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    Clinical Trial Results:
    A multi-part, randomized, double-blind, placebo-controlled study to assess the safety, tolerability and efficacy of tropifexor (LJN452) in patients with Primary Biliary Cholangitis

    Summary
    EudraCT number
    2015-001590-41
    Trial protocol
    DE   PL  
    Global end of trial date
    02 Aug 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    22 Aug 2019
    First version publication date
    22 Aug 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CLJN452X2201
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02516605
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.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
    02 Aug 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Aug 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Primary Objectives: 1) To determine the effect of tropifexor on cholestatic markers in patients with PBC. 2) To determine the safety and tolerability of daily dosing of tropifexor in patients with PBC.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    09 Sep 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 13
    Country: Number of subjects enrolled
    Russian Federation: 3
    Country: Number of subjects enrolled
    Poland: 5
    Country: Number of subjects enrolled
    United Kingdom: 16
    Country: Number of subjects enrolled
    Germany: 17
    Country: Number of subjects enrolled
    Canada: 7
    Worldwide total number of subjects
    61
    EEA total number of subjects
    38
    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)
    49
    From 65 to 84 years
    12
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    This study comprised of an escalating multiple dose design in PBC patients with incomplete biochemical response to, but still taking, ursodeoxycholic acid (UDCA).

    Period 1
    Period 1 title
    Overall Study (overall period)
    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
    LJN452 - 0.03 mg qd
    Arm description
    Tropifexor 0.03 mg daily for 28 days
    Arm type
    Experimental

    Investigational medicinal product name
    Tropifexor
    Investigational medicinal product code
    LJN452
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    0.01 mg or 0.03 mg was prepared and supplied by Novartis as single blind patient-specific packs to be dispensed by the unblinded pharmacist at the investigator site.

    Arm title
    LJN452 - 0.06 mg qd
    Arm description
    Tropifexor 0.06 mg daily for 28 days
    Arm type
    Experimental

    Investigational medicinal product name
    Tropifexor
    Investigational medicinal product code
    LJN452
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    0.01 mg or 0.03 mg was prepared and supplied by Novartis as single blind patient-specific packs to be dispensed by the unblinded pharmacist at the investigator site.

    Arm title
    LJN452 - 0.09 mg qd
    Arm description
    Tropifexor 0.09 mg daily for 28 days
    Arm type
    Experimental

    Investigational medicinal product name
    Tropifexor
    Investigational medicinal product code
    LJN452
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    0.01 mg or 0.03 mg was prepared and supplied by Novartis as single blind patient-specific packs to be dispensed by the unblinded pharmacist at the investigator site.

    Arm title
    LJN452 - 0.15 mg qd
    Arm description
    Tropifexor 0.15 mg daily for 28 days
    Arm type
    Experimental

    Investigational medicinal product name
    Tropifexor
    Investigational medicinal product code
    LJN452
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    0.01 mg or 0.03 mg was prepared and supplied by Novartis as single blind patient-specific packs to be dispensed by the unblinded pharmacist at the investigator site.

    Arm title
    Placebo qd
    Arm description
    Tropifexor placebo daily for 28 days
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    0.01 mg or 0.03 mg matching placebo was prepared and supplied by Novartis as single blind patient-specific packs to be dispensed by the unblinded pharmacist at the investigator site.

    Number of subjects in period 1
    LJN452 - 0.03 mg qd LJN452 - 0.06 mg qd LJN452 - 0.09 mg qd LJN452 - 0.15 mg qd Placebo qd
    Started
    11
    9
    12
    8
    21
    Completed
    11
    9
    12
    7
    20
    Not completed
    0
    0
    0
    1
    1
         Consent withdrawn by subject
    -
    -
    -
    1
    -
         Protocol deviation
    -
    -
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    LJN452 - 0.03 mg qd
    Reporting group description
    Tropifexor 0.03 mg daily for 28 days

    Reporting group title
    LJN452 - 0.06 mg qd
    Reporting group description
    Tropifexor 0.06 mg daily for 28 days

    Reporting group title
    LJN452 - 0.09 mg qd
    Reporting group description
    Tropifexor 0.09 mg daily for 28 days

    Reporting group title
    LJN452 - 0.15 mg qd
    Reporting group description
    Tropifexor 0.15 mg daily for 28 days

    Reporting group title
    Placebo qd
    Reporting group description
    Tropifexor placebo daily for 28 days

