The Enhanced Liver Fibrosis (ELF™) test is a composite of three serum biomarkers of hepatobiliary fibrosis: hyaluronic acid, procollagen III amino‐terminal peptide, and tissue inhibitor of metalloproteinase. A typical range for ELF™ test scores in PSC is between 6 and 14. Higher ELF™ test scores are associated with more severe liver disease.
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 ± ± -
    Fibroscan Score
    Change in liver stiffness was measured by FibroScan® scores. FibroScan measures liver scarring by measuring the stiffness of the liver. It's normally between 2 and 6 kPa. Many people with liver disease(s) have a result that's higher than the normal range. Higher scores indicate increased scarring of the liver.
    Units: kilopascals (kPa)
        arithmetic mean (standard deviation)
    		 ± ± -
    Subject analysis sets

    Subject analysis set title
    Cilofexor 100 mg (Blinded Phase)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received cilofexor 100 mg tablet, orally, once daily for up to 100.3 weeks. Safety Analysis Set included all participants who took at least 1 dose of study drug.

    Subject analysis set title
    Placebo (Blinded Phase)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received placebo to match cilofexor 100 mg tablet, orally, once daily for up to 98.1 weeks. Participants in the Safety Analysis Set were analyzed.

    Subject analysis set title
    Cilofexor 100 mg (Blinded Phase)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received cilofexor 100 mg tablet, orally, once daily for up to 100.3 weeks. Participants in the Safety Analysis Set with available data were analyzed.

    Subject analysis set title
    Placebo (Blinded Phase)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received placebo to match cilofexor 100 mg tablet, orally, once daily for up to 98.1 weeks. Participants in the Safety Analysis Set with available data were analyzed.

    Subject analysis set title
    Cilofexor 100 mg (Blinded Phase)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received cilofexor 100 mg tablet, orally, once daily for up to 100.3 weeks. Participants in the Safety Analysis Set with available data were analyzed.

    Subject analysis set title
    Placebo (Blinded Phase)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received placebo to match cilofexor 100 mg tablet, orally, once daily for up to 98.1 weeks. Participants in the Safety Analysis Set with available data were analyzed.

    Subject analysis set title
    Cilofexor 100 mg (Blinded Phase)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received cilofexor 100 mg tablet, orally, once daily for up to 100.3 weeks. Participants in the Safety Analysis Set with available data were analyzed.

    Subject analysis set title
    Placebo (Blinded Phase)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received placebo to match cilofexor 100 mg tablet, orally, once daily for up to 98.1 weeks. Participants in the Safety Analysis Set with available data were analyzed.

    Subject analysis sets values
    		 Cilofexor 100 mg (Blinded Phase) Placebo (Blinded Phase) Cilofexor 100 mg (Blinded Phase) Placebo (Blinded Phase) Cilofexor 100 mg (Blinded Phase) Placebo (Blinded Phase) Cilofexor 100 mg (Blinded Phase) Placebo (Blinded Phase)
    Number of subjects
    277
    139
    262
    132
    276
    137
    253
    125
    Age categorical
    Units: Subjects
        18 – 64 Years
        65 – 84 Years
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    Gender categorical
    Units: Subjects
        Female
        Male
    Race
    Units: Subjects
        White
        Asian
        Black or African American
        Unknown or Not Reported
        Other or More Than One Race
    Ethnicity
    Units: Subjects
        Hispanic or Latino
        Not Hispanic or Latino
        Unknown or Not Reported
    Alkaline Phosphatase (ALP)
    Units: units per liter (U/L)
        arithmetic mean (standard deviation)
    223 ± 177.7
    243 ± 189.5
    ±
    ±
    ±
    ±
    ±
    ±
    Aspartate Aminotransferase (AST)
    Units: U/L
        arithmetic mean (standard deviation)
    49 ± 34.1
    51 ± 34.6
    ±
    ±
    ±
    ±
    ±
    ±
    Fasting Total Bile Acids
    Units: micromoles per liter (μmol/L)
        arithmetic mean (standard deviation)
    ±
    ±
    24.2 ± 37.57
    18.6 ± 22.49
    ±
    ±
    ±
    ±
    Enhanced Liver Fibrosis (ELF™) Test Score
    The Enhanced Liver Fibrosis (ELF™) test is a composite of three serum biomarkers of hepatobiliary fibrosis: hyaluronic acid, procollagen III amino‐terminal peptide, and tissue inhibitor of metalloproteinase. A typical range for ELF™ test scores in PSC is between 6 and 14. Higher ELF™ test scores are associated with more severe liver disease.
    Units: score on a scale
        arithmetic mean (standard deviation)
    ±
    ±
    ±
    ±
    9.14 ± 0.910
    9.13 ± 0.963
    ±
    ±
    Fibroscan Score
    Change in liver stiffness was measured by FibroScan® scores. FibroScan measures liver scarring by measuring the stiffness of the liver. It's normally between 2 and 6 kPa. Many people with liver disease(s) have a result that's higher than the normal range. Higher scores indicate increased scarring of the liver.
    Units: kilopascals (kPa)
        arithmetic mean (standard deviation)
    ±
    ±
    ±
    ±
    ±
    ±
    7.8 ± 4.91
    8.0 ± 4.07

    End points

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    End points reporting groups
    Reporting group title
    Cilofexor 100 mg (Blinded Phase)
    Reporting group description
    		 Participants received cilofexor 100 mg tablet, orally, once daily for up to 100.3 weeks.

