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    Clinical Trial Results:
    A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Dose-Finding, Clinical Trial Evaluating the Efficacy and Safety of Obeticholic Acid in Subjects with Primary Sclerosing Cholangitis

    Summary
    EudraCT number
    		 2014-002205-38
    Trial protocol
    		 IT  
    Global end of trial date
    22 Mar 2018

    Results information
    Results version number
    		 v2(current)
    This version publication date
    28 Jun 2021
    First version publication date
    23 Mar 2018
    Other versions
    		 v1
    Version creation reason
    • New data added to full data set
    Updating with long-term safety extension (LTSE) phase results.

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    747-207
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02177136
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Intercept Pharmaceuticals, Inc.
    Sponsor organisation address
    9520 Towne Centre Drive, Suite 200, San Diego, CA, United States, 92121
    Public contact
    Medical Information , Intercept Pharmaceuticals, Inc., +1.844. 782.4278, medinfo@interceptpharma.com
    Scientific contact
    Medical Information , Intercept Pharmaceuticals, Inc., +1.844. 782.4278, medinfo@interceptpharma.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
    22 Mar 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 Mar 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Mar 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    This was a phase 2, double-blind (DB), placebo-controlled trial in participants with primary sclerosing cholangitis to evaluate the effect of obeticholic acid on liver biochemistry, in particular, serum alkaline phosphatase; and, safety. The LTSE phase was conducted to evaluate the safety, tolerability, and efficacy of long-term, open-label use of obeticholic acid (OCA) in participants with primary sclerosing cholangitis who had completed the DB phase of the study.
    Protection of trial subjects
    This study was conducted in accordance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice, and the principles of the Declaration of Helsinki, in addition to following the laws and regulations of the country or countries in which a study is conducted.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    09 Feb 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 24 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Italy: 4
    Country: Number of subjects enrolled
    United States: 73
    Worldwide total number of subjects
    77
    EEA total number of subjects
    4
    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)
    72
    From 65 to 84 years
    5
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment started December 2014 and completed September 2016. All participants were required to undergo thorough screening procedures, to confirm they met the eligibility criteria, during the 30-day period preceding the first dose.

    Pre-assignment
    Screening details
    		 DB Phase: 77 participants were randomized to receive placebo, 1.5 milligrams (mg) OCA titrated to 3 mg OCA or 5 mg OCA titrated to 10 mg OCA; 1 participant did not receive treatment, 1 participant received 5 mg OCA titrated to 10 mg OCA instead of placebo. LTSE Phase: Open-label OCA doses up to 10 mg daily were evaluated.

    Period 1
    Period 1 title
    DB Phase
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 1.5 mg OCA Titrating to 3 mg OCA
    Arm description
    		 Participants randomized to 1.5 mg OCA took 1.5 mg OCA daily for 12 weeks during the DB phase. If tolerated, the dose was increased to 3 mg OCA daily for an additional 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    OCA
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants randomized to 1.5 mg OCA took 1.5 mg OCA daily for 12 weeks. If tolerated, the dose was increased to 3 mg OCA daily for an additional 12 weeks.

    Arm title
    		 5 mg OCA Titrating to 10 mg OCA
    Arm description
    		 Participants randomized to 5 mg OCA took 5 mg OCA daily for 12 weeks during the DB phase. If tolerated, the dose was increased to 10 mg OCA daily for an additional 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    OCA
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants randomized to 5 mg OCA took 5 mg OCA daily for 12 weeks. If tolerated, the dose was increased to 10 mg OCA daily for an additional 12 weeks.

    Arm title
    		 Placebo
    Arm description
    		 Participants randomized to placebo took placebo daily for 24 weeks during the DB phase.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants randomized to placebo took placebo daily for 24 weeks.

    Number of subjects in period 1 [1]
    		1.5 mg OCA Titrating to 3 mg OCA 5 mg OCA Titrating to 10 mg OCA Placebo
    Started
    25
    26
    25
    Received At Least 1 Dose Of Study Drug
    25
    26
    25
    Completed
    19
    21
    21
    Not completed
    6
    5
    4
         Consent withdrawn by subject
    2
    -
    -
         Adverse event, non-fatal
    4
    5
    3
         Protocol deviation
    -
    -
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: One participant randomized to receive 1.5 mg OCA titrating to 3 mg OCA withdrew prior to dosing.
    Period 2
    Period 2 title
    LTSE Phase
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 LTSE OCA Total
    Arm description
    		 Following completion of the DB phase, participants were asked to reconfirm their consent for participation in the LTSE phase (planned as a further 24 months) beginning at 5 or 10 mg OCA, based on the last treatment received during the DB phase. Doses up to 10 mg daily were evaluated. All participants received open-label OCA during the LTSE phase of the study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    OCA
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    All participants received open-label OCA during the LTSE phase of the study. Participants started treatment at 5 mg OCA once daily, except that those participants who completed treatment in the DB phase with 10 mg OCA once daily would continue at 10 mg OCA unless safety and tolerability warranted a dose reduction to 5 mg. Those participants who did not up-titrate their dose at DB Week 12 could remain on their DB dose at LTSE Day 1 or start at 5 mg per Investigator decision based on safety and tolerability of the DB dose at Week 24.