    Reporting group values
    LJN452 - 0.03 mg qd LJN452 - 0.06 mg qd LJN452 - 0.09 mg qd LJN452 - 0.15 mg qd Placebo qd Total
    Number of subjects
    11 9 12 8 21 61
    Age categorical
    Units: Subjects
        In utero
    0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0 0 0
        Newborns (0-27 days)
    0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0 0 0
        Children (2-11 years)
    0 0 0 0 0 0
        Adolescents (12-17 years)
    0 0 0 0 0 0
        Adults (18-64 years)
    7 6 11 6 19 49
        From 65-84 years
    4 3 1 2 2 12
        85 years and over
    0 0 0 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    58.6 ( 12.42 ) 57.9 ( 11.21 ) 53.6 ( 7.42 ) 57.4 ( 13.81 ) 53.7 ( 10.19 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    11 7 12 8 21 59
        Male
    0 2 0 0 0 2
    Race/Ethnicity, Customized
    Units: Subjects
        Caucasian
    10 8 12 8 19 57
        Asian
    0 0 0 0 1 1
        Other
    1 1 0 0 1 3

    End points

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    End points reporting groups
    Reporting group title
    LJN452 - 0.03 mg qd
    Reporting group description
    Tropifexor 0.03 mg daily for 28 days

    Reporting group title
    LJN452 - 0.06 mg qd
    Reporting group description
    Tropifexor 0.06 mg daily for 28 days

    Reporting group title
    LJN452 - 0.09 mg qd
    Reporting group description
    Tropifexor 0.09 mg daily for 28 days

    Reporting group title
    LJN452 - 0.15 mg qd
    Reporting group description
    Tropifexor 0.15 mg daily for 28 days

    Reporting group title
    Placebo qd
    Reporting group description
    Tropifexor placebo daily for 28 days

    Subject analysis set title
    LJN452 - 0.03 mg qd vs Placebo qd
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Tropifexor 0.03 mg daily for 28 days Tropifexor placebo daily for 28 days

    Subject analysis set title
    LJN452 - 0.06 mg qd vs. Placebo qd
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Tropifexor 0.06 mg daily for 28 days Tropifexor placebo daily for 28 days

    Subject analysis set title
    LJN452 - 0.09 mg qd vs. Placebo qd
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Tropifexor 0.09 mg daily for 28 days Tropifexor placebo daily for 28 days

    Subject analysis set title
    LJN452 - 0.15 mg qd vs. Placebo qd
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Tropifexor 0.15 mg daily for 28 days Tropifexor placebo daily for 28 days

    Subject analysis set title
    LJN452 - 0.03 mg qd vs Placebo qd
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Tropifexor 0.03 mg daily for 28 days Tropifexor placebo daily for 28 days

    Subject analysis set title
    LJN452 - 0.03 mg qd vs Placebo qd
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Tropifexor 0.03 mg daily for 28 days Tropifexor placebo daily for 28 days

    Subject analysis set title
    LJN452 - 0.06 mg qd vs. Placebo qd
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Tropifexor 0.06 mg daily for 28 days Tropifexor placebo daily for 28 days

    Subject analysis set title
    LJN452 - 0.09 mg qd vs. Placebo qd
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Tropifexor 0.09 mg daily for 28 days Tropifexor placebo daily for 28 days

    Subject analysis set title
    LJN452 - 0.15 mg qd vs. Placebo qd
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Tropifexor 0.15 mg daily for 28 days Tropifexor placebo daily for 28 days

    Primary: Fold change in serum gamma-glutamyl transferase (GGT)

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    End point title
    Fold change in serum gamma-glutamyl transferase (GGT) [1] [2]
    End point description
    Fold change in serum gamma-glutamyl transferase (GGT) from baseline to Day 28
    End point type
    Primary
    End point timeframe
    Baseline to Day 28
    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: p-values were obtained from ANCOVA test but not shown due to system limitation.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: p-values were obtained from ANCOVA test but not shown due to system limitation.
    End point values
    LJN452 - 0.03 mg qd LJN452 - 0.06 mg qd LJN452 - 0.09 mg qd LJN452 - 0.15 mg qd LJN452 - 0.03 mg qd vs Placebo qd LJN452 - 0.06 mg qd vs. Placebo qd LJN452 - 0.09 mg qd vs. Placebo qd LJN452 - 0.15 mg qd vs. Placebo qd
    Number of subjects analysed
    11 [3]
    9 [4]
    12 [5]
    8 [6]
    11
    9
    12
    8
    Units: U/L
        number (confidence interval 90%)
    0.86 (0.68 to 1.09)
    0.47 (0.37 to 0.60)
    0.32 (0.26 to 0.40)
    0.36 (0.27 to 0.47)
    0.86 (0.68 to 1.09)
    0.47 (0.37 to 0.60)
    0.32 (0.26 to 0.40)
    0.36 (0.27 to 0.47)
    Notes
    [3] - Overall Study LJN452 - 0.03 mg qd vs placebo
    [4] - Overall Study LJN452 - 0.06 mg qd vs placebo
    [5] - Overall Study LJN452 - 0.09 mg qd vs placebo
    [6] - Overall Study LJN452 - 0.15 mg qd vs placebo
    No statistical analyses for this end point