    Reporting group title
    Placebo (Blinded Phase)
    Reporting group description
    		 Participants received placebo to match cilofexor 100 mg tablet, orally, once daily for up to 98.1 weeks.
    Reporting group title
    Cilofexor From Cilofexor 100 mg (OLE Phase)
    Reporting group description
    		 Participants who received cilofexor in blinded phase and had entered the open-label extension (OLE) phase received open-label cilofexor 100 mg tablet, orally, once daily for up to 44.7 weeks.

    Reporting group title
    Cilofexor From Placebo (OLE Phase)
    Reporting group description
    		 Participants who received placebo in blinded phase and had entered the OLE phase received open-label cilofexor 100 mg tablet, orally, once daily for up to 45.0 weeks.

    Subject analysis set title
    Cilofexor 100 mg (Blinded Phase)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received cilofexor 100 mg tablet, orally, once daily for up to 100.3 weeks. Safety Analysis Set included all participants who took at least 1 dose of study drug.

    Subject analysis set title
    Placebo (Blinded Phase)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received placebo to match cilofexor 100 mg tablet, orally, once daily for up to 98.1 weeks. Participants in the Safety Analysis Set were analyzed.

    Subject analysis set title
    Cilofexor 100 mg (Blinded Phase)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received cilofexor 100 mg tablet, orally, once daily for up to 100.3 weeks. Participants in the Safety Analysis Set with available data were analyzed.

    Subject analysis set title
    Placebo (Blinded Phase)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received placebo to match cilofexor 100 mg tablet, orally, once daily for up to 98.1 weeks. Participants in the Safety Analysis Set with available data were analyzed.

    Subject analysis set title
    Cilofexor 100 mg (Blinded Phase)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received cilofexor 100 mg tablet, orally, once daily for up to 100.3 weeks. Participants in the Safety Analysis Set with available data were analyzed.

    Subject analysis set title
    Placebo (Blinded Phase)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received placebo to match cilofexor 100 mg tablet, orally, once daily for up to 98.1 weeks. Participants in the Safety Analysis Set with available data were analyzed.

    Subject analysis set title
    Cilofexor 100 mg (Blinded Phase)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received cilofexor 100 mg tablet, orally, once daily for up to 100.3 weeks. Participants in the Safety Analysis Set with available data were analyzed.

    Subject analysis set title
    Placebo (Blinded Phase)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received placebo to match cilofexor 100 mg tablet, orally, once daily for up to 98.1 weeks. Participants in the Safety Analysis Set with available data were analyzed.

    Primary: Percentage of Participants With Progression of Liver Fibrosis at Blinded Phase Week 96

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    End point title
    		 Percentage of Participants With Progression of Liver Fibrosis at Blinded Phase Week 96
    End point description
    Progression of liver fibrosis was defined as having a ≥ 1-stage increase from baseline in fibrosis according to the Ludwig classification at Blinded Phase Week 96. The stages of fibrosis was assessed according to Ludwig classification. Ludwig classification fibrosis stages range from 0 to 4, with higher scores indicating greater fibrosis (0=no fibrosis, 4=cirrhosis). Full Analysis Set included all randomized participants who took at least 1 dose of study drug. Participants in the Full Analysis Set who had nonmissing data at both baseline and Week 96 in the Blinded Study Phase were analyzed.
    End point type
    Primary
    End point timeframe
    Blinded Phase Week 96
    End point values
    		 Cilofexor 100 mg (Blinded Phase) Placebo (Blinded Phase)
    Number of subjects analysed
    133
    64
    Units: percentage of participants
        number (not applicable)
    30.8
    32.8
    Statistical analysis title
    		 Cilofexor 100 mg vs Placebo
    Comparison groups
    Cilofexor 100 mg (Blinded Phase) v Placebo (Blinded Phase)
    Number of subjects included in analysis
    197
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4186 [1]
    Method
    		 Mantel-Haenszel
    Parameter type
    		 Difference in Percentages
    Point estimate
    -1.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -15.2
         upper limit
    		 12.3
    Notes
    [1] - The difference of cilofexor and placebo,95% confidence interval(CI),and P value(1-sided)were obtained by the stratum-adjusted Mantel-Haenszel (MH) method,with baseline ursodeoxycholic acid(UDCA)use and Ludwig fibrosis stage as stratification factors.