    Number of subjects in period 2 [2]
    		LTSE OCA Total
    Started
    59
    Received At Least 1 Dose Of Study Drug
    59
    Completed
    35
    Not completed
    24
         Consent withdrawn by subject
    6
         Physician decision
    2
         Adverse event, non-fatal
    10
         Pruritus
    4
         Participant Moved
    1
         Lost to follow-up
    1
    Notes
    [2] - 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: Eligible participants who completed the DB phase could enroll in the LTSE phase.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    1.5 mg OCA Titrating to 3 mg OCA
    Reporting group description
    		 Participants randomized to 1.5 mg OCA took 1.5 mg OCA daily for 12 weeks during the DB phase. If tolerated, the dose was increased to 3 mg OCA daily for an additional 12 weeks.

    Reporting group title
    5 mg OCA Titrating to 10 mg OCA
    Reporting group description
    		 Participants randomized to 5 mg OCA took 5 mg OCA daily for 12 weeks during the DB phase. If tolerated, the dose was increased to 10 mg OCA daily for an additional 12 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants randomized to placebo took placebo daily for 24 weeks during the DB phase.

    Reporting group values
    		 1.5 mg OCA Titrating to 3 mg OCA 5 mg OCA Titrating to 10 mg OCA Placebo Total
    Number of subjects
    		 25 26 25 76
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 24 23 24 71
        From 65-84 years
    		 1 3 1 5
        85 years and over
    		 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 41.6 ( 12.56 ) 44.9 ( 14.28 ) 43.7 ( 13.05 ) -
    Gender categorical
    Units: Subjects
        Female
    		 10 14 11 35
        Male
    		 15 12 14 41
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 2 2 1 5
        Not Hispanic or Latino
    		 23 24 24 71
    Race
    Units: Subjects
        Asian
    		 1 0 0 1
        Black or African American
    		 3 4 3 10
        White
    		 21 22 22 65
    Alkaline Phosphatase (ALP)
    Units: Units/Litre (U/L)
        arithmetic mean (standard deviation)
    		 422.5 ( 123.07 ) 428.5 ( 178.19 ) 562.8 ( 300.22 ) -
    Total Bilirubin
    Units: Micromoles (umol)/L
        arithmetic mean (standard deviation)
    		 16.3 ( 8.17 ) 19.4 ( 10.94 ) 20.9 ( 11.48 ) -
    Weight
    Units: Kilograms (kg)
        arithmetic mean (standard deviation)
    		 74.5 ( 12.51 ) 73.6 ( 12.76 ) 73.0 ( 12.95 ) -
    Height
    Units: Centimetre
        arithmetic mean (standard deviation)
    		 174.4 ( 8.95 ) 170.4 ( 11.61 ) 172.6 ( 10.70 ) -
    Body Mass Index
    Units: kg/metre squared
        arithmetic mean (standard deviation)
    		 24.6 ( 4.38 ) 25.3 ( 3.74 ) 24.5 ( 3.71 ) -
    International Normalized Ratio (INR)
    Units: n/a
        arithmetic mean (standard deviation)
    		 1.0 ( 0.06 ) 1.0 ( 0.10 ) 1.0 ( 0.07 ) -

    End points

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    End points reporting groups
    Reporting group title
    1.5 mg OCA Titrating to 3 mg OCA
    Reporting group description
    		 Participants randomized to 1.5 mg OCA took 1.5 mg OCA daily for 12 weeks during the DB phase. If tolerated, the dose was increased to 3 mg OCA daily for an additional 12 weeks.

    Reporting group title
    5 mg OCA Titrating to 10 mg OCA
    Reporting group description
    		 Participants randomized to 5 mg OCA took 5 mg OCA daily for 12 weeks during the DB phase. If tolerated, the dose was increased to 10 mg OCA daily for an additional 12 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants randomized to placebo took placebo daily for 24 weeks during the DB phase.
    Reporting group title
    LTSE OCA Total
    Reporting group description
    		 Following completion of the DB phase, participants were asked to reconfirm their consent for participation in the LTSE phase (planned as a further 24 months) beginning at 5 or 10 mg OCA, based on the last treatment received during the DB phase. Doses up to 10 mg daily were evaluated. All participants received open-label OCA during the LTSE phase of the study.

    Primary: DB Phase: Change From Baseline In Serum ALP

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    End point title
    		 DB Phase: Change From Baseline In Serum ALP
    End point description
    The primary efficacy analysis will compare the Week 24 change from Baseline in ALP between OCA treatment group and placebo using an analysis of covariance (ANCOVA) model with fixed effects for treatment group and randomization strata, and Baseline as a covariate. Results are reported in U/L.
    End point type
    Primary
    End point timeframe
    Baseline, Week 24
    End point values
    		 1.5 mg OCA Titrating to 3 mg OCA 5 mg OCA Titrating to 10 mg OCA Placebo
    Number of subjects analysed
    25
    26
    25
    Units: U/L
        least squares mean (standard error)
    -105.05 ( 38.02 )
    -110.19 ( 33.77 )
    -26.76 ( 36.65 )
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    The primary efficacy analysis compared the Week-24 change from Baseline in ALP between OCA treatment group and placebo using an ANCOVA model with fixed effects for treatment group and randomization strata, and Baseline as a covariate.
    Comparison groups
    Placebo v 5 mg OCA Titrating to 10 mg OCA
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0434
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Statistical analysis 2
    Comparison groups
    1.5 mg OCA Titrating to 3 mg OCA v Placebo
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0665
    Method
    		 ANCOVA
    Confidence interval

    Primary: LTSE Phase: Incidence Of Adverse Events Of Special Interest (AESIs)