    Primary: Blood pressure

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    End point title
    Blood pressure [7]
    End point description
    Vital signs - Systolic Blood pressure
    End point type
    Primary
    End point timeframe
    Screening, Baseline, day 1, day 7, day 14, day 21, day 28, day 56, day 84
    Notes
    [7] - 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: descriptive analysis
    End point values
    LJN452 - 0.03 mg qd LJN452 - 0.06 mg qd LJN452 - 0.09 mg qd LJN452 - 0.15 mg qd Placebo qd
    Number of subjects analysed
    11
    9
    12
    8
    21
    Units: mm Hg
    arithmetic mean (standard deviation)
        Screening
    122.5 ( 12.21 )
    125.8 ( 11.79 )
    129.3 ( 14.42 )
    129.5 ( 17.42 )
    123.0 ( 15.40 )
        Baseline
    124.7 ( 17.66 )
    128.4 ( 13.83 )
    122.0 ( 18.18 )
    132.3 ( 18.09 )
    118.7 ( 12.76 )
        Day 1
    129.6 ( 20.48 )
    122.4 ( 20.24 )
    119.9 ( 11.84 )
    129.1 ( 25.12 )
    123.0 ( 21.84 )
        Day 7
    127.2 ( 20.18 )
    123.7 ( 13.04 )
    125.6 ( 14.22 )
    128.0 ( 26.58 )
    120.9 ( 19.57 )
        Day 14
    122.4 ( 16.30 )
    124.6 ( 20.67 )
    127.1 ( 16.45 )
    127.3 ( 12.45 )
    118.7 ( 12.88 )
        Day 21
    121.5 ( 11.25 )
    126.3 ( 27.65 )
    123.9 ( 13.14 )
    124.0 ( 14.23 )
    124.5 ( 19.8 )
        Day 28
    118.0 ( 11.22 )
    127.1 ( 28.55 )
    121.4 ( 12.82 )
    126.0 ( 7.71 )
    120.1 ( 22.38 )
        Day 56
    121.4 ( 10.76 )
    125.4 ( 18.48 )
    121.5 ( 11.55 )
    129.1 ( 26.45 )
    123.8 ( 19.74 )
        Day 84
    131.3 ( 16.04 )
    124.6 ( 15.77 )
    122.3 ( 7.70 )
    130.4 ( 25.51 )
    123.6 ( 19.09 )
    No statistical analyses for this end point

    Primary: Pulse rate

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    End point title
    Pulse rate [8]
    End point description
    Vital signs
    End point type
    Primary
    End point timeframe
    Screening, Baseline, day 1, day 7, day 14, day 21, day 28, day 56, day 84
    Notes
    [8] - 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: descriptive analysis
    End point values
    LJN452 - 0.03 mg qd LJN452 - 0.06 mg qd LJN452 - 0.09 mg qd LJN452 - 0.15 mg qd Placebo qd
    Number of subjects analysed
    11
    9
    12
    8
    21
    Units: bpm
    arithmetic mean (standard deviation)
        Screening
    68.6 ( 10.63 )
    61.2 ( 7.05 )
    75.3 ( 8.22 )
    72.8 ( 8.26 )
    69.3 ( 10.69 )
        Baseline
    64.3 ( 7.79 )
    64.1 ( 8.70 )
    70.8 ( 8.63 )
    74.4 ( 5.15 )
    66.3 ( 9.30 )
        Day 1
    67.7 ( 11.93 )
    64.2 ( 8.07 )
    69.7 ( 7.50 )
    74.1 ( 11.62 )
    67.6 ( 8.35 )
        Day 7
    65.2 ( 9.98 )
    66.8 ( 11.31 )
    70.1 ( 11.64 )
    73.5 ( 8.33 )
    65.2 ( 8.92 )
        Day 14
    62.9 ( 10.03 )
    64.8 ( 8.09 )
    70.5 ( 14.16 )
    75.1 ( 6.74 )
    66.1 ( 9.61 )
        Day 21
    65.5 ( 8.26 )
    65.8 ( 11.18 )
    73.2 ( 8.43 )
    72.5 ( 6.75 )
    67.7 ( 10.18 )
        Day 28
    65.5 ( 10.83 )
    68.9 ( 10.60 )
    68.5 ( 9.01 )
    67.2 ( 3.42 )
    65.8 ( 9.29 )
        Day 56
    66.8 ( 9.64 )
    67.7 ( 7.53 )
    69.7 ( 8.17 )
    69.7 ( 4.07 )
    68.1 ( 10.11 )
        Day 84
    65.6 ( 10.24 )
    64.0 ( 9.11 )
    70.2 ( 8.14 )
    72.8 ( 8.12 )
    68.1 ( 9.82 )
    No statistical analyses for this end point