    Secondary: Percentage of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) in The Blinded Phase

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    End point title
    		 Percentage of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) in The Blinded Phase
    End point description
    An AE was any untoward medical occurrence in a clinical study participant administered a study drug that does not necessarily have a causal relationship with the treatment. An AE can therefore be any unfavorable and/or unintended sign, symptom, or disease temporally associated with the use of a study drug, whether or not the AE is considered related to the study drug. For Blinded Study Phase and OLE Phase, TEAEs were defined as 1 or both of the following: Any AEs with an onset date on or after the study drug start date and no later than 30 days after permanent discontinuation of study drug and/or any AEs leading to premature discontinuation of study drug. Safety Analysis Set included all participants who took at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    First dose date in the Blinded Phase up to 100.3 weeks plus 30 days
    End point values
    		 Cilofexor 100 mg (Blinded Phase) Placebo (Blinded Phase)
    Number of subjects analysed
    277
    139
    Units: percentage of participants
        number (not applicable)
    97.1
    95.0
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Experienced TEAEs in The OLE Phase

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    End point title
    		 Percentage of Participants Who Experienced TEAEs in The OLE Phase
    End point description
    An AE was any untoward medical occurrence in a clinical study participant administered a study drug that does not necessarily have a causal relationship with the treatment. An AE can therefore be any unfavorable and/or unintended sign, symptom, or disease temporally associated with the use of a study drug, whether or not the AE is considered related to the study drug. For Blinded Study Phase and OLE Phase, TEAEs were defined as 1 or both of the following: Any AEs with an onset date on or after the study drug start date and no later than 30 days after permanent discontinuation of study drug and/or any AEs leading to premature discontinuation of study drug. OLE Analysis Set included all participants who took at least 1 dose of study drug in the OLE Phase.
    End point type
    Secondary
    End point timeframe
    First dose date in the OLE Phase up to 45 weeks plus 30 days
    End point values
    		 Cilofexor From Cilofexor 100 mg (OLE Phase) Cilofexor From Placebo (OLE Phase)
    Number of subjects analysed
    80
    45
    Units: percentage of participants
        number (not applicable)
    66.3
    73.3
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Experienced Treatment-emergent Serious Adverse Events (SAEs) in the Blinded Phase

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    End point title
    		 Percentage of Participants Who Experienced Treatment-emergent Serious Adverse Events (SAEs) in the Blinded Phase
    End point description
    An SAE was defined as an event that, at any dose, results in the following: death, a life-threatening situation; in-patient hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity, a congenital anomaly/birth defect or a medically important event or reaction. Participants in the Safety Analysis Set were analyzed.
    End point type
    Secondary
    End point timeframe
    First dose date in the Blinded Phase up to 100.3 weeks plus 30 days
    End point values
    		 Cilofexor 100 mg (Blinded Phase) Placebo (Blinded Phase)
    Number of subjects analysed
    277
    139
    Units: percentage of participants
        number (not applicable)
    19.1
    18.7
    No statistical analyses for this end point

    Secondary: Change From Baseline in Serum Concentrations of Alkaline Phosphatase (ALP) at Blinded Phase Week 96

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    End point title
    		 Change From Baseline in Serum Concentrations of Alkaline Phosphatase (ALP) at Blinded Phase Week 96
    End point description
    Participants in the Full Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline, Blinded Phase Week 96
    End point values
    		 Cilofexor 100 mg (Blinded Phase) Placebo (Blinded Phase)
    Number of subjects analysed
    146
    74
    Units: units per liter (U/L)
        least squares mean (confidence interval 95%)
    0 (-17 to 16)
    3 (-19 to 25)
    Statistical analysis title
    		 Cilofexor 100 mg vs Placebo
    Comparison groups
    Cilofexor 100 mg (Blinded Phase) v Placebo (Blinded Phase)
    Number of subjects included in analysis
    220
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3884 [2]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in Least Squares Mean (LSM)
    Point estimate
    -4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -28
         upper limit
    		 21
    Notes
    [2] - The LSM,95% CI and P-value(1-sided) were obtained by an analysis of covariance(ANCOVA)model with change at Week 96 as dependent variable,baseline value of outcome measure,baseline UDCA use, and baseline Ludwig fibrosis stage as independent variables.

    Secondary: Percentage of Participants Who Experienced Treatment-emergent SAEs in the OLE Phase

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    End point title
    		 Percentage of Participants Who Experienced Treatment-emergent SAEs in the OLE Phase
    End point description
    An SAE was defined as an event that, at any dose, results in the following: death, a life-threatening situation; in-patient hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity, a congenital anomaly/birth defect or a medically important event or reaction. Participants in the OLE Analysis Set were analyzed.
    End point type
    Secondary
    End point timeframe
    First dose date in the OLE Phase up to 45 weeks plus 30 days
    End point values
    		 Cilofexor From Cilofexor 100 mg (OLE Phase) Cilofexor From Placebo (OLE Phase)
    Number of subjects analysed
    80
    45
    Units: percentage of participants
        number (not applicable)
    11.3
    2.2
    No statistical analyses for this end point

