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    Clinical Trial Results:
    A Phase 2, Randomized, Double-Blind, Placebo Controlled Study Evaluating the Safety, Tolerability, and Efficacy of GS-9674 in Subjects with Primary Sclerosing Cholangitis Without Cirrhosis

    Summary
    EudraCT number
    		 2016-002442-23
    Trial protocol
    		 GB   AT  
    Global end of trial date
    18 May 2020

    Results information
    Results version number
    		 v2(current)
    This version publication date
    27 May 2021
    First version publication date
    31 Jul 2019
    Other versions
    		 v1
    Version creation reason
    • New data added to full data set
    Updated the record to post final results.

    Trial information

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    Trial identification
    Sponsor protocol code
    GS-US-428-4025
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02943460
    WHO universal trial number (UTN)
    		 -
    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
    18 May 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Feb 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    18 May 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the safety and tolerability of cilofexor in 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
    29 Nov 2016
    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 Kingdom: 7
    Country: Number of subjects enrolled
    Austria: 1
    Country: Number of subjects enrolled
    United States: 36
    Country: Number of subjects enrolled
    Canada: 8
    Worldwide total number of subjects
    52
    EEA total number of subjects
    8
    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)
    52
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled at study sites in North America and Europe. The first participant was screened on 29 November 2016. The last study visit occurred on 18 May 2020.

    Pre-assignment
    Screening details
    		 105 participants were screened.

    Period 1
    Period 1 title
    Blinded Study Phase
    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
    Arm description
    		 Cilofexor 100 mg tablet + placebo to match cilofexor 30 mg tablet orally once daily with food for up to 12.6 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cilofexor
    Investigational medicinal product code
    Other name
    GS-9674
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg administered once daily

    Investigational medicinal product name
    Placebo to match cilofexor 30 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered once daily

    Arm title
    		 Cilofexor 30 mg
    Arm description
    		 Cilofexor 30 mg tablet + placebo to match cilofexor 100 mg tablet orally once daily with food for up to 12.7 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cilofexor
    Investigational medicinal product code
    Other name
    GS-9674
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    30 mg administered once daily

    Investigational medicinal product name
    Placebo to match cilofexor 100 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered once daily

    Arm title
    		 Placebo
    Arm description
    		 Placebo to match cilofexor 30 mg tablet + placebo to match cilofexor 100 mg tablet orally once daily with food for up to 12.3 weeks
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo to match cilofexor 30 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered once daily

    Investigational medicinal product name
    Placebo to match cilofexor 100 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered once daily

    Number of subjects in period 1
    		Cilofexor 100 mg Cilofexor 30 mg Placebo
    Started
    22
    20
    10
    Completed
    19
    19
    10
    Not completed
    3
    1
    0
         Withdrew Consent
    -
    1
    -
         Adverse Event
    3
    -
    -
    Period 2
    Period 2 title
    Open Label Extension (OLE) Phase
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cilofexor 100 mg to Cilofexor 100 mg
    Arm description
    		 Cilofexor 100 mg tablet orally once daily with food for an additional up to 97.4 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cilofexor
    Investigational medicinal product code
    Other name
    GS-9674
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg administered once daily

    Arm title
    		 Cilofexor 30 mg to Cilofexor 100 mg
    Arm description
    		 Cilofexor 100 mg tablet orally once daily with food for an additional up to 97 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cilofexor
    Investigational medicinal product code
    Other name
    GS-9674
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg administered once daily

    Arm title
    		 Placebo to Cilofexor 100 mg
    Arm description
    		 Cilofexor 100 mg tablet orally once daily with food for an additional up to 97 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cilofexor
    Investigational medicinal product code
    Other name
    GS-9674
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg administered once daily

    Number of subjects in period 2 [1]
    		Cilofexor 100 mg to Cilofexor 100 mg Cilofexor 30 mg to Cilofexor 100 mg Placebo to Cilofexor 100 mg
    Started
    19
    18
    10
    Completed
    14
    11
    8
    Not completed
    5
    7
    2
         Withdrew Consent
    2
    1
    -
         Adverse Event
    2
    5
    2
         Investigator's Discretion
    1
    1
    -
    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: One participant from the 'Cilofexor 30 mg' group completed the Blinded Study Phase, but did not continue in the OLE Phase.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cilofexor 100 mg
    Reporting group description
    		 Cilofexor 100 mg tablet + placebo to match cilofexor 30 mg tablet orally once daily with food for up to 12.6 weeks