    Primary: Body Temperature

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    End point title
    Body Temperature [9]
    End point description
    Vital signs
    End point type
    Primary
    End point timeframe
    Screening, Baseline, day 1, day 7, day 14, day 21, day 28, day 56, day 84
    Notes
    [9] - 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: descriptive analysis
    End point values
    LJN452 - 0.03 mg qd LJN452 - 0.06 mg qd LJN452 - 0.09 mg qd LJN452 - 0.15 mg qd Placebo qd
    Number of subjects analysed
    11
    9
    12
    8
    21
    Units: Celsius
    arithmetic mean (standard deviation)
        screening
    36.605 ( 0.2813 )
    36.567 ( 0.2000 )
    36.424 ( 0.3429 )
    36.650 ( 0.1604 )
    36.460 ( 0.4500 )
        baseline
    36.582 ( 0.2960 )
    36.644 ( 0.2128 )
    36.398 ( 0.3385 )
    36.638 ( 0.1506 )
    36.376 ( 0.5118 )
        day 1
    36.436 ( 0.3139 )
    36.537 ( 0.3076 )
    36.482 ( 0.2636 )
    36.575 ( 0.1982 )
    36.390 ( 0.4867 )
        day 7
    36.582 ( 0.2040 )
    36.533 ( 0.1323 )
    36.258 ( 0.3965 )
    36.600 ( 0.1195 )
    36.345 ( 0.4639 )
        day 14
    36.516 ( 0.1793 )
    36.444 ( 0.2007 )
    36.291 ( 0.4109 )
    36.500 ( 0.1826 )
    36.310 ( 0.4576 )
        day 21
    36.500 ( 0.2490 )
    36.267 ( 0.4637 )
    36.308 ( 0.3288 )
    36.433 ( 0.1966 )
    36.455 ( 0.4236 )
        day 28
    36.382 ( 0.2228 )
    36.444 ( 0.2128 )
    36.308 ( 0.3397 )
    36.520 ( 0.2950 )
    36.380 ( 0.4047 )
        day 56
    36.527 ( 0.2102 )
    36.500 ( 0.2179 )
    36.350 ( 0.4602 )
    36.443 ( 0.3309 )
    36.285 ( 0.4246 )
        day 84
    36.482 ( 0.2483 )
    36.500 ( 0.1500 )
    36.383 ( 0.2980 )
    36.638 ( 0.1506 )
    36.295 ( 0.4248 )
    No statistical analyses for this end point

    Primary: ECG - Heart Rate

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    End point title
    ECG - Heart Rate [10]
    End point description
    Electrocardiogram (ECG)
    End point type
    Primary
    End point timeframe
    Screening, Baseline, day 1, day 28
    Notes
    [10] - 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: descriptive analysis
    End point values
    LJN452 - 0.03 mg qd LJN452 - 0.06 mg qd LJN452 - 0.09 mg qd LJN452 - 0.15 mg qd Placebo qd
    Number of subjects analysed
    11
    9
    12
    8
    21
    Units: bpm
    arithmetic mean (standard deviation)
        Screening
    65.8 ( 11.32 )
    61.8 ( 9.97 )
    67.3 ( 5.58 )
    67.8 ( 6.54 )
    63.4 ( 9.35 )
        Baseline
    60.5 ( 8.99 )
    61.4 ( 8.75 )
    64.6 ( 7.95 )
    67.9 ( 6.45 )
    63.8 ( 9.41 )
        Day 1
    61.5 ( 11.16 )
    63.4 ( 11.17 )
    63.9 ( 8.21 )
    66.9 ( 11.97 )
    63.5 ( 7.12 )
        Day 28
    60.5 ( 11.39 )
    65.2 ( 11.95 )
    63.5 ( 9.95 )
    65.8 ( 4.55 )
    60.8 ( 7.03 )
    No statistical analyses for this end point