    Secondary: Change From Baseline in Serum Concentrations of Alanine Aminotransferase (ALT) at Blinded Phase Week 96

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    End point title
    		 Change From Baseline in Serum Concentrations of Alanine Aminotransferase (ALT) at Blinded Phase Week 96
    End point description
    Participants in the Full Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline, Blinded Phase Week 96
    End point values
    		 Cilofexor 100 mg (Blinded Phase) Placebo (Blinded Phase)
    Number of subjects analysed
    145
    74
    Units: U/L
        least squares mean (confidence interval 95%)
    -13 (-20 to -6)
    -3 (-12 to 6)
    Statistical analysis title
    		 Cilofexor 100 mg vs Placebo
    Comparison groups
    Cilofexor 100 mg (Blinded Phase) v Placebo (Blinded Phase)
    Number of subjects included in analysis
    219
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.039 [3]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LSM
    Point estimate
    -9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -20
         upper limit
    		 1
    Notes
    [3] - The LSM, 95% CI and P-value (1-sided) were obtained by ANCOVA model to evaluate change at Week 96 as the dependent variable, baseline value of the outcome measure, baseline UDCA use, and baseline Ludwig fibrosis stage as independent variables.

    Secondary: Change From Baseline in Serum Concentrations of Fasting Total Bile Acids at Blinded Phase Week 96

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    End point title
    		 Change From Baseline in Serum Concentrations of Fasting Total Bile Acids at Blinded Phase Week 96
    End point description
    Participants in the Full Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline, Blinded Phase Week 96
    End point values
    		 Cilofexor 100 mg (Blinded Phase) Placebo (Blinded Phase)
    Number of subjects analysed
    147
    74
    Units: micromoles per liter (μmol/L)
        least squares mean (confidence interval 95%)
    7.2 (0.9 to 13.5)
    9.8 (1.8 to 17.9)
    Statistical analysis title
    		 Cilofexor 100 mg vs Placebo
    Comparison groups
    Cilofexor 100 mg (Blinded Phase) v Placebo (Blinded Phase)
    Number of subjects included in analysis
    221
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2845 [4]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LSM
    Point estimate
    -2.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.6
         upper limit
    		 6.4
    Notes
    [4] - The LSM, 95% CI and P-value (1-sided) were obtained by ANCOVA model to evaluate change at Week 96 as the dependent variable, baseline value of the outcome measure, baseline UDCA use, and baseline Ludwig fibrosis stage as independent variables.

    Secondary: Percentage of Participants With ≥ 25% Relative Reduction in Serum ALP Concentration From Baseline and No Worsening of Fibrosis According to the Ludwig Classification at Blinded Phase Week 96

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    End point title
    		 Percentage of Participants With ≥ 25% Relative Reduction in Serum ALP Concentration From Baseline and No Worsening of Fibrosis According to the Ludwig Classification at Blinded Phase Week 96
    End point description
    The stages of fibrosis was assessed according to Ludwig classification. Ludwig classification fibrosis stages range from 0 to 4, with higher scores indicating greater fibrosis (0=no fibrosis, 4=cirrhosis).The percentage of participants with ≥ 25% reduction in serum ALP Concentration from baseline and no increase in fibrosis according to the Ludwig Classification at Blinded Phase Week 96 was analyzed. Participants in the Full Analysis Set with available data who had nonmissing data at both baseline and Week 96 in the blinded phase were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline, Blinded Phase Week 96
    End point values
    		 Cilofexor 100 mg (Blinded Phase) Placebo (Blinded Phase)
    Number of subjects analysed
    122
    61
    Units: percentage of participants
        number (not applicable)
    9.8
    6.6
    Statistical analysis title
    		 Cilofexor 100 mg vs Placebo
    Comparison groups
    Placebo (Blinded Phase) v Cilofexor 100 mg (Blinded Phase)
    Number of subjects included in analysis
    183
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1978 [5]
    Method
    		 Mantel-Haenszel
    Parameter type
    		 Difference in Percentages
    Point estimate
    4.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.3
         upper limit
    		 13.5
    Notes
    [5] - The difference between cilofexor and Placebo, 95% CI, and the p-value (1-sided) were obtained by the stratum-adjusted MH method, with baseline UDCA use and Ludwig fibrosis stage as stratification factors.