    Reporting group title
    Cilofexor 30 mg
    Reporting group description
    		 Cilofexor 30 mg tablet + placebo to match cilofexor 100 mg tablet orally once daily with food for up to 12.7 weeks

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo to match cilofexor 30 mg tablet + placebo to match cilofexor 100 mg tablet orally once daily with food for up to 12.3 weeks

    Reporting group values
    		 Cilofexor 100 mg Cilofexor 30 mg Placebo Total
    Number of subjects
    		 22 20 10 52
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 42 ( 8.6 ) 46 ( 12.1 ) 42 ( 10.9 ) -
    Gender categorical
    Units: Subjects
        Female
    		 11 6 5 22
        Male
    		 11 14 5 30
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 0 3 0 3
        Not Hispanic or Latino
    		 21 17 9 47
        Not Permitted
    		 1 0 1 2
    Race
    Not Permitted = local regulators did not allow collection of race information.
    Units: Subjects
        Asian
    		 0 2 1 3
        Black or African American
    		 4 3 1 8
        White
    		 17 15 7 39
        Not Permitted
    		 0 0 1 1
        Other
    		 1 0 0 1

    End points

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    End points reporting groups
    Reporting group title
    Cilofexor 100 mg
    Reporting group description
    		 Cilofexor 100 mg tablet + placebo to match cilofexor 30 mg tablet orally once daily with food for up to 12.6 weeks

    Reporting group title
    Cilofexor 30 mg
    Reporting group description
    		 Cilofexor 30 mg tablet + placebo to match cilofexor 100 mg tablet orally once daily with food for up to 12.7 weeks

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo to match cilofexor 30 mg tablet + placebo to match cilofexor 100 mg tablet orally once daily with food for up to 12.3 weeks
    Reporting group title
    Cilofexor 100 mg to Cilofexor 100 mg
    Reporting group description
    		 Cilofexor 100 mg tablet orally once daily with food for an additional up to 97.4 weeks

    Reporting group title
    Cilofexor 30 mg to Cilofexor 100 mg
    Reporting group description
    		 Cilofexor 100 mg tablet orally once daily with food for an additional up to 97 weeks

    Reporting group title
    Placebo to Cilofexor 100 mg
    Reporting group description
    		 Cilofexor 100 mg tablet orally once daily with food for an additional up to 97 weeks

    Primary: Percentage of Participants Experiencing Treatment-Emergent Adverse Events During the Blinded Phase

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    End point title
    		 Percentage of Participants Experiencing Treatment-Emergent Adverse Events During the Blinded Phase [1]
    End point description
    Treatment-emergent adverse events occurring during the Blinded Phase were defined as 1 or both of the following: 1) Any adverse events (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 in the Blinded Phase (and before the first dosing date in the Open Label Extension (OLE) Phase), or 2) Any AEs leading to premature discontinuation of study drug in the Blinded Phase. Safety Analysis Set included all participants who received at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    First dose date up to last dose date plus 30 days (Up to 17 weeks)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical comparison was planned or performed.
    End point values
    		 Cilofexor 100 mg Cilofexor 30 mg Placebo
    Number of subjects analysed
    22
    20
    10
    Units: percentage of participants
        number (not applicable)
    81.8
    70.0
    100.0
    No statistical analyses for this end point

    Primary: Percentage of Participants Experiencing Treatment-Emergent Serious Adverse Events During the Blinded Phase

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    End point title
    		 Percentage of Participants Experiencing Treatment-Emergent Serious Adverse Events During the Blinded Phase [2]
    End point description
    A serious adverse event was defined as an event that, at any dose, resulted in any of the following: death, life-threatening, 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
    Primary
    End point timeframe
    First dose date up to last dose date plus 30 days (Up to 17 weeks)
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical comparison was planned or performed.
    End point values
    		 Cilofexor 100 mg Cilofexor 30 mg Placebo
    Number of subjects analysed
    22
    20
    10
    Units: percentage of participants
        number (not applicable)
    13.6
    0
    0
    No statistical analyses for this end point

