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    Clinical Trial Results:
    A two-part, randomized, placebo controlled, double blind, multicenter, Phase 3 study to evaluate the efficacy and safety of linerixibat for the treatment of cholestatic pruritus in participants with primary biliary cholangitis (PBC).

    Summary
    EudraCT number
    		 2021-000007-21
    Trial protocol
    		 FR   BE   IT   CZ   GR   ES  
    Global end of trial date
    20 Dec 2024

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

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    212620
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04950127
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    GlaxoSmithKline
    Sponsor organisation address
    Great West Road, Brentford, Middlesex, United Kingdom, TW8 9GS
    Public contact
    GSK Response Center, GlaxoSmithKline, 1 8664357343, GSKClinicalSupportHD@gsk.com
    Scientific contact
    GSK Response Center, GlaxoSmithKline, 1 8664357343, GSKClinicalSupportHD@gsk.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
    11 Feb 2025
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Dec 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate the effect of treatment with oral linerixibat compared with placebo on itch in PBC patients with cholestatic pruritus over 24 weeks (Part A).
    Protection of trial subjects
    None
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 Aug 2021
    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
    Argentina: 24
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    Brazil: 12
    Country: Number of subjects enrolled
    Bulgaria: 7
    Country: Number of subjects enrolled
    Canada: 6
    Country: Number of subjects enrolled
    China: 38
    Country: Number of subjects enrolled
    Czechia: 7
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    Germany: 4
    Country: Number of subjects enrolled
    Greece: 1
    Country: Number of subjects enrolled
    Israel: 6
    Country: Number of subjects enrolled
    Italy: 15
    Country: Number of subjects enrolled
    Japan: 34
    Country: Number of subjects enrolled
    Mexico: 13
    Country: Number of subjects enrolled
    Poland: 8
    Country: Number of subjects enrolled
    Russian Federation: 3
    Country: Number of subjects enrolled
    Spain: 4
    Country: Number of subjects enrolled
    United Kingdom: 18
    Country: Number of subjects enrolled
    United States: 36
    Worldwide total number of subjects
    238
    EEA total number of subjects
    48
    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)
    178
    From 65 to 84 years
    60
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 238 participants from Europe, North America, Latin America and Asia were enrolled and randomized.

    Pre-assignment
    Screening details
    		 This study was conducted in 2 parts: Part A,Part B. Participants were randomized in 1:1:1:1 ratio to receive either:linerixibat 40 milligram(mg) twice a day(BID) in Part A and Part B, linerixibat 40mg twice a day(BID) in Part A and placebo in Part B, placebo in Part A and Part B, or placebo in Part A and linerixibat 40mg twice a day(BID) in Part B

    Period 1
    Period 1 title
    Part A (Day 1 to Week 24)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Part A: Linerixibat 40 milligrams (mg)
    Arm description
    		 Participants were randomized to receive linerixibat 40 mg tablet orally twice a day (BID) in Part A (up to Week 24)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Linerixibat
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet taken twice daily

    Arm title
    		 Part A: Placebo
    Arm description
    		 Participants were randomized to receive Placebo orally twice a day (BID) in Part A (up to Week 24).
    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
    1 tablet taken twice daily

    Number of subjects in period 1
    		Part A: Linerixibat 40 milligrams (mg) Part A: Placebo
    Started
    119
    119
    Safety Population
    119
    118
    Completed
    103
    108
    Not completed
    16
    11
         Consent withdrawn by subject
    9
    7
         Physician decision
    3
    2
         Adverse event, non-fatal
    4
    2
    Period 2
    Period 2 title
    Part B (Week 24 to Week 32)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Part B: Placebo in Part A and Part B
    Arm description
    		 Participants who were randomized to receive Placebo (up to Week 24) orally twice a day (BID) in Part A, continued to receive Placebo (from Week 24 to Week 32) orally twice a day (BID) in Part B.
    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
    1 tablet taken twice daily

    Arm title
    		 Part B: Placebo in Part A and Linerixibat 40 mg in Part B
    Arm description
    		 Participants who were randomized to receive Placebo (up to Week 24) orally twice a day (BID) in Part A, switched to receive linerixibat 40 mg tablet orally twice a day (BID) (from Week 24 to Week 32) in Part B.
    Arm type
    		 Placebo in Part A and Linerixibat in Part B

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet taken twice daily.