    Secondary: Percentage of Participants With Fibrosis Improvement According to the Ludwig Classification at Blinded Phase Week 96

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    End point title
    		 Percentage of Participants With Fibrosis Improvement According to the Ludwig Classification at Blinded Phase Week 96
    End point description
    Fibrosis improvement was defined as ≥ 1-stage decrease from baseline in the Ludwig classification score at Blinded Study Phase Week 96. The stages of fibrosis was assessed according to Ludwig classification. Ludwig classification fibrosis stages range from 0 to 4, with higher scores indicating greater fibrosis (0=no fibrosis, 4=cirrhosis). Participants in the Full Analysis Set with available data who had nonmissing data at both baseline and Week 96 in the blinded phase were analyzed.
    End point type
    Secondary
    End point timeframe
    Blinded Phase Week 96
    End point values
    		 Cilofexor 100 mg (Blinded Phase) Placebo (Blinded Phase)
    Number of subjects analysed
    133
    64
    Units: percentage of participants
        number (not applicable)
    25.6
    17.2
    Statistical analysis title
    		 Cilofexor 100 mg vs Placebo
    Comparison groups
    Cilofexor 100 mg (Blinded Phase) v Placebo (Blinded Phase)
    Number of subjects included in analysis
    197
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0797 [6]
    Method
    		 Mantel-Haenszel
    Parameter type
    		 Difference in Percentages
    Point estimate
    8.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.5
         upper limit
    		 21.2
    Notes
    [6] - The difference between cilofexor and Placebo, 95% CI, and the p-value (1-sided) were obtained by the stratum-adjusted MH method, with baseline UDCA use and Ludwig fibrosis stage as stratification factors.

    Secondary: Change From Baseline in Primary Sclerosing Cholangitis (PSC) Symptoms - Module 1 based on disease-specific Patient Reported Outcome (PSC-PRO) at Blinded Phase Week 96

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    End point title
    		 Change From Baseline in Primary Sclerosing Cholangitis (PSC) Symptoms - Module 1 based on disease-specific Patient Reported Outcome (PSC-PRO) at Blinded Phase Week 96
    End point description
    The PSC-PRO addressed the severity of common everyday symptoms of PSC (eg, pruritus, fatigue, and right upper quadrant abdominal discomfort); and their functional impact (eg, on physical function, activities of daily living, and work productivity, etc). PSC-PRO module 1 – PSC symptoms contains a total of 12 questions asking about the severity of specific PSC symptoms on a scale of 0 (no symptoms) to 10 (symptoms as bad as you could imagine) with a 24-hour recall period. The total score, which is computed as 12 times the average of nonmissing scores of the 12 questions, can potentially range between 0 and 120, with higher scores indicating more severe symptoms. A positive change from baseline indicates worsening of symptoms. Participants in the Full Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline, Blinded Phase Week 96
    End point values
    		 Cilofexor 100 mg (Blinded Phase) Placebo (Blinded Phase)
    Number of subjects analysed
    274
    137
    Units: score on a scale
    arithmetic mean (standard deviation)
        Baseline
    11 ± 11.0
    11 ± 11.8
        Change at Blinded Phase Wk 96 (N=163, 78)
    1 ± 9.0
    0 ± 6.8
    Statistical analysis title
    		 Cilofexor 100 mg vs Placebo
    Comparison groups
    Cilofexor 100 mg (Blinded Phase) v Placebo (Blinded Phase)
    Number of subjects included in analysis
    411
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7275 [7]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LSM
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1
         upper limit
    		 3
    Notes
    [7] - The LSM, 95% CI and P-value (1-sided) were obtained by ANCOVA model to evaluate change at Week 96 as the dependent variable, baseline value of the outcome measure, baseline UDCA use, and baseline Ludwig fibrosis stage as independent variables.

    Secondary: Change From Baseline in Enhanced Liver Fibrosis (ELF™ ) Test Score at Blinded Phase Week 96

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    End point title
    		 Change From Baseline in Enhanced Liver Fibrosis (ELF™ ) Test Score at Blinded Phase Week 96
    End point description
    The Enhanced Liver Fibrosis (ELF™) test is a composite of three serum biomarkers of hepatobiliary fibrosis: hyaluronic acid, procollagen III amino‐terminal peptide, and tissue inhibitor of metalloproteinase. A typical range for ELF™ test scores in PSC is between 6 and 14. Higher ELF™ test scores are associated with more severe liver disease. A positive change from baseline indicated worsening of fibrosis. Participants in the Full Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline, Blinded Phase Week 96
    End point values
    		 Cilofexor 100 mg (Blinded Phase) Placebo (Blinded Phase)
    Number of subjects analysed
    163
    78
    Units: score on a scale
        least squares mean (confidence interval 95%)
    0.27 (0.16 to 0.38)
    0.30 (0.15 to 0.45)
    Statistical analysis title
    		 Cilofexor 100 mg vs Placebo
    Comparison groups
    Cilofexor 100 mg (Blinded Phase) v Placebo (Blinded Phase)
    Number of subjects included in analysis
    241
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3636 [8]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LSM
    Point estimate
    -0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.2
         upper limit
    		 0.14
    Notes
    [8] - The LSM, 95% CI and P-value (1-sided) were obtained by ANCOVA model to evaluate change at Week 96 as the dependent variable, baseline value of the outcome measure, baseline UDCA use, and baseline Ludwig fibrosis stage as independent variables.