    Primary: Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities During the Blinded Phase

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    End point title
    		 Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities During the Blinded Phase [3]
    End point description
    Treatment-emergent laboratory abnormalities occurring during the Blinded Phase were defined as values that increase at least 1 toxicity grade from baseline at any postbaseline time point, up to and including the date of last dose of study drug in the Blinded Phase plus 30 days (and prior to or on the first dose date of the OLE phase). The Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 was used for assigning toxicity grades (0 to 4, with higher grades indicating more severity). Participants in the Safety Analysis Set were analyzed.
    End point type
    Primary
    End point timeframe
    First dose date up to last dose date plus 30 days (Up to 17 weeks)
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical comparison was planned or performed.
    End point values
    		 Cilofexor 100 mg Cilofexor 30 mg Placebo
    Number of subjects analysed
    22
    20
    10
    Units: percentage of participants
    number (not applicable)
        Any Grade 1 or Higher
    90.9
    85.0
    100.0
        Grade 1
    22.7
    25.0
    10.0
        Grade 2
    36.4
    35.0
    60.0
        Grade 3
    27.3
    20.0
    30.0
        Grade 4
    4.5
    5.0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Blinded Phase: First dose date up to last dose date plus 30 days (Up to 17 weeks); OLE Phase: First dose date up to last dose date plus 30 days (Up to 102 weeks)
    Adverse event reporting additional description
    Safety Analysis Set included all participants who received at least 1 dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Cilofexor 100 mg (Blinded Phase)
    Reporting group description
    		 Cilofexor 100 mg tablet + placebo to match cilofexor 30 mg tablet orally once daily with food for up to 12.6 weeks

    Reporting group title
    Cilofexor 30 mg (Blinded Phase)
    Reporting group description
    		 Cilofexor 30 mg tablet + placebo to match cilofexor 100 mg tablet orally once daily with food for up to 12.7 weeks

    Reporting group title
    Placebo (Blinded Phase)
    Reporting group description
    		 Placebo to match cilofexor 30 mg tablet + placebo to match cilofexor 100 mg tablet orally once daily with food for up to 12.3 weeks

    Reporting group title
    Cilofexor 100 mg (Open Label Extension Phase)
    Reporting group description
    		 Following the Blinded Phase, eligible participants received cilofexor 100 mg tablet orally once daily for an additional up to 97.4 weeks