    Investigational medicinal product name
    Linerixibat
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet taken twice daily

    Arm title
    		 Part B: Linerixibat 40 mg in Part A and Placebo in Part B
    Arm description
    		 Participants who were randomized to receive linerixibat 40 mg tablet orally BID (up to Week 24) in Part A, switched to receive Placebo (from Week 24 to Week 32) orally twice a day (BID) in Part B.
    Arm type
    		 Linerixibat in Part A and Placebo in Part B

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet taken twice daily

    Investigational medicinal product name
    Linerixibat
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet taken twice daily

    Arm title
    		 Part B: Linerixibat 40 mg in Part A and Part B
    Arm description
    		 Participants who were randomized to receive linerixibat 40 mg tablet orally twice a day (BID) (up to Week 24) in Part A, continued to receive linerixibat 40 mg twice a day (BID) (from Week 24 to Week 32) in Part B.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Linerixibat
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet taken twice daily

    Number of subjects in period 2
    		Part B: Placebo in Part A and Part B Part B: Placebo in Part A and Linerixibat 40 mg in Part B Part B: Linerixibat 40 mg in Part A and Placebo in Part B Part B: Linerixibat 40 mg in Part A and Part B
    Started
    55
    53
    49
    54
    Safety Population
    53 [1]
    52 [2]
    46 [3]
    45 [4]
    Completed
    55
    53
    49
    49
    Not completed
    0
    0
    0
    5
         Consent withdrawn by subject
    -
    -
    -
    4
         Physician decision
    -
    -
    -
    1
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The Safety Population includes participants who received at least 1 dose in Part B.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The Safety Population includes participants who received at least 1 dose in Part B.
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The Safety Population includes participants who received at least 1 dose in Part B.
    [4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The Safety Population includes participants who received at least 1 dose in Part B.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part A: Linerixibat 40 milligrams (mg)
    Reporting group description
    		 Participants were randomized to receive linerixibat 40 mg tablet orally twice a day (BID) in Part A (up to Week 24)

    Reporting group title
    Part A: Placebo
    Reporting group description
    		 Participants were randomized to receive Placebo orally twice a day (BID) in Part A (up to Week 24).

    Reporting group values
    		 Part A: Linerixibat 40 milligrams (mg) Part A: Placebo Total
    Number of subjects
    		 119 119 238
    Age Categorical
    Units: Participants
        18-49 Years
    		 42 30 72
        50-64 Years
    		 52 54 106
        >=65 Years
    		 25 35 60
    Age continuous
    One participant from Placebo arm was not dosed and hence was not included in the age continuous calculation (N=118).
    Units: years
        arithmetic mean (standard deviation)
    		 54.7 ( 11.19 ) 57.0 ( 10.96 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 113 113 226
        Male
    		 6 6 12

    End points

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    End points reporting groups
    Reporting group title
    Part A: Linerixibat 40 milligrams (mg)
    Reporting group description
    		 Participants were randomized to receive linerixibat 40 mg tablet orally twice a day (BID) in Part A (up to Week 24)

    Reporting group title
    Part A: Placebo
    Reporting group description
    		 Participants were randomized to receive Placebo orally twice a day (BID) in Part A (up to Week 24).
    Reporting group title
    Part B: Placebo in Part A and Part B
    Reporting group description
    		 Participants who were randomized to receive Placebo (up to Week 24) orally twice a day (BID) in Part A, continued to receive Placebo (from Week 24 to Week 32) orally twice a day (BID) in Part B.

    Reporting group title
    Part B: Placebo in Part A and Linerixibat 40 mg in Part B
    Reporting group description
    		 Participants who were randomized to receive Placebo (up to Week 24) orally twice a day (BID) in Part A, switched to receive linerixibat 40 mg tablet orally twice a day (BID) (from Week 24 to Week 32) in Part B.

    Reporting group title
    Part B: Linerixibat 40 mg in Part A and Placebo in Part B
    Reporting group description
    		 Participants who were randomized to receive linerixibat 40 mg tablet orally BID (up to Week 24) in Part A, switched to receive Placebo (from Week 24 to Week 32) orally twice a day (BID) in Part B.

    Reporting group title
    Part B: Linerixibat 40 mg in Part A and Part B
    Reporting group description
    		 Participants who were randomized to receive linerixibat 40 mg tablet orally twice a day (BID) (up to Week 24) in Part A, continued to receive linerixibat 40 mg twice a day (BID) (from Week 24 to Week 32) in Part B.