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    End point title
    		 LTSE Phase: Incidence Of Adverse Events Of Special Interest (AESIs) [1]
    End point description
    The primary safety analysis evaluated the effects of OCA treatment on AESIs of pruritus, hepatic disorders, and dyslipidemia. All adverse event (AE) summaries were restricted to treatment-emergent AEs (TEAEs), which were defined as any AEs that newly appeared, increased in frequency, or worsened in severity following initiation of investigational product. Treatment-emergent pruritus was defined as any preferred term including “Prur-”. Hepatic disorder AESIs were defined using specific Hepatic Disorders Standardized Medical Dictionary for Regulatory Activities (MedDRA) Query (SMQ) terms. AE lipid profile changes, defined in the Dyslipidemia SMQ, were reported. Verbatim terms were mapped to PTs and system organ classes using MedDRA version 17.1 for all AE summaries except those for hepatic disorder AESIs, which used MedDRA version 18.1. A summary of serious and all other non-serious AEs, regardless of causality, is located in the Reported Adverse Events module.
    End point type
    Primary
    End point timeframe
    LTSE Baseline (DB Week 24) to Month 26
    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: Statistical analyses data were not calculated for adverse events per study protocol.
    End point values
    		 LTSE OCA Total
    Number of subjects analysed
    59
    Units: Participants
        Dyslipidaemia
    1
        Hepatic Disorder
    23
        Pruritus
    34
    No statistical analyses for this end point

    Secondary: DB Phase: Change From Baseline In Serum Alanine Transaminase (ALT)

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    End point title
    		 DB Phase: Change From Baseline In Serum Alanine Transaminase (ALT)
    End point description
    As a marker of hepatic biochemistry and liver function, the median change in ALT from Baseline at Week 24 is reported. Results are reported in U/L.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 1.5 mg OCA Titrating to 3 mg OCA 5 mg OCA Titrating to 10 mg OCA Placebo
    Number of subjects analysed
    25
    26
    25
    Units: U/L
        median (inter-quartile range (Q1-Q3))
    -33.0 (-50.5 to 5.0)
    -5.5 (-30.0 to 4.5)
    -19.5 (-49.0 to 4.0)
    No statistical analyses for this end point

    Secondary: DB Phase: Change From Baseline In Serum Aspartate Aminotransferase (AST)

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    End point title
    		 DB Phase: Change From Baseline In Serum Aspartate Aminotransferase (AST)
    End point description
    As a marker of hepatic biochemistry and liver function, the median change in AST from Baseline at Week 24 is reported. Results are reported in U/L.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 1.5 mg OCA Titrating to 3 mg OCA 5 mg OCA Titrating to 10 mg OCA Placebo
    Number of subjects analysed
    25
    26
    25
    Units: U/L
        median (inter-quartile range (Q1-Q3))
    -8.0 (-20.0 to 19.0)
    0.5 (-17.5 to 32.8)
    -14.0 (-35.5 to 8.0)
    No statistical analyses for this end point

    Secondary: DB Phase: Change From Baseline In Serum Total Bilirubin

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    End point title
    		 DB Phase: Change From Baseline In Serum Total Bilirubin
    End point description
    As a marker of hepatic biochemistry and liver function, the median change in serum total bilirubin from Baseline at Week 24 is reported. Results are reported in umol/L.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 1.5 mg OCA Titrating to 3 mg OCA 5 mg OCA Titrating to 10 mg OCA Placebo
    Number of subjects analysed
    25
    26
    25
    Units: umol/L
        median (inter-quartile range (Q1-Q3))
    0.8 (-1.7 to 4.3)
    1.3 (-1.3 to 6.9)
    0.0 (-5.1 to 4.3)
    No statistical analyses for this end point

    Secondary: DB Phase: Change From Baseline In Serum Direct Bilirubin

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    End point title
    		 DB Phase: Change From Baseline In Serum Direct Bilirubin
    End point description
    As a marker of hepatic biochemistry and liver function, the median change in serum direct bilirubin from Baseline at Week 24 is reported. Results are reported in umol/L.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 1.5 mg OCA Titrating to 3 mg OCA 5 mg OCA Titrating to 10 mg OCA Placebo
    Number of subjects analysed
    25
    26
    25
    Units: umol/L
        median (inter-quartile range (Q1-Q3))
    0.8 (-0.9 to 0.9)
    0.9 (-0.9 to 6.4)
    0.0 (-1.7 to 4.3)
    No statistical analyses for this end point

    Secondary: DB Phase: Change From Baseline In Serum Gamma-glutamyl Transferase (GGT)

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    End point title
    		 DB Phase: Change From Baseline In Serum Gamma-glutamyl Transferase (GGT)
    End point description
    As a marker of hepatic biochemistry and liver function, the median change in serum GGT from Baseline at Week 24 is reported. Results are reported in U/L.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 1.5 mg OCA Titrating to 3 mg OCA 5 mg OCA Titrating to 10 mg OCA Placebo
    Number of subjects analysed
    25
    26
    25
    Units: U/L
        median (inter-quartile range (Q1-Q3))
    -79.0 (-171.0 to -9.7)
    -78.5 (-235.5 to 14.0)
    -89.0 (-167.0 to 20.0)
    No statistical analyses for this end point

    Secondary: DB Phase: Change From Baseline In Plasma Fibroblast Growth Factor-19 (FGF-19)