    Primary: ECG Intervals - PR interval

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    End point title
    ECG Intervals - PR interval [11]
    End point description
    Electrocardiogram (ECG)
    End point type
    Primary
    End point timeframe
    Screening, Baseline, day 1, day 28
    Notes
    [11] - 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: descriptive analysis
    End point values
    LJN452 - 0.03 mg qd LJN452 - 0.06 mg qd LJN452 - 0.09 mg qd LJN452 - 0.15 mg qd Placebo qd
    Number of subjects analysed
    11
    9
    12
    8
    21
    Units: msec
    arithmetic mean (standard deviation)
        Screening
    159.2 ( 27.34 )
    158.0 ( 23.71 )
    172.0 ( 24.12 )
    159.9 ( 17.24 )
    162.6 ( 19.03 )
        Baseline
    165.8 ( 20.81 )
    156.2 ( 18.99 )
    175.0 ( 34.96 )
    152.0 ( 22.21 )
    160.3 ( 19.77 )
        Day 1
    165.5 ( 21.76 )
    162.9 ( 27.06 )
    175.7 ( 28.29 )
    160.0 ( 20.32 )
    161.6 ( 20.28 )
        Day 28
    164.9 ( 19.75 )
    157.1 ( 26.70 )
    180.4 ( 31.63 )
    155.4 ( 23.51 )
    160.2 ( 28.70 )
    No statistical analyses for this end point

    Primary: Haemoglobin

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    End point title
    Haemoglobin [12]
    End point description
    Hematology panel for safety laboratory assessments.
    End point type
    Primary
    End point timeframe
    Screening, Baseline, day 1, day 7, day 14, day 21, day 28, day 56, day 84
    Notes
    [12] - 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: descriptive analysis
    End point values
    LJN452 - 0.03 mg qd LJN452 - 0.06 mg qd LJN452 - 0.09 mg qd LJN452 - 0.15 mg qd Placebo qd
    Number of subjects analysed
    11
    9
    12
    8
    21
    Units: g/L
    arithmetic mean (standard deviation)
        screening
    127.9 ( 9.24 )
    125.6 ( 11.70 )
    130.5 ( 9.73 )
    133.9 ( 12.70 )
    132.2 ( 8.81 )
        baseline
    126.5 ( 8.58 )
    127.4 ( 11.85 )
    130.5 ( 11.90 )
    134.6 ( 13.24 )
    131.3 ( 8.02 )
        day 1
    124.7 ( 8.21 )
    132.9 ( 10.05 )
    127.0 ( 9.03 )
    133.1 ( 11.37 )
    126.8 ( 7.63 )
        day 7
    124.0 ( 8.23 )
    128.8 ( 16.97 )
    132.4 ( 10.66 )
    134.0 ( 8.75 )
    128.6 ( 9.18 )
        day 14
    126.5 ( 9.83 )
    127.3 ( 12.64 )
    128.6 ( 7.82 )
    135.4 ( 13.50 )
    128.7 ( 10.84 )
        day 21
    127.5 ( 8.32 )
    128.0 ( 13.49 )
    130.5 ( 10.40 )
    134.2 ( 9.91 )
    128.8 ( 10.79 )
        day 28
    125.3 ( 9.18 )
    127.1 ( 14.67 )
    129.6 ( 10.02 )
    136.4 ( 13.50 )
    125.7 ( 9.71 )
        day 56
    126.7 ( 6.96 )
    125.8 ( 11.15 )
    128.6 ( 10.63 )
    133.6 ( 12.00 )
    129.3 ( 11.39 )
        day 84
    126.5 ( 8.78 )
    124.9 ( 9.75 )
    125.9 ( 11.19 )
    131.1 ( 10.91 )
    129.3 ( 9.24 )
    No statistical analyses for this end point

    Secondary: Plasma PK parameter - AUC 0-8h

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    End point title
    Plasma PK parameter - AUC 0-8h [13]
    End point description
    Tropifexor levels were determined in plasma using a validated LC-MS/MS method. AUC0-t=The area under the plasma concentration-time curve from time zero to time ‘t’ where t is a defined time point after administration [mass x time / volume]
    End point type
    Secondary
    End point timeframe
    Day 1, Day 28
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: descriptive analysis
    End point values
    LJN452 - 0.03 mg qd LJN452 - 0.06 mg qd LJN452 - 0.09 mg qd LJN452 - 0.15 mg qd
    Number of subjects analysed
    9
    7
    3
    4
    Units: hr*ng/mL
    arithmetic mean (standard deviation)
        Day 1
    4.98 ( 2.87 )
    12.1 ( 2.68 )
    999 ( 999 )
    24.5 ( 15.9 )
        Day 28
    7.95 ( 4.21 )
    17.6 ( 5.30 )
    23.4 ( 8.70 )
    44.2 ( 25.8 )
    No statistical analyses for this end point