    Primary: Part A: Mean Change from Baseline in Monthly Itch Scores over 24 weeks using Numerical Rating Scale (NRS)

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    End point title
    		 Part A: Mean Change from Baseline in Monthly Itch Scores over 24 weeks using Numerical Rating Scale (NRS)
    End point description
    Itch Scores were assessed using a NRS twice daily, ranging from 0 to 10, where 0 represents no itching and 10 the worst imaginable itching. The worst daily itch score was defined as the worst of the two scores recorded daily. The weekly itch score was defined as the average of the worst daily itch scores in one week. The monthly itch score was defined as the worst weekly itch score for the month (4 weeks). Higher monthly itch scores indicate worse itching. Baseline is the worst weekly itch score in the 28 days prior to randomization (Day 1). Change from Baseline is defined as the post dose value minus baseline value. Least-squares (LS) means and the corresponding 95% confidence intervals are reported by taking average of LS means of change from baseline in monthly itch scores obtained over 24 weeks using equal weighting for all time points. Analyzed using Mixed Model Repeated Measures (MMRM) method. The analysis was performed on the ITT set that included all randomized participants.
    End point type
    Primary
    End point timeframe
    Baseline and up to week 24
    End point values
    		 Part A: Linerixibat 40 milligrams (mg) Part A: Placebo
    Number of subjects analysed
    119
    118
    Units: Scores on a scale
        least squares mean (confidence interval 95%)
    -2.86 (-3.23 to -2.50)
    -2.15 (-2.51 to -1.78)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    The mixed model repeated measures analysis includes Treatment Group, Visit, Visit*Treatment Group interaction, Baseline PBC-40 domain scores, Visit*Baseline PBC-40 domain scores interaction, Baseline Concomitant Itch Medication.
    Comparison groups
    Part A: Placebo v Part A: Linerixibat 40 milligrams (mg)
    Number of subjects included in analysis
    237
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.15
         upper limit
    		 -0.28

    Secondary: Part A: Mean Change from Baseline in Weekly Itch Score using NRS at Week 2

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    End point title
    		 Part A: Mean Change from Baseline in Weekly Itch Score using NRS at Week 2
    End point description
    Itch Score was assessed using a twice daily NRS, ranging from 0 to 10, where 0 represents no itching and 10 the worst imaginable itching. The worst daily itch score was defined as the worst of the two scores recorded daily. The weekly itch score was defined as the average of the worst daily itch scores in one week. Higher weekly itch scores indicate worse itching. Baseline is the average of the Worst Daily Itch scores in the 7 days prior to randomization (Day 1). Change from Baseline is defined as the Week 2 value minus baseline value. Key secondary endpoints were tested in a step-down/hierarchical approach. Mean Change from Baseline in Weekly Itch Score at Week 2 was the first endpoint tested in the hierarchical analysis. LS mean and the corresponding 95% confidence intervals are reported using Mixed Model Repeated Measures (MMRM) method.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 2
    End point values
    		 Part A: Linerixibat 40 milligrams (mg) Part A: Placebo
    Number of subjects analysed
    117
    116
    Units: Scores on a scale
        least squares mean (confidence interval 95%)
    -1.78 (-2.08 to -1.48)
    -1.07 (-1.37 to -0.77)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    The mixed model repeated measures analysis includes Treatment Group, Week, Week*Treatment Group interaction, Baseline Weekly Itch score (WIS), Visit*Baseline WIS interaction, Baseline Concomitant Itch Medication.
    Comparison groups
    Part A: Placebo v Part A: Linerixibat 40 milligrams (mg)
    Number of subjects included in analysis
    233
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [1]
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.07
         upper limit
    		 -0.34
    Notes
    [1] - Adjusted for multiplicity as per Statistical Analysis Plan (SAP)

    Secondary: Part A: Mean Change from Baseline in Monthly Sleep Score as measured by NRS over 24 weeks

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    End point title
    		 Part A: Mean Change from Baseline in Monthly Sleep Score as measured by NRS over 24 weeks
    End point description
    Sleep Scores were assessed using an NRS scale, ranging from 0 to 10, where 0 represents no sleep interference and 10 is complete sleep interference. The weekly sleep scale is the average of the daily sleep scores for each week. The monthly sleep score was defined as the worst weekly sleep score for the month (4 weeks). Higher monthly sleep scores indicate higher impact on sleep. Baseline is the worst Weekly Sleep Score in the 28 days prior to randomization (Day 1). Change from Baseline is defined as the post dose value minus baseline value. LS means and the corresponding 95% confidence intervals are reported by taking average of LS means of change from baseline in monthly sleep scores obtained over 24 weeks using equal weighting for all time points analyzed using Mixed Model Repeated Measures (MMRM) method. Mean Change from Baseline in Monthly Sleep Score over 24 weeks was the second endpoint tested in the hierarchical analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and up to week 24
    End point values
    		 Part A: Linerixibat 40 milligrams (mg) Part A: Placebo
    Number of subjects analysed
    119
    118
    Units: Scores on a scale
        least squares mean (confidence interval 95%)
    -2.77 (-3.15 to -2.38)
    -2.24 (-2.62 to -1.86)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    The mixed model repeated measures analysis includes Treatment Group, Visit, Visit*Treatment Group interaction, Baseline PBC-40 domain scores, Visit*Baseline PBC-40 domain scores interaction, Baseline Concomitant Itch Medication.
    Comparison groups
    Part A: Placebo v Part A: Linerixibat 40 milligrams (mg)
    Number of subjects included in analysis
    237
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.024 [2]
    Method
    		 Mixed Model Repeated Analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.98
         upper limit
    		 -0.07
    Notes
    [2] - Adjusted for multiplicity as per Statistical Analysis Plan (SAP)