    Serious adverse events
    		 Cilofexor 100 mg (Blinded Phase) Cilofexor 30 mg (Blinded Phase) Placebo (Blinded Phase) Cilofexor 100 mg (Open Label Extension Phase)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 22 (13.64%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    10 / 47 (21.28%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Meniscus injury
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    0 / 47 (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
    Seizure
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain lower
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    0 / 47 (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
    Bile duct obstruction
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    2 / 47 (4.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholangitis sclerosing
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Organising pneumonia
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    0 / 47 (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
    Infections and infestations
    Influenza
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    0 / 47 (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
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         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) Cilofexor 30 mg (Blinded Phase) Placebo (Blinded Phase) Cilofexor 100 mg (Open Label Extension Phase)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    18 / 22 (81.82%)
    14 / 20 (70.00%)
    10 / 10 (100.00%)
    41 / 47 (87.23%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Benign neoplasm of skin
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    1 / 10 (10.00%)
    0 / 47 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Haemangioma
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    1 / 10 (10.00%)
    0 / 47 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Melanocytic naevus
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    1 / 10 (10.00%)
    0 / 47 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Seborrhoeic keratosis
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    1 / 10 (10.00%)
    0 / 47 (0.00%)
         occurrences all number
    0
    0
    1
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    3 / 22 (13.64%)
    3 / 20 (15.00%)
    2 / 10 (20.00%)
    6 / 47 (12.77%)
         occurrences all number
    3
    3
    2
    6
    Pyrexia
         subjects affected / exposed
    1 / 22 (4.55%)
    2 / 20 (10.00%)
    0 / 10 (0.00%)
    3 / 47 (6.38%)
         occurrences all number
    1
    2
    0
    4
    Chills
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    0 / 10 (0.00%)
    2 / 47 (4.26%)
         occurrences all number
    0
    1
    0
    2
    Pain
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Reproductive system and breast disorders
    Erectile dysfunction
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    1 / 10 (10.00%)
    2 / 47 (4.26%)
         occurrences all number
    0
    0
    1
    2
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    2 / 10 (20.00%)
    2 / 47 (4.26%)
         occurrences all number
    0
    0
    2
    3
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 20 (0.00%)
    1 / 10 (10.00%)
    2 / 47 (4.26%)
         occurrences all number
    1
    0
    1
    2
    Blood bilirubin increased
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    1 / 10 (10.00%)
    3 / 47 (6.38%)
         occurrences all number
    0
    0
    1
    3
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    2 / 10 (20.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    0
    2
    2
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    0 / 10 (0.00%)
    2 / 47 (4.26%)
         occurrences all number
    0
    1
    0
    4
    Electrocardiogram abnormal
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    0 / 10 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    1
    0
    2
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    1 / 10 (10.00%)
    0 / 47 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Injury, poisoning and procedural complications
    Stoma site pain
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 22 (4.55%)
    4 / 20 (20.00%)
    2 / 10 (20.00%)
    7 / 47 (14.89%)
         occurrences all number
    1
    6
    3
    7
    Dizziness
         subjects affected / exposed
    2 / 22 (9.09%)
    1 / 20 (5.00%)
    0 / 10 (0.00%)
    2 / 47 (4.26%)
         occurrences all number
    3
    1
    0
    2
    Paraesthesia
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 20 (5.00%)
    0 / 10 (0.00%)
    3 / 47 (6.38%)
         occurrences all number
    1
    1
    0
    4
    Sinus headache
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Eye disorders
    Blepharitis
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    4 / 22 (18.18%)
    2 / 20 (10.00%)
    1 / 10 (10.00%)
    5 / 47 (10.64%)
         occurrences all number
    4
    2
    1
    5
    Nausea
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    3 / 10 (30.00%)
    5 / 47 (10.64%)
         occurrences all number
    0
    1
    4
    7
    Abdominal discomfort
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 20 (0.00%)
    1 / 10 (10.00%)
    4 / 47 (8.51%)
         occurrences all number
    2
    0
    2
    6
    Abdominal distension
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 20 (0.00%)
    1 / 10 (10.00%)
    4 / 47 (8.51%)
         occurrences all number
    3
    0
    1
    4
    Abdominal pain
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 20 (0.00%)
    1 / 10 (10.00%)
    4 / 47 (8.51%)
         occurrences all number
    1
    0
    1
    10
    Diarrhoea
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 20 (5.00%)
    0 / 10 (0.00%)
    4 / 47 (8.51%)
         occurrences all number
    2
    1
    0
    4
    Vomiting
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    1 / 10 (10.00%)
    2 / 47 (4.26%)
         occurrences all number
    0
    1
    1
    3
    Constipation
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 20 (0.00%)
    1 / 10 (10.00%)
    0 / 47 (0.00%)
         occurrences all number
    3
    0
    1
    0
    Dyspepsia
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    1 / 10 (10.00%)
    2 / 47 (4.26%)
         occurrences all number
    0
    0
    1
    2
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    3 / 47 (6.38%)
         occurrences all number
    0
    0
    0
    3
    Faeces pale