    Secondary: Plasma PK parameter - Cmax

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    End point title
    Plasma PK parameter - Cmax [14]
    End point description
    Tropifexor levels were determined in plasma using a validated LC-MS/MS method. Cmax=The observed maximum plasma concentration following drug administration [mass /volume]
    End point type
    Secondary
    End point timeframe
    Day 1, Day 28
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: descriptive analysis
    End point values
    LJN452 - 0.03 mg qd LJN452 - 0.06 mg qd LJN452 - 0.09 mg qd LJN452 - 0.15 mg qd
    Number of subjects analysed
    11
    9
    12
    8
    Units: ng/mL
    arithmetic mean (standard deviation)
        Day 1
    1.04 ( 0.484 )
    1.80 ( 0.585 )
    2.37 ( 1.56 )
    4.84 ( 2.59 )
        Day 28
    1.25 ( 0.559 )
    2.55 ( 0.946 )
    4.30 ( 2.10 )
    6.37 ( 3.40 )
    No statistical analyses for this end point

    Secondary: Plasma PK parameter - Tmax

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    End point title
    Plasma PK parameter - Tmax [15]
    End point description
    Tropifexor levels were determined in plasma using a validated LC-MS/MS method. Tmax = The time to reach the maximum concentration after drug administration [time]
    End point type
    Secondary
    End point timeframe
    Day 1, Day 28
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: descriptive analysis
    End point values
    LJN452 - 0.03 mg qd LJN452 - 0.06 mg qd LJN452 - 0.09 mg qd LJN452 - 0.15 mg qd
    Number of subjects analysed
    11
    9
    12
    8
    Units: hr
    median (inter-quartile range (Q1-Q3))
        Day 1
    4.12 (2.00 to 8.00)
    4.00 (3.70 to 6.00)
    4.00 (0 to 7.83)
    4.00 (4.00 to 4.18)
        Day 28
    4.08 (2.00 to 8.00)
    4.00 (3.13 to 7.60)
    4.00 (0 to 6.00)
    5.00 (3.03 to 6.00)
    No statistical analyses for this end point

    Secondary: Changes from baseline in total PBC-40 score

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    End point title
    Changes from baseline in total PBC-40 score
    End point description
    Median difference: LJN452 vs Placebo. Baseline is defined as the latest available predose value. The PBC-40 is a paper-based patient-derived, disease specific quality of life patient reported outcome (PRO) measure which was developed and validated for use in subjects with PBC (Jacoby et al 2005). It consists of 40 questions arranged in 8 domains with between 3 and 11 questions in each domain. Each question is scored from 1 to 5 in increasing order of severity. The difference in total sum score between each treated group and placebo at Day 28 is presented.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 28, Day 56, Day 84
    End point values
    LJN452 - 0.03 mg qd vs Placebo qd LJN452 - 0.06 mg qd vs. Placebo qd LJN452 - 0.09 mg qd vs. Placebo qd LJN452 - 0.15 mg qd vs. Placebo qd
    Number of subjects analysed
    10
    9
    12
    8
    Units: PBC-40 points
    median (confidence interval 90%)
        Day 28
    1.0 (-7.0 to 6.0)
    1.5 (-5.0 to 7.0)
    4.0 (-3.0 to 8.0)
    2.0 (-2.0 to 9.0)
        Day 56
    2.0 (-4.0 to 10.0)
    -2.0 (-12.0 to 4.0)
    -6.0 (-14.0 to 1.0)
    -11.0 (-21.0 to -1.0)
        Day 84
    -3.0 (-11.0 to 4.0)
    -1.0 (-10.0 to 8.0)
    -6.5 (-15.0 to 1.0)
    -3.5 (-11.0 to 3.0)
    No statistical analyses for this end point

    Secondary: Change from baseline in itch subdomain of PBC-40 score

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    End point title
    Change from baseline in itch subdomain of PBC-40 score
    End point description
    Median difference: LJN452 vs Placebo. Baseline is defined as the latest available predose value. The domain specifically relates to cholestatic itch symptomatology. In addition to the investigation of the total PBC-40 sum score, the sum scores from the 3 question itch sub-domain of the PBC-40 questionnaire was determined and used to test for an effect of tropifexor relative to placebo.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 28, Day 56, Day 84
    End point values
    LJN452 - 0.06 mg qd vs. Placebo qd LJN452 - 0.09 mg qd vs. Placebo qd LJN452 - 0.15 mg qd vs. Placebo qd LJN452 - 0.03 mg qd vs Placebo qd
    Number of subjects analysed
    9
    12
    8
    9
    Units: PBC-40 points
    median (confidence interval 90%)
        Day 28
    1.0 (0.0 to 2.0)
    2.0 (0.0 to 4.0)
    2.0 (0.0 to 5.0)
    1.0 (-1.0 to 2.0)
        Day 56
    1.0 (0.0 to 2.0)
    0.0 (-1.0 to 2.0)
    0.0 (-1.0 to 1.0)
    0.0 (-1.0 to 2.0)
        Day 84
    0.0 (-2.0 to 1.0)
    0.0 (-2.0 to 1.0)
    0.0 (-2.0 to 1.0)
    -1.0 (-3.0 to 1.0)
    No statistical analyses for this end point