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    End point title
    		 DB Phase: Change From Baseline In Plasma Fibroblast Growth Factor-19 (FGF-19)
    End point description
    To assess farnesoid X receptor (FXR) activity, the change in FGF-19 from Baseline at Week 24 is reported. Results are reported in picograms/millilitre (pg/mL).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 1.5 mg OCA Titrating to 3 mg OCA 5 mg OCA Titrating to 10 mg OCA Placebo
    Number of subjects analysed
    25
    26
    25
    Units: pg/mL
        median (inter-quartile range (Q1-Q3))
    32.00 (-16.00 to 110.00)
    147.00 (-6.35 to 714.50)
    -19.50 (-79.56 to 28.00)
    No statistical analyses for this end point

    Secondary: DB Phase: Change From Baseline In Plasma 7α-Hydroxy-4-cholesten-3-one (C4)

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    End point title
    		 DB Phase: Change From Baseline In Plasma 7α-Hydroxy-4-cholesten-3-one (C4)
    End point description
    To assess FXR activity, the change in plasma C4 from Baseline at Week 24 is reported. Results are reported in nanograms (ng)/mL.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 1.5 mg OCA Titrating to 3 mg OCA 5 mg OCA Titrating to 10 mg OCA Placebo
    Number of subjects analysed
    25
    26
    25
    Units: ng/mL
        median (inter-quartile range (Q1-Q3))
    -2.80 (-7.50 to 0.55)
    -2.90 (-6.94 to -1.12)
    0.05 (-2.25 to 10.84)
    No statistical analyses for this end point

    Secondary: LTSE Phase: Change From Baseline In Serum ALP At Month 12

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    End point title
    		 LTSE Phase: Change From Baseline In Serum ALP At Month 12
    End point description
    The median change in serum ALP from Baseline to the last available visit is reported. The DB value at Week 24 was used as the Baseline. Results are reported in U/L.
    End point type
    Secondary
    End point timeframe
    LTSE Baseline (DB Week 24), Month 12
    End point values
    		 LTSE OCA Total
    Number of subjects analysed
    34
    Units: U/L
        median (inter-quartile range (Q1-Q3))
    -91.5 (-144.0 to -17.0)
    No statistical analyses for this end point

    Secondary: LTSE Phase: Change From Baseline In Serum ALT At Month 12

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    End point title
    		 LTSE Phase: Change From Baseline In Serum ALT At Month 12
    End point description
    As a marker of hepatic biochemistry and liver function, the median change in ALT from Baseline at Month 12 is reported. The DB value at Week 24 was used as the Baseline. Results are reported in U/L.
    End point type
    Secondary
    End point timeframe
    LTSE Baseline (DB Week 24), Month 12
    End point values
    		 LTSE OCA Total
    Number of subjects analysed
    35
    Units: U/L
        median (inter-quartile range (Q1-Q3))
    -37.0 (-60.5 to -7.5)
    No statistical analyses for this end point

    Secondary: LTSE Phase: Change From Baseline In Serum AST At Month 12

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    End point title
    		 LTSE Phase: Change From Baseline In Serum AST At Month 12
    End point description
    As a marker of hepatic biochemistry and liver function, the median change in AST from Baseline at Month 12 is reported. The DB value at Week 24 was used as the Baseline. Results are reported in U/L.
    End point type
    Secondary
    End point timeframe
    LTSE Baseline (DB Week 24), Month 12
    End point values
    		 LTSE OCA Total
    Number of subjects analysed
    35
    Units: U/L
        median (inter-quartile range (Q1-Q3))
    -14.5 (-30.5 to 9.5)
    No statistical analyses for this end point

    Secondary: LTSE Phase: Change From Baseline In Serum Total Bilirubin At Month 12

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    End point title
    		 LTSE Phase: Change From Baseline In Serum Total Bilirubin At Month 12
    End point description
    As a marker of hepatic biochemistry and liver function, the median change in serum total bilirubin from Baseline at Month 12 is reported. The DB value at Week 24 was used as the Baseline. Results are reported in umol/L.
    End point type
    Secondary
    End point timeframe
    LTSE Baseline (DB Week 24), Month 12
    End point values
    		 LTSE OCA Total
    Number of subjects analysed
    34
    Units: umol/L
        median (inter-quartile range (Q1-Q3))
    0.5 (-1.7 to 5.2)
    No statistical analyses for this end point

    Secondary: LTSE Phase: Change From Baseline In Serum Direct Bilirubin At Month 12

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    End point title
    		 LTSE Phase: Change From Baseline In Serum Direct Bilirubin At Month 12
    End point description
    As a marker of hepatic biochemistry and liver function, the median change in serum direct bilirubin from Baseline at Month 12 is reported. The DB value at Week 24 was used as the Baseline. Results are reported in umol/L.
    End point type
    Secondary
    End point timeframe
    LTSE Baseline (DB Week 24), Month 12
    End point values
    		 LTSE OCA Total
    Number of subjects analysed
    34
    Units: umol/L
        median (inter-quartile range (Q1-Q3))
    0.0 (-1.7 to 1.8)
    No statistical analyses for this end point

    Secondary: LTSE Phase: Change From Baseline In Serum GGT At Month 12

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    End point title
    		 LTSE Phase: Change From Baseline In Serum GGT At Month 12
    End point description
    As a marker of hepatic biochemistry and liver function, the median change in serum GGT from Baseline at Month 12 is reported. The DB value at Week 24 was used as the Baseline. Results are reported in U/L.
    End point type
    Secondary
    End point timeframe
    LTSE Baseline (DB Week 24), Month 12
    End point values
    		 LTSE OCA Total
    Number of subjects analysed
    34
    Units: U/L
        median (inter-quartile range (Q1-Q3))
    -120.3 (-238.0 to 39.0)
    No statistical analyses for this end point