    Secondary: Change From Baseline in Liver Stiffness by FibroScan® at Blinded Phase Week 96

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    End point title
    		 Change From Baseline in Liver Stiffness by FibroScan® at Blinded Phase Week 96
    End point description
    Change in liver stiffness was measured by FibroScan® scores. FibroScan measures liver scarring by measuring the stiffness of the liver. It's normally between 2 and 6 kPa. Many people with liver disease(s) have a result that's higher than the normal range. Higher scores indicate increased scarring of the liver. A positive change from baseline indicates severe liver disease(s). Participants in the Full Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline, Blinded Phase Week 96
    End point values
    		 Cilofexor 100 mg (Blinded Phase) Placebo (Blinded Phase)
    Number of subjects analysed
    154
    73
    Units: kilopascals (kPa)
        least squares mean (confidence interval 95%)
    2.4 (1.2 to 3.6)
    2.8 (1.1 to 4.4)
    Statistical analysis title
    		 Cilofexor 100 mg vs Placebo
    Comparison groups
    Cilofexor 100 mg (Blinded Phase) v Placebo (Blinded Phase)
    Number of subjects included in analysis
    227
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3595 [9]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LSM
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.2
         upper limit
    		 1.5
    Notes
    [9] - The LSM, 95% CI and P-value (1-sided) were obtained by ANCOVA model to evaluate change at Week 96 as the dependent variable, baseline value of the outcome measure, baseline UDCA use, and baseline Ludwig fibrosis stage as independent variables.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All-cause mortality: Randomization up to 3.4 years; Adverse events: Blinded Phase: First dose date in the Blinded Phase up to 100.3 weeks plus 30 days; Open-Label Extension (OLE) Phase: First dose date in the OLE Phase up to 45 weeks plus 30 days
    Adverse event reporting additional description
    All-cause mortality: All Randomized Analysis Set included all participants who were randomized in the study. Adverse Events: Safety Analysis Set included all participants who took at least 1 dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    Cilofexor 100 mg (Blinded Phase)
    Reporting group description
    		 Participants received cilofexor 100 mg tablet, orally, once daily for up to 100.3 weeks.

    Reporting group title
    Placebo (Blinded Phase)
    Reporting group description
    		 Participants received placebo to match cilofexor 100 mg tablet, orally, once daily for up to 98.1 weeks.

    Reporting group title
    Cilofexor From Cilofexor 100 mg (OLE Phase)
    Reporting group description
    		 Participants who received cilofexor in blinded phase and had entered the OLE phase received open-label cilofexor 100 mg tablet, orally, once daily for up to 44.7 weeks.

    Reporting group title
    Cilofexor From Placebo (OLE Phase)
    Reporting group description
    		 Participants who received placebo in blinded phase and had entered the OLE phase received open-label cilofexor 100 mg tablet, orally, once daily for up to 45.0 weeks.