    Secondary: Change from baseline in Global Itch Visual Analogue Scale (VAS)

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    End point title
    Change from baseline in Global Itch Visual Analogue Scale (VAS)
    End point description
    The Global Itch Visual Analogue Scale, a 100 mm visual analogue scale (VAS) was used to assess the severity of patients itch (ranging from 0 = none at all to 10 = the worst imaginable itch) and the 100 mm Sleep Disturbance Visual Analogue Scale was used to assess the impact of nocturnal itch on sleep (from 0 = no sleep loss to 10 = cannot sleep at all). The score (distance in mm from left) on the VAS was recorded for both parameters by the patient marking with a line and used to test for an effect of tropifexor over placebo.
    End point type
    Secondary
    End point timeframe
    Day 7, Day 14, Day 21, Day 28, Day 56, and Day 84
    End point values
    LJN452 - 0.03 mg qd vs Placebo qd LJN452 - 0.06 mg qd vs. Placebo qd LJN452 - 0.09 mg qd vs. Placebo qd LJN452 - 0.15 mg qd vs. Placebo qd
    Number of subjects analysed
    10
    9
    12
    8
    Units: mm
    arithmetic mean (confidence interval 90%)
        Day 7
    -2.78 (-16.91 to 11.34)
    11.34 (-2.78 to 25.46)
    13.92 (0.58 to 27.25)
    26.70 (11.97 to 41.44)
        Day 14
    -14.07 (-27.85 to -0.28)
    7.74 (-6.05 to 21.52)
    0.48 (-12.57 to 13.53)
    8.17 (-6.96 to 23.29)
        Day 21
    7.78 (-6.81 to 22.38)
    16.79 (2.20 to 31.38)
    5.02 (-8.79 to 18.83)
    5.90 (-10.86 to 22.66)
        Day 28
    7.03 (-8.36 to 22.43)
    14.05 (-1.35 to 29.44)
    0.19 (-14.38 to 14.77)
    8.91 (-9.34 to 27.15)
        Day 56
    -15.25 (-27.30 to -3.19)
    -1.75 (-13.80 to 10.31)
    -13.82 (-25.21 to -2.43)
    -11.08 (-23.95 to 1.80)
        Day 84
    -16.93 (-31.31 to -2.54)
    -10.90 (-25.29 to 3.48)
    -18.23 (-31.81 to -4.64)
    -16.93 (-31.94 to -1.92)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 56 days post last dose.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    LJN452 - 0.03 mg qd
    Reporting group description
    Tropifexor 0.03 mg daily for 28 days

    Reporting group title
    Placebo qd
    Reporting group description
    Tropifexor placebo daily for 28 days

    Reporting group title
    LJN452 - 0.15 mg qd
    Reporting group description
    Tropifexor 0.15 mg daily for 28 days

    Reporting group title
    LJN452 - 0.06 mg qd
    Reporting group description
    Tropifexor 0.06 mg daily for 28 days

    Reporting group title
    LJN452 - 0.09 mg qd
    Reporting group description
    Tropifexor 0.09 mg daily for 28 days