    Secondary: Part A: Percentage of Responders Defined as Achieving more than or equal to (>=) 2-point Reduction from Baseline in the Monthly Itch Score (MIS) at Week 24

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    End point title
    		 Part A: Percentage of Responders Defined as Achieving more than or equal to (>=) 2-point Reduction from Baseline in the Monthly Itch Score (MIS) at Week 24
    End point description
    Monthly Itch Score was assessed using an NRS, ranging from 0 to 10, where 0 represents no itching and 10 the worst imaginable itching. The Monthly Itch Score was determined from the worst weekly itch score for the month (4 weeks). Baseline is the worst weekly itch score in the 28 days prior to randomization (Day 1). Responders were defined as participants achieving >=2-point reduction (improvement) from baseline in the Monthly Itch Score. Percentage of Responders achieving >= 2-point Reduction from Baseline in the Monthly Itch Score at Week 24 was the third endpoint tested in the hierarchical analysis. The analysis was performed on the ITT set that included all randomized participants. Participants in the ITT Population were classified according to the treatment as randomized. Percentage values were rounded to the nearest whole number.
    End point type
    Secondary
    End point timeframe
    At Week 24
    End point values
    		 Part A: Linerixibat 40 milligrams (mg) Part A: Placebo
    Number of subjects analysed
    119
    119
    Units: Percentage of participants
        number (not applicable)
    68.0
    64.0
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Cochran-Mantel-Haenszel (CMH) stratified analysis adjusted for baseline factors: Baseline Itch Severity (Moderate: >=4 and less than [<]7, Severe: >=7); Concomitant cholestatic pruritus treatment regimen (Regimen contains Bile Acid Binding Resin [BABR], Regimen does not contain BABR, No defined treatment). Multiple imputation of missing Monthly itch scores was done before deriving responder definitions. Imputed datasets were analyzed using the CMH method and combined.
    Comparison groups
    Part A: Placebo v Part A: Linerixibat 40 milligrams (mg)
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.539 [3]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Percentage Difference
    Point estimate
    4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9
         upper limit
    		 17
    Notes
    [3] - Adjusted for multiplicity as per Statistical Analysis Plan (SAP)

    Secondary: Part A: Percentage of Responders Defined as Achieving a >=3-point Reduction from Baseline in the Monthly Itch Score (MIS) at Week 24

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    End point title
    		 Part A: Percentage of Responders Defined as Achieving a >=3-point Reduction from Baseline in the Monthly Itch Score (MIS) at Week 24
    End point description
    Monthly Itch Score was assessed using an NRS, ranging from 0 to 10, where 0 represents no itching and 10 the worst imaginable itching. The Monthly Itch Score was determined from the worst weekly itch score for the month (4 weeks). Baseline is the worst weekly itch score in the 28 days prior to randomization. Responders were defined as participants achieving >=3-point reduction (improvement) from baseline in the Monthly Itch Score. Percentage of Responders achieving >= 3-point Reduction from Baseline in the Monthly Itch Score at Week 24 was the fourth endpoint to be tested in the hierarchical analysis. The analysis was performed on the ITT set that included all randomized participants. Participants in the ITT Population were classified according to the treatment as randomized. Percentage values were rounded to the nearest whole number.
    End point type
    Secondary
    End point timeframe
    At Week 24
    End point values
    		 Part A: Linerixibat 40 milligrams (mg) Part A: Placebo
    Number of subjects analysed
    119
    119
    Units: Percentage of participants
        number (not applicable)
    56.0
    43.0
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Cochran-Mantel-Haenszel (CMH) stratified analysis adjusted for baseline factors: Baseline Itch Severity (Moderate: greater than or equal to [>=]4 and less than [<]7, Severe: >=7); Concomitant cholestatic pruritus treatment regimen (Regimen contains Bile Acid Binding Resin [BABR], Regimen does not contain BABR, No defined treatment). Multiple imputation of missing MIS was done before deriving responder definitions. Imputed datasets were analyzed using the CMH method and combined.
    Comparison groups
    Part A: Placebo v Part A: Linerixibat 40 milligrams (mg)
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.043 [4]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Percentage Difference
    Point estimate
    13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 27
    Notes
    [4] - Adjusted for multiplicity; two-sided p-values <0.05 were considered to be nominally significant as per SAP.