    Secondary: LTSE Phase: Change From Baseline In Albumin At Month 12

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    End point title
    		 LTSE Phase: Change From Baseline In Albumin At Month 12
    End point description
    As a marker of hepatic biochemistry and liver function, the median change in albumin from Baseline at Month 12 is reported. The DB value at Week 24 was used as the Baseline. Results are reported in grams (g)/L.
    End point type
    Secondary
    End point timeframe
    LTSE Baseline (DB Week 24), Month 12
    End point values
    		 LTSE OCA Total
    Number of subjects analysed
    35
    Units: g/L
        median (inter-quartile range (Q1-Q3))
    -0.5 (-3.5 to 1.0)
    No statistical analyses for this end point

    Secondary: LTSE Phase: Change From Baseline In INR At Month 12

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    End point title
    		 LTSE Phase: Change From Baseline In INR At Month 12
    End point description
    As a marker of hepatic biochemistry and liver function, the median change in INR from Baseline at Month 12 is reported. The DB value at Week 24 was used as the Baseline.
    End point type
    Secondary
    End point timeframe
    LTSE Baseline (DB Week 24), Month 12
    End point values
    		 LTSE OCA Total
    Number of subjects analysed
    35
    Units: Ratio
        median (inter-quartile range (Q1-Q3))
    0.0 (0.0 to 0.1)
    No statistical analyses for this end point

    Secondary: LTSE Phase: Change From Baseline In Transient Elastography (TE) At Month 12

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    End point title
    		 LTSE Phase: Change From Baseline In Transient Elastography (TE) At Month 12
    End point description
    As a marker of hepatic inflammation and fibrosis, the median change in TE, as a measure of hepatic stiffness, from Baseline at Month 12 is reported. The DB value at Week 24 was used as the Baseline. Results are reported in kilopascal (kPa).
    End point type
    Secondary
    End point timeframe
    LTSE Baseline (DB Week 24), Month 12
    End point values
    		 LTSE OCA Total
    Number of subjects analysed
    29
    Units: kPa
        median (inter-quartile range (Q1-Q3))
    1.8 (-0.8 to 6.0)
    No statistical analyses for this end point

    Secondary: LTSE Phase: Change From Baseline In Enhanced Liver Fibrosis (ELF) At Month 12

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    End point title
    		 LTSE Phase: Change From Baseline In Enhanced Liver Fibrosis (ELF) At Month 12
    End point description
    As a marker of hepatic inflammation and fibrosis, the change in ELF score from Baseline at Month 12 is reported. The ELF score and its components (hyaluronic acid [HA]; procollagen-3 N-terminal peptide [P3NP]; tissue inhibitor of metalloproteinase 1 [TIMP-1]) was calculated as follows: 2.278 + 0.851 x ln(HA (ng/mL)) + 0.751 x ln(P3NP (ng/mL)) + 0.394 x ln(TIMP-1 (ng/mL). The DB value at Week 24 was used as the Baseline. An increase in score indicates an improvement/worsening of symptoms.
    End point type
    Secondary
    End point timeframe
    LTSE Baseline (DB Week 24), Month 12
    End point values
    		 LTSE OCA Total
    Number of subjects analysed
    34
    Units: Units on a scale
        median (inter-quartile range (Q1-Q3))
    0.3 (0.0 to 1.0)
    No statistical analyses for this end point

    Secondary: LTSE Phase: Change From Baseline In Plasma FGF-19 At Month 12

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    End point title
    		 LTSE Phase: Change From Baseline In Plasma FGF-19 At Month 12
    End point description
    To assess FXR activity, the change in FGF-19 from Baseline at Month 12 is reported. The DB value at Week 24 was used as the Baseline. Results are reported in pg/mL.
    End point type
    Secondary
    End point timeframe
    LTSE Baseline (DB Week 24), Month 12
    End point values
    		 LTSE OCA Total
    Number of subjects analysed
    35
    Units: pg/mL
        median (inter-quartile range (Q1-Q3))
    77.7 (-37.0 to 194.0)
    No statistical analyses for this end point

    Secondary: LTSE Phase: Change From Baseline In Plasma C4 At Month 12

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    End point title
    		 LTSE Phase: Change From Baseline In Plasma C4 At Month 12
    End point description
    To assess FXR activity, the change in plasma C4 from Baseline at Month 12 is reported. The DB value at Week 24 was used as the Baseline. Results are reported in ng/mL.
    End point type
    Secondary
    End point timeframe
    LTSE Baseline (DB Week 24), Month 12
    End point values
    		 LTSE OCA Total
    Number of subjects analysed
    35
    Units: ng/mL
        median (inter-quartile range (Q1-Q3))
    -3.8 (-8.1 to -0.9)
    No statistical analyses for this end point

    Secondary: LTSE Phase: Participants Experiencing Ulcerative Colitis Remission At Month 12

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    End point title
    		 LTSE Phase: Participants Experiencing Ulcerative Colitis Remission At Month 12
    End point description
    To assess inflammatory bowel disease (IBD) activity, the number of participants experiencing ulcerative colitis remission at Month 12 is reported. Remission was defined as a partial Mayo score of ≤2 with no individual sub-score exceeding 1 point.
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    		 LTSE OCA Total
    Number of subjects analysed
    59
    Units: Participants
        Yes
    16
        No
    0
    No statistical analyses for this end point

    Secondary: LTSE Phase: Participants Experiencing Crohn’s Disease Remission At Month 12