    Serious adverse events
    		 Cilofexor 100 mg (Blinded Phase) Placebo (Blinded Phase) Cilofexor From Cilofexor 100 mg (OLE Phase) Cilofexor From Placebo (OLE Phase)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    53 / 277 (19.13%)
    26 / 139 (18.71%)
    9 / 80 (11.25%)
    1 / 45 (2.22%)
         number of deaths (all causes)
    2
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cholangiocarcinoma
         subjects affected / exposed
    0 / 277 (0.00%)
    2 / 139 (1.44%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Adenocarcinoma of colon
         subjects affected / exposed
    0 / 277 (0.00%)
    0 / 139 (0.00%)
    1 / 80 (1.25%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast cancer metastatic
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 139 (0.00%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 139 (0.00%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric cancer
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 139 (0.72%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gallbladder cancer
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 139 (0.00%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal neoplasm
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 139 (0.00%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Marginal zone lymphoma
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 139 (0.00%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 139 (0.72%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Cholecystectomy
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 139 (0.00%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colorectostomy
         subjects affected / exposed
    0 / 277 (0.00%)
    0 / 139 (0.00%)
    1 / 80 (1.25%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Liver transplant
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 139 (0.00%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ligament operation
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 139 (0.72%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    4 / 277 (1.44%)
    1 / 139 (0.72%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 139 (0.72%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 139 (0.00%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactoid reaction
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 139 (0.00%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    General physical condition abnormal
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 139 (0.00%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 139 (0.72%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endoscopic retrograde ~ cholangiopancreatography
         subjects affected / exposed
    1 / 277 (0.36%)
    1 / 139 (0.72%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    International normalised ratio ~ increased
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 139 (0.00%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic enzyme abnormal
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 139 (0.00%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Post procedural complication
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 139 (0.72%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal procedural ~ complication
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 139 (0.00%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clavicle fracture
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 139 (0.00%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ligament rupture
         subjects affected / exposed
    1 / 277 (0.36%)
    1 / 139 (0.72%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 139 (0.00%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 139 (0.00%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 139 (0.72%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 139 (0.00%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 139 (0.00%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peroneal nerve palsy
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 139 (0.00%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Migraine with aura
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 139 (0.00%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 277 (0.00%)
    0 / 139 (0.00%)
    1 / 80 (1.25%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 139 (0.00%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 139 (0.72%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    3 / 277 (1.08%)
    0 / 139 (0.00%)
    1 / 80 (1.25%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Crohn's disease
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 139 (0.00%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    2 / 277 (0.72%)
    0 / 139 (0.00%)
    1 / 80 (1.25%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea haemorrhagic
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 139 (0.00%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 139 (0.00%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 139 (0.00%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 139 (0.72%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 139 (0.00%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Obstructive pancreatitis
         subjects affected / exposed
    0 / 277 (0.00%)
    0 / 139 (0.00%)
    1 / 80 (1.25%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 139 (0.72%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 139 (0.72%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pouchitis
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 139 (0.00%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    10 / 277 (3.61%)
    7 / 139 (5.04%)
    2 / 80 (2.50%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    1 / 17
    1 / 10
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bile duct stenosis
         subjects affected / exposed
    1 / 277 (0.36%)
    2 / 139 (1.44%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    4 / 277 (1.44%)
    0 / 139 (0.00%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholangitis acute
         subjects affected / exposed
    4 / 277 (1.44%)
    0 / 139 (0.00%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bile duct stone
         subjects affected / exposed
    2 / 277 (0.72%)
    0 / 139 (0.00%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    2 / 277 (0.72%)
    0 / 139 (0.00%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    2 / 277 (0.72%)
    0 / 139 (0.00%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholangitis sclerosing
         subjects affected / exposed
    2 / 277 (0.72%)
    0 / 139 (0.00%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    1 / 277 (0.36%)
    1 / 139 (0.72%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    1 / 277 (0.36%)
    1 / 139 (0.72%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Biliary colic
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 139 (0.00%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Biliary dilatation
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 139 (0.00%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic haematoma
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 139 (0.00%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic cholecystitis
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 139 (0.72%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 139 (0.72%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    2 / 277 (0.72%)
    0 / 139 (0.00%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 139 (0.00%)
    1 / 80 (1.25%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal abscess
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 139 (0.00%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 139 (0.72%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholangitis infective
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 139 (0.72%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile infection
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 139 (0.00%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 277 (0.00%)
    0 / 139 (0.00%)
    1 / 80 (1.25%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis salmonella