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    0 / 10 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    1
    0
    1
    Flatulence
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    0 / 10 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    2
    0
    2
    Pouchitis
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    0 / 10 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    1
    0
    1
    Colitis ulcerative
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Noninfective sialoadenitis
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    1 / 10 (10.00%)
    0 / 47 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Tongue disorder
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    1 / 10 (10.00%)
    0 / 47 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    3 / 47 (6.38%)
         occurrences all number
    1
    0
    0
    3
    Hepatitis acute
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hepatitis cholestatic
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    1 / 10 (10.00%)
    0 / 47 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    8 / 22 (36.36%)
    5 / 20 (25.00%)
    6 / 10 (60.00%)
    20 / 47 (42.55%)
         occurrences all number
    8
    5
    6
    22
    Rash
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 20 (0.00%)
    1 / 10 (10.00%)
    2 / 47 (4.26%)
         occurrences all number
    1
    0
    1
    2
    Dermatitis
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    1 / 10 (10.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    0
    1
    1
    Urticaria
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    1 / 10 (10.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    0
    1
    1
    Dermal cyst
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    1 / 10 (10.00%)
    0 / 47 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Rash pruritic
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Renal and urinary disorders
    Chromaturia
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    1 / 10 (10.00%)
    0 / 47 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    1 / 10 (10.00%)
    5 / 47 (10.64%)
         occurrences all number
    0
    1
    1
    6
    Back pain
         subjects affected / exposed
    1 / 22 (4.55%)
    2 / 20 (10.00%)
    0 / 10 (0.00%)
    2 / 47 (4.26%)
         occurrences all number
    2
    2
    0
    2
    Muscle spasms
         subjects affected / exposed
    1 / 22 (4.55%)
    2 / 20 (10.00%)
    0 / 10 (0.00%)
    2 / 47 (4.26%)
         occurrences all number
    1
    2
    0
    2
    Pain in extremity
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    1 / 10 (10.00%)
    2 / 47 (4.26%)
         occurrences all number
    0
    0
    1
    2
    Flank pain
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    1 / 10 (10.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    0
    2
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    5 / 22 (22.73%)
    5 / 20 (25.00%)
    2 / 10 (20.00%)
    14 / 47 (29.79%)
         occurrences all number
    5
    5
    2
    18
    Influenza
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    1 / 10 (10.00%)
    4 / 47 (8.51%)
         occurrences all number
    0
    0
    1
    4
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 20 (0.00%)
    1 / 10 (10.00%)
    2 / 47 (4.26%)
         occurrences all number
    2
    0
    1
    2
    Sinusitis
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    1 / 10 (10.00%)
    2 / 47 (4.26%)
         occurrences all number
    0
    0
    1
    2
    Viral infection
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    2
    0
    0
    1
    Conjunctivitis
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 20 (5.00%)
    0 / 10 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Respiratory tract infection
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    1 / 10 (10.00%)
    0 / 47 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    1 / 10 (10.00%)
    1 / 47 (2.13%)
         occurrences all number
    0
    0
    1
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Sep 2016
    ● Increased number of months of prior ursodeoxycholic acid (UDCA) use to allow longer duration for UDCA induced reductions in alkaline phosphatase to appear. ● Added clarity that participants with nonalcoholic steatohepatitis (NASH) should be excluded and definition of inflammatory bowel disease (IBD) and liver fibrosis scoring updated. ● Additional visits added for safety monitoring in the Open Label Extension. ● Updated with additional available safety and PK data. ● Inclusion criteria updated to further ensure participants with more advanced liver disease/cirrhosis and IBD are not included. ● Prohibited concomitant mediations updated based on additional available drug-drug interaction (DDI) data. ● Updated to add exclusion of chronic antibiotic use for the treatment of PSC. ● Clarified that rescreening once is allowed. ● Updated contraception requirements section based on DDI and pre-clinical embryofetal toxicity data now available.
    21 Dec 2016
    ● Language added for clarification that direct bilirubin will be used instead of total bilirubin in FibroSURE/FibroTest® calculations in participants with Gilbert’s syndrome or hemolysis, and that in subjects with FibroSURE/FibroTest® ≥0.75 may be included if a biopsy within 12 months of screening has excluded cirrhosis. ● Updated to reflect final non-clinical toxicology data to support dosing beyond 12 weeks. ● Updated inclusion criteria from creatinine clearance to serum creatinine. ● Language added to clarify that study drug should not be dosed within 4 hours of dosing with bile acid sequestrants. ● Language added to clarify retesting/rescreening eligibility for subjects. ● Clarified that cirrhosis assessments include review of historical information including liver histology and FibroScan results if available. ● Language added for pregnancy requirement for clarification.
    09 Feb 2017
    ● Updated section on toxicity management observation for drug induced liver injury (DILI) for clarification and removed elevated serum alkaline phosphatase (ALP) as one of the close observation criteria.

    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.
    An unplanned review of unblinded clinical trial data was performed in this study that was not prospectively specified in the protocol. There was no impact on the overall integrity or conclusions of the study.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/30661255
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