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    End point title
    		 LTSE Phase: Participants Experiencing Crohn’s Disease Remission At Month 12
    End point description
    To assess IBD activity, the number of participants experiencing Crohn’s Disease remission at Month 12 is reported. Remission was defined as a Crohn’s Disease Activity Index (CDAI) score of <150.
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    		 LTSE OCA Total
    Number of subjects analysed
    59
    Units: Participants
        Yes
    5
        No
    1
    No statistical analyses for this end point

    Secondary: LTSE Phase: Change From Baseline In Total Bile Acids At Month 12

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    End point title
    		 LTSE Phase: Change From Baseline In Total Bile Acids At Month 12
    End point description
    To assess the effects on bile acids, the median change in total bile acids from Baseline at Month 12 is reported. The DB value at Week 24 was used as the Baseline. Results are reported in umol/L.
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    		 LTSE OCA Total
    Number of subjects analysed
    35
    Units: umol/L
        median (inter-quartile range (Q1-Q3))
    -1.59 (-8.12 to 6.49)
    No statistical analyses for this end point

    Secondary: LTSE Phase: Change From Baseline In Pruritus Visual Analogue Scale (VAS) At Month 12

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    End point title
    		 LTSE Phase: Change From Baseline In Pruritus Visual Analogue Scale (VAS) At Month 12
    End point description
    To assess the effects on disease-specific symptoms, the median change in the pruritus VAS score from Baseline at Month 12 is reported. The score is derived from the VAS participant questionnaire, which has the participant draw a line anywhere on a scale that best represents the severity of the itch; the scale ranges from 0 (no itching) to 10 (worst possible itching), in increments of 2. An increase in score represents an increase in severity of symptoms. The DB value at Week 24 was used as the Baseline.
    End point type
    Secondary
    End point timeframe
    LTSE Baseline (DB Week 24), Month 12
    End point values
    		 LTSE OCA Total
    Number of subjects analysed
    37
    Units: Units on a scale
        median (inter-quartile range (Q1-Q3))
    1.0 (0.0 to 20.0)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    DB Phase: From informed consent to end of DB phase study participation, up to 24 weeks. LTSE Phase: Baseline (DB Week 24) to Month 26.
    Adverse event reporting additional description
    Adverse event reporting is based on safety population, where treatment group was defined by the treatment actually received. One (1) placebo participant actually received 5 mg OCA titrating to 10 mg OCA. All adverse event summaries are based on TEAEs. Verbatim terms were mapped using MedDRA 17.1; MedDRA 18.1 was used for hepatic disorder AESIs.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    1.5 mg OCA Titrating to 3 mg OCA
    Reporting group description
    		 Participants randomized to 1.5 mg OCA will take 1.5 mg OCA daily for 12 weeks during the DB phase. If tolerated, the dose will be increased to 3 mg OCA daily for an additional 12 weeks.

    Reporting group title
    5 mg OCA Titrating to 10 mg OCA
    Reporting group description
    		 Participants randomized to 5 mg OCA will take 5 mg OCA daily for 12 weeks during the DB phase. If tolerated, the dose will be increased to 10 mg OCA daily for an additional 12 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants randomized to placebo will take placebo daily for 24 weeks during the DB phase.

    Reporting group title
    LTSE OCA Total
    Reporting group description
    		 Following completion of the DB phase, participants were asked to reconfirm their consent for participation in the LTSE phase (planned as a further 24 months) beginning at 5 or 10 mg OCA, based on the last treatment received during the DB phase. Doses up to 10 mg daily were evaluated. All participants received open-label OCA during the LTSE phase of the study.