    Serious adverse events
    LJN452 - 0.03 mg qd Placebo qd LJN452 - 0.15 mg qd LJN452 - 0.06 mg qd LJN452 - 0.09 mg qd
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    LJN452 - 0.03 mg qd Placebo qd LJN452 - 0.15 mg qd LJN452 - 0.06 mg qd LJN452 - 0.09 mg qd
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 11 (81.82%)
    16 / 21 (76.19%)
    8 / 8 (100.00%)
    8 / 9 (88.89%)
    11 / 12 (91.67%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 21 (4.76%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    0
    1
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Oedema peripheral
         subjects affected / exposed
    0 / 11 (0.00%)
    2 / 21 (9.52%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Reproductive system and breast disorders
    Vulvovaginal discomfort
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 21 (4.76%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Epistaxis
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 21 (4.76%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Nasal congestion
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Productive cough
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    1
    Sinus congestion
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Psychiatric disorders
    Initial insomnia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 21 (4.76%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Insomnia
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 21 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    0
    1
    Sleep disorder
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 21 (4.76%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    1
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 21 (0.00%)
    2 / 8 (25.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 21 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    2
    Blood creatinine increased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 21 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Low density lipoprotein increased
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 21 (4.76%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Weight increased
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    2 / 11 (18.18%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    Muscle strain
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 21 (4.76%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Cardiac disorders
    Trifascicular block
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 21 (4.76%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Dizziness
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 21 (4.76%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Dysgeusia
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Headache
         subjects affected / exposed
    0 / 11 (0.00%)
    3 / 21 (14.29%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    3
    1
    0
    2
    Hypoaesthesia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    1
    Optic neuritis
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 21 (4.76%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Leukopenia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Thrombocytopenia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Eye disorders
    Dry eye
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 21 (4.76%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Eye pruritus
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 21 (4.76%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Abdominal distension
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Abdominal pain lower
         subjects affected / exposed
    2 / 11 (18.18%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    1 / 11 (9.09%)
    3 / 21 (14.29%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    3
    0
    0
    1
    Constipation
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    1
    Diarrhoea
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    1
    Dry mouth
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 21 (4.76%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Dyspepsia
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 21 (0.00%)
    1 / 8 (12.50%)
    2 / 9 (22.22%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    1
    2
    0
    Epigastric discomfort
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Flatulence
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    2
    0
    0
    0
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 21 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 21 (4.76%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Nausea
         subjects affected / exposed
    1 / 11 (9.09%)
    3 / 21 (14.29%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    2 / 12 (16.67%)
         occurrences all number
    1
    3
    0
    1
    2
    Varices oesophageal
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Vomiting
         subjects affected / exposed
    1 / 11 (9.09%)
    2 / 21 (9.52%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    2
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    3 / 11 (27.27%)
    6 / 21 (28.57%)
    7 / 8 (87.50%)
    6 / 9 (66.67%)
    5 / 12 (41.67%)
         occurrences all number
    3
    7
    7
    7
    5
    Pruritus generalised
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    1
    Psoriasis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Rash
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 21 (4.76%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    2
    0
    0
    Rash maculo-papular
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    1
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    1
    Pollakiuria
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 21 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Proteinuria
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 21 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Costochondritis
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 21 (4.76%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Muscle spasms
         subjects affected / exposed
    2 / 11 (18.18%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    Pain in extremity
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Infections and infestations
    Fungal infection
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    2 / 11 (18.18%)
    1 / 21 (4.76%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    2
    1
    0
    0
    1
    Overgrowth bacterial
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 21 (4.76%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Pneumonia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    0
    1
    Rash pustular
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Sinusitis
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Tooth abscess
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    0
    0
    0
    2
    Viral infection
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 21 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 21 (0.00%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 11 (0.00%)
    2 / 21 (9.52%)
    1 / 8 (12.50%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    2
    1
    0
    0
    Hypercholesterolaemia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 21 (4.76%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    Hyperlipidaemia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 21 (4.76%)
    0 / 8 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Iron deficiency
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 21 (0.00%)
    0 / 8 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Sep 2015
    The purpose of this amendment was to address comments from a health authority. Additional inclusion criterion for Part 2 were updated.
    06 Nov 2015
    During the creation of Version No. 01 of the protocol, pregnancy testing was inadvertently removed from the Assessment Schedule. The purpose of this amendment was to re-add pregnancy testing into the protocol.
    18 Mar 2016
    The purpose of this amendment was to add a separate renal function exclusion criteria (criteria no.14). Exclusion criteria 2 and 3 were updated. In addition, other minor changes, such as the inclusion of ALP isozyme analysis, a patient dosing diary to monitor compliance, and typographical corrections were made to the protocol.
    14 Jul 2016
    The purpose of this amendment was to address feedback from a health authority. Changes have also been made to the protocol to reduce the burden on the patients participating in the study. Additional changes were made including clarification and slight modification of eligibility criteria (BMI range in the inclusion criteria 5 was updated, additional inclusion criteria for Part 1 were updated and exclusion criteria 3 and 4 were updated), addition of updated text describing the statistical analysis, addition of a higher dosage form, and addition of minor editorial updates.
    22 Jun 2017
    To enable higher dose(s) in Part 1 & 2 of the study, supported by new preclinical safety data, and to update the Part 2 study design to allow 12 wks of treatment in patients with PBC, to provide longer-term safety, tolerability and efficacy data. The additional incl criteria for Part 2 were updated to add further details. Exclusion criteria 2 & 10 were updated. Excl criteria 3, 4, 15, 16, 17 & 18 were added in this amendment.
    27 Nov 2017
    The purpose of this amendment was to address comments received from a health authority in response to protocol amendment 5. In addition, the blood volume was updated to enable the collection of additional samples for Vitamin D, biomarker and PK back-up samples. The inclusion criteria 4 was updated to included additional biochemical criteria at enrollment. The exclusion 4, 14 and 15 were updated to add additional details.

    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.
    Part 2 was not executed and a decision was made to terminate the study early as data revealed that Part 1 fulfilled the strategic purpose of the study.
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    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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