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 139 (0.00%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 139 (0.72%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Klebsiella infection
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 139 (0.00%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 139 (0.00%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 139 (0.72%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 139 (0.72%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 139 (0.00%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 139 (0.00%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural sepsis
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 139 (0.72%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postoperative abscess
         subjects affected / exposed
    0 / 277 (0.00%)
    1 / 139 (0.72%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 139 (0.00%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Streptococcal sepsis
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 139 (0.00%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 139 (0.00%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 139 (0.00%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Type 1 diabetes mellitus
         subjects affected / exposed
    1 / 277 (0.36%)
    0 / 139 (0.00%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cilofexor 100 mg (Blinded Phase) Placebo (Blinded Phase) Cilofexor From Cilofexor 100 mg (OLE Phase) Cilofexor From Placebo (OLE Phase)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    232 / 277 (83.75%)
    109 / 139 (78.42%)
    34 / 80 (42.50%)
    24 / 45 (53.33%)
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    8 / 277 (2.89%)
    7 / 139 (5.04%)
    0 / 80 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    10
    8
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    32 / 277 (11.55%)
    18 / 139 (12.95%)
    1 / 80 (1.25%)
    0 / 45 (0.00%)
         occurrences all number
    44
    21
    1
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    34 / 277 (12.27%)
    24 / 139 (17.27%)
    3 / 80 (3.75%)
    0 / 45 (0.00%)
         occurrences all number
    37
    28
    3
    0
    Pyrexia
         subjects affected / exposed
    33 / 277 (11.91%)
    9 / 139 (6.47%)
    3 / 80 (3.75%)
    2 / 45 (4.44%)
         occurrences all number
    48
    12
    3
    4
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    40 / 277 (14.44%)
    20 / 139 (14.39%)
    1 / 80 (1.25%)
    2 / 45 (4.44%)
         occurrences all number
    50
    22
    1
    2
    Abdominal pain
         subjects affected / exposed
    38 / 277 (13.72%)
    17 / 139 (12.23%)
    1 / 80 (1.25%)
    0 / 45 (0.00%)
         occurrences all number
    52
    20
    1
    0
    Nausea
         subjects affected / exposed
    34 / 277 (12.27%)
    16 / 139 (11.51%)
    4 / 80 (5.00%)
    0 / 45 (0.00%)
         occurrences all number
    42
    19
    4
    0
    Diarrhoea
         subjects affected / exposed
    21 / 277 (7.58%)
    11 / 139 (7.91%)
    2 / 80 (2.50%)
    1 / 45 (2.22%)
         occurrences all number
    24
    12
    2
    1
    Abdominal distension
         subjects affected / exposed
    9 / 277 (3.25%)
    9 / 139 (6.47%)
    0 / 80 (0.00%)
    2 / 45 (4.44%)
         occurrences all number
    10
    9
    0
    2
    Vomiting
         subjects affected / exposed
    12 / 277 (4.33%)
    7 / 139 (5.04%)
    1 / 80 (1.25%)
    0 / 45 (0.00%)
         occurrences all number
    12
    7
    1
    0
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    135 / 277 (48.74%)
    50 / 139 (35.97%)
    14 / 80 (17.50%)
    11 / 45 (24.44%)
         occurrences all number
    184
    58
    14
    13
    Rash
         subjects affected / exposed
    16 / 277 (5.78%)
    7 / 139 (5.04%)
    1 / 80 (1.25%)
    0 / 45 (0.00%)
         occurrences all number
    17
    8
    2
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    14 / 277 (5.05%)
    2 / 139 (1.44%)
    1 / 80 (1.25%)
    2 / 45 (4.44%)
         occurrences all number
    15
    2
    1
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    15 / 277 (5.42%)
    14 / 139 (10.07%)
    2 / 80 (2.50%)
    0 / 45 (0.00%)
         occurrences all number
    18
    14
    2
    0
    Back pain
         subjects affected / exposed
    21 / 277 (7.58%)
    8 / 139 (5.76%)
    3 / 80 (3.75%)
    0 / 45 (0.00%)
         occurrences all number
    22
    9
    3
    0
    Infections and infestations
    Covid-19
         subjects affected / exposed
    65 / 277 (23.47%)
    26 / 139 (18.71%)
    11 / 80 (13.75%)
    11 / 45 (24.44%)
         occurrences all number
    68
    27
    11
    11
    Nasopharyngitis
         subjects affected / exposed
    15 / 277 (5.42%)
    12 / 139 (8.63%)
    0 / 80 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    22
    13
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    14 / 277 (5.05%)
    7 / 139 (5.04%)
    1 / 80 (1.25%)
    2 / 45 (4.44%)
         occurrences all number
    17
    8
    1
    2
    Urinary tract infection
         subjects affected / exposed
    8 / 277 (2.89%)
    5 / 139 (3.60%)
    5 / 80 (6.25%)
    0 / 45 (0.00%)
         occurrences all number
    11
    5
    5
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Mar 2019
    - In various sections within the protocol, liver stiffness by FibroScan® will be assessed if available. - In various sections within the protocol, sample size power was calculated using the “Pearson’s” Chi-square test for clarity. - In various sections within the protocol, “study procedures manual” and “study reference binder” were revised to “Site Operations Manual” for alignment.
    23 Oct 2019
    - In various sections within the protocol, GS-9674 was updated to use the study drug name cilofexor, abbreviated as CILO
    07 Apr 2020
    - Clarified that IBD includes ulcerative colitis, Crohn’s disease, and indeterminant colitis - Clarified that Partial Mayo score collection is not required for subjects using external ostomy bags - The term study medication has been updated to study drug - The term medicinal product has been updated to investigational product - Appendix 2.: Study Procedures Table and the associated footnotes updated to align with the key changes
    30 Jun 2021
    - Section 1.2.7 and 1.2.8 have been updated with final results from study GS-US-428-4025. - The terminology for the Blinded Study Phase was added and the corresponding sections were updated accordingly. - The protocol synopsis and the study procedure table(s) were updated to align with the updates to the body of the protocol. - Administrative changes throughout, including abbreviations, updates to terminology, updates to section headings, consistency with revised protocol template, language and additional minor edits.
    16 Mar 2022
    - Objectives and endpoints were updated (Section 2): • Time point “Blinded Study Phase Week 96” was added to the primary objective (Sections 2 and 8.1.1). • Evaluation of GGT was moved from secondary objectives/endpoints to exploratory objectives/endpoints (Sections 2, 8.1.1, 8.1.3, and 8.5.2). • Secondary objective/endpoint “To evaluate changes in liver fibrosis including hepatic collagen content and progression to cirrhosis at Blinded Study Phase Week 96” was moved to the exploratory objectives/endpoints” (Sections 2, 8.1.1, and 8.5.2). • Text updated to clarify that change in primary sclerosing cholangitis (PSC) symptoms will be evaluated based on the disease-specific PSC-patient-reported outcome (PSC-PRO) Module 1 at Blinded Study Phase Week 96 (Sections 2, 8.1.1, 8.1.3, and 8.5.2). - Text added to clarify that if the Blinded Study Phase follow-up visit and the OLE Phase baseline/Day 1 visit occur on the same day, study assessment procedures should be performed according to the OLE Phase baseline/Day 1 visit (Sections 3.1, and 6.4.7).

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    26 Sep 2022
    Following recommendation of the external Data Monitoring Committee, after it reviewed the results of a planned interim futility analysis.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    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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