    Serious adverse events
    		 1.5 mg OCA Titrating to 3 mg OCA 5 mg OCA Titrating to 10 mg OCA Placebo LTSE OCA Total
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 25 (16.00%)
    4 / 27 (14.81%)
    2 / 24 (8.33%)
    19 / 59 (32.20%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of colon
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    1 / 59 (1.69%)
         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
    Injury, poisoning and procedural complications
    Anastomotic leak
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    1 / 59 (1.69%)
         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
    Ankle fracture
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    1 / 59 (1.69%)
         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
    Delayed recovery from anaesthesia
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    1 / 59 (1.69%)
         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
    Forearm fracture
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    1 / 59 (1.69%)
         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
    Oedema peripheral
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    0 / 59 (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
    Peripheral swelling
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    0 / 59 (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
    Gastrointestinal disorders
    Ascites
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 27 (3.70%)
    1 / 24 (4.17%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophageal varices haemorrhage
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    1 / 24 (4.17%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    2 / 59 (3.39%)
         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
    Abdominal pain upper
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    1 / 59 (1.69%)
         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
    Colon dysplasia
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    1 / 59 (1.69%)
         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
    Crohn's disease
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    1 / 59 (1.69%)
         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
    Gastric ulcer
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    1 / 59 (1.69%)
         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 haemorrhage
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    1 / 59 (1.69%)
         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
    Pouchitis
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    1 / 59 (1.69%)
         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
    Small intestinal obstruction
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    1 / 59 (1.69%)
         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
    Hepatobiliary disorders
    Bile duct stenosis
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    0 / 59 (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
    Cholangitis
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholangitis acute
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    1 / 24 (4.17%)
    0 / 59 (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
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    0 / 59 (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
    Bile duct obstruction
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    1 / 59 (1.69%)
         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
    Pulmonary oedema
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    1 / 59 (1.69%)
         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
    Infections and infestations
    Cholangitis infective
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
    0 / 59 (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
    Pneumonia bacterial
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
    0 / 59 (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
    Pseudomonal sepsis
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    0 / 59 (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
    Peritonitis
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    1 / 59 (1.69%)
         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
    Abdominal abscess
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    1 / 59 (1.69%)
         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
    Enteritis infectious
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    1 / 59 (1.69%)
         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
    Gastroenteritis viral
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    1 / 59 (1.69%)
         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
    Pelvic abscess
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    1 / 59 (1.69%)
         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
    Perirectal abscess
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    1 / 59 (1.69%)
         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
    Pneumonia pneumococcal
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    1 / 59 (1.69%)
         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
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    1 / 59 (1.69%)
         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: 4.99%
    Non-serious adverse events
    		 1.5 mg OCA Titrating to 3 mg OCA 5 mg OCA Titrating to 10 mg OCA Placebo LTSE OCA Total
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    23 / 25 (92.00%)
    26 / 27 (96.30%)
    21 / 24 (87.50%)
    53 / 59 (89.83%)
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 27 (0.00%)
    2 / 24 (8.33%)
    2 / 59 (3.39%)
         occurrences all number
    3
    0
    2
    2
    Blood bilirubin increased
         subjects affected / exposed
    1 / 25 (4.00%)
    3 / 27 (11.11%)
    3 / 24 (12.50%)
    4 / 59 (6.78%)
         occurrences all number
    1
    3
    3
    4
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 27 (0.00%)
    1 / 24 (4.17%)
    3 / 59 (5.08%)
         occurrences all number
    1
    0
    1
    3
    Liver function test abnormal
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    3 / 59 (5.08%)
         occurrences all number
    0
    0
    0
    3
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 27 (7.41%)
    0 / 24 (0.00%)
    2 / 59 (3.39%)
         occurrences all number
    0
    3
    0
    2
    Headache
         subjects affected / exposed
    2 / 25 (8.00%)
    2 / 27 (7.41%)
    0 / 24 (0.00%)
    2 / 59 (3.39%)
         occurrences all number
    3
    2
    0
    2
    Paraesthesia
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 27 (7.41%)
    0 / 24 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    0
    2
    0
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 25 (4.00%)
    3 / 27 (11.11%)
    2 / 24 (8.33%)
    4 / 59 (6.78%)
         occurrences all number
    2
    3
    2
    5
    Oedema peripheral
         subjects affected / exposed
    1 / 25 (4.00%)
    2 / 27 (7.41%)
    0 / 24 (0.00%)
    3 / 59 (5.08%)
         occurrences all number
    3
    2
    0
    4
    Pyrexia
         subjects affected / exposed
    3 / 25 (12.00%)
    4 / 27 (14.81%)
    1 / 24 (4.17%)
    4 / 59 (6.78%)
         occurrences all number
    5
    4
    1
    6
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 27 (7.41%)
    0 / 24 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 27 (0.00%)
    2 / 24 (8.33%)
    1 / 59 (1.69%)
         occurrences all number
    2
    0
    2
    1
    Abdominal pain
         subjects affected / exposed
    2 / 25 (8.00%)
    2 / 27 (7.41%)
    4 / 24 (16.67%)
    7 / 59 (11.86%)
         occurrences all number
    2
    3
    5
    8
    Abdominal pain upper
         subjects affected / exposed
    1 / 25 (4.00%)
    2 / 27 (7.41%)
    4 / 24 (16.67%)
    7 / 59 (11.86%)
         occurrences all number
    2
    2
    4
    8
    Ascites
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 27 (3.70%)
    1 / 24 (4.17%)
    4 / 59 (6.78%)
         occurrences all number
    1
    2
    1
    4
    Constipation
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 27 (7.41%)
    0 / 24 (0.00%)
    4 / 59 (6.78%)
         occurrences all number
    0
    2
    0
    4
    Crohn's disease
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 27 (7.41%)
    1 / 24 (4.17%)
    3 / 59 (5.08%)
         occurrences all number
    0
    2
    1
    3
    Diarrhoea
         subjects affected / exposed
    1 / 25 (4.00%)
    3 / 27 (11.11%)
    2 / 24 (8.33%)
    8 / 59 (13.56%)
         occurrences all number
    1
    3
    3
    13
    Frequent bowel movements
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    2 / 24 (8.33%)
    0 / 59 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Nausea
         subjects affected / exposed
    2 / 25 (8.00%)
    6 / 27 (22.22%)
    3 / 24 (12.50%)
    8 / 59 (13.56%)
         occurrences all number
    2
    7
    3
    10
    Vomiting
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 27 (3.70%)
    4 / 24 (16.67%)
    8 / 59 (13.56%)
         occurrences all number
    1
    1
    4
    8
    Colitis ulcerative
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 27 (0.00%)
    1 / 24 (4.17%)
    4 / 59 (6.78%)
         occurrences all number
    1
    0
    1
    6
    Haemorrhoids
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    4 / 59 (6.78%)
         occurrences all number
    0
    0
    0
    6
    Abdominal pain lower
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    3 / 59 (5.08%)
         occurrences all number
    0
    0
    0
    3
    Varices oesophageal
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    3 / 59 (5.08%)
         occurrences all number
    0
    0
    0
    3
    Hepatobiliary disorders
    Bile duct stenosis
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    3 / 59 (5.08%)
         occurrences all number
    1
    0
    0
    3
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 27 (7.41%)
    0 / 24 (0.00%)
    3 / 59 (5.08%)
         occurrences all number
    0
    2
    0
    3
    Jaundice
         subjects affected / exposed
    2 / 25 (8.00%)
    1 / 27 (3.70%)
    1 / 24 (4.17%)
    5 / 59 (8.47%)
         occurrences all number
    2
    1
    1
    5
    Cholangitis
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 27 (0.00%)
    1 / 24 (4.17%)
    4 / 59 (6.78%)
         occurrences all number
    1
    0
    3
    6
    Portal hypertension
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    3 / 59 (5.08%)
         occurrences all number
    0
    0
    0
    3
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 27 (3.70%)
    3 / 24 (12.50%)
    1 / 59 (1.69%)
         occurrences all number
    1
    1
    3
    2
    Nasal congestion
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    2 / 24 (8.33%)
    1 / 59 (1.69%)
         occurrences all number
    0
    0
    2
    1
    Oropharyngeal pain
         subjects affected / exposed
    2 / 25 (8.00%)
    3 / 27 (11.11%)
    1 / 24 (4.17%)
    2 / 59 (3.39%)
         occurrences all number
    2
    3
    1
    2
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    15 / 25 (60.00%)
    18 / 27 (66.67%)
    11 / 24 (45.83%)
    33 / 59 (55.93%)
         occurrences all number
    31
    38
    17
    62
    Urticaria
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    1 / 59 (1.69%)
         occurrences all number
    2
    0
    0
    1
    Rash
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 27 (3.70%)
    1 / 24 (4.17%)
    4 / 59 (6.78%)
         occurrences all number
    1
    1
    2
    4
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 25 (0.00%)
    3 / 27 (11.11%)
    1 / 24 (4.17%)
    3 / 59 (5.08%)
         occurrences all number
    0
    3
    1
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 25 (8.00%)
    1 / 27 (3.70%)
    1 / 24 (4.17%)
    1 / 59 (1.69%)
         occurrences all number
    5
    1
    1
    1
    Back pain
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    2 / 24 (8.33%)
    1 / 59 (1.69%)
         occurrences all number
    0
    0
    2
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 27 (0.00%)
    3 / 24 (12.50%)
    4 / 59 (6.78%)
         occurrences all number
    1
    0
    3
    4
    Sinusitis
         subjects affected / exposed
    1 / 25 (4.00%)
    3 / 27 (11.11%)
    0 / 24 (0.00%)
    2 / 59 (3.39%)
         occurrences all number
    1
    3
    0
    3
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 27 (7.41%)
    0 / 24 (0.00%)
    2 / 59 (3.39%)
         occurrences all number
    0
    2
    0
    2
    Urinary tract infection
         subjects affected / exposed
    2 / 25 (8.00%)
    1 / 27 (3.70%)
    2 / 24 (8.33%)
    4 / 59 (6.78%)
         occurrences all number
    2
    1
    2
    4
    Bronchitis
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    4 / 59 (6.78%)
         occurrences all number
    0
    0
    0
    4
    Influenza
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    3 / 59 (5.08%)
         occurrences all number
    0
    0
    0
    4
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    3 / 24 (12.50%)
    2 / 59 (3.39%)
         occurrences all number
    0
    0
    3
    2
    Hypokalaemia
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    3 / 59 (5.08%)
         occurrences all number
    2
    0
    0
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Sep 2014
    Amendment 2: - Changed maximum frequency of dose titrations during the LTSE phase from monthly to every 3 months. - Added 2 additional evaluations for disease-specific symptoms: Pruritus 5-D questionnaire and CDAI. - Changed the co-primary efficacy endpoints of Week 12 and Week 24 change from Baseline in ALP to a single primary endpoint of Week 24 change from Baseline in ALP. - Revised secondary efficacy analyses to employ a hierarchical approach. - Added a formal unblinded interim analysis for planning purposes. - Required that, at a minimum, the occurrence of 2 life-threatening serious AEs (SAEs) or an SAE resulting in death would trigger an unscheduled and unblinded review of the data by the data safety monitoring committee to determine if the trial should continue. - Added criterion requiring study withdrawal of participants who experience 3 or more IBD flares in 1 year. - Specified categories of hospitalizations that are not to be considered SAEs.
    26 Aug 2015
    Amendment 3: - Included changes to clarify eligibility criteria and procedures. - Added intolerable pruritus as a criterion for discontinuation from the trial. - Added statins as an allowed medication. - Clarified that participants would not automatically enroll into the LTSE phase and be required to reconfirm their consent, but instead would be asked to reconfirm their consent to participate in the LTSE phase. - Clarified that if the Investigator did not want a participant's dose to be titrated in line with the protocol recommendations, the Investigator may (not should) discuss this decision with the Medical Monitor. - Added a safety contact at Week 2 of the LTSE phase. - Deleted: A few Sponsor representatives may be unblinded during the trial/DB phase of the study. If there are any findings regarding safety, tolerability, or efficacy that indicate an alternative optimal LTSE starting dose, the starting dose in the LTSE may be reduced. - Clarified that the doses of OCA in the LTSE phase should be titrated, rather than may be titrated.
    08 Feb 2016
    Amendment 4: - Clarified eligibility criteria.
    18 Mar 2016
    Amendment 5: - Clarified that intermediate doses (for example, 6.5 mg) may be considered as deemed appropriate by the Investigator during the LTSE phase, and that the dose should not exceed 10 mg. - Clarified criteria, investigational product storage instructions. - Clarified titration adjustments.

    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.
    Due to administrative reasons, the study was terminated by the Sponsor prior to most participants completing LTSE Month 24.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/32165251
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