    Secondary: Part A: Proportion of Responders Defined as Achieving a >=4-point Reduction from Baseline in the Monthly Itch Score (MIS) at Week 24

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    End point title
    		 Part A: Proportion of Responders Defined as Achieving a >=4-point Reduction from Baseline in the Monthly Itch Score (MIS) at Week 24
    End point description
    Monthly Itch Score was assessed using an NRS, ranging from 0 to 10, where 0 represents no itching and 10 the worst imaginable itching. The Monthly Itch Score was determined from the worst weekly itch score for the month (4 weeks). Baseline is the worst weekly itch score in the 28 days prior to randomization. Responders were defined as participants achieving >=4-point reduction (improvement) from baseline in the Monthly Itch Score. Percentage of Responders achieving >= 4-point Reduction from Baseline in the Monthly Itch Score at Week 24 was the fifth endpoint to be tested in the hierarchical analysis. The analysis was performed on the ITT set that included all randomized participants. Participants in the ITT Population were classified according to the treatment as randomized. Percentage values were rounded to the nearest whole number.
    End point type
    Secondary
    End point timeframe
    At Week 24
    End point values
    		 Part A: Linerixibat 40 milligrams (mg) Part A: Placebo
    Number of subjects analysed
    119
    119
    Units: Percentage of participants
        number (not applicable)
    41.0
    29.0
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Cochran-Mantel-Haenszel (CMH) stratified analysis adjusted for baseline factors: Baseline Itch Severity (Moderate: >=4 and <7, Severe: >=7); Concomitant cholestatic pruritus treatment regimen (Regimen contains BABR, Regimen does not contain BABR, No defined treatment). Multiple imputation of missing Monthly itch scores was done before deriving responder definitions. Imputed datasets were analyzed using the CMH method and combined.
    Comparison groups
    Part A: Placebo v Part A: Linerixibat 40 milligrams (mg)
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.539 [5]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Percentage Difference
    Point estimate
    12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 24
    Notes
    [5] - Adjusted for multiplicity; two-sided p-values <0.05 were considered to be nominally significant as per SAP.

    Secondary: Part A: Mean Change from Baseline in Primary Biliary Cholangitis-40 (PBC-40) Domain Scores at Week 24

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    End point title
    		 Part A: Mean Change from Baseline in Primary Biliary Cholangitis-40 (PBC-40) Domain Scores at Week 24
    End point description
    PBC40 is disease-specific health-related quality of life(HRQoL) questionnaire. It consists of 40 questions, which are grouped into 6 domains. Each question is scored from 1(least impact) to 5(greatest impact). For all questions, an answer of “Does/Did not apply” was scored 0. All questions within a domain are summed to obtain domain score. Domains were Symptoms(7 questions)-score range 6-35,Itch(3 questions)-score range 0-15,Fatigue(11 questions)-score range 11-55,Cognitive(6 questions)-score range 6-30,Emotional(3 questions)-score range 3-15,Social(10 questions)-score range 8-50. Higher scores for individual domains represent poorer quality of life. Baseline is the last assessment prior to Day 1. Change from Baseline was calculated as Week24 minus Baseline. ITT set included all randomized participants. Number of Participants Analyzed (N) was maximum number of participants analyzed for any domain, while Number analyzed (n) was number of participants included in model for each domain.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    		 Part A: Linerixibat 40 milligrams (mg) Part A: Placebo
    Number of subjects analysed
    95
    100
    Units: Scores on a scale
    least squares mean (confidence interval 95%)
        Cognitive (score range:6-30)(n=99, 95)
    -0.71 (-1.60 to 0.18)
    -1.47 (-2.36 to -0.58)
        Emotional (score range:3-15)(n=99, 95)
    -1.07 (-1.57 to -0.57)
    -1.34 (-1.83 to -0.84)
        Fatigue (score range:11-55)(n=100, 95)
    -2.94 (-4.63 to -1.26)
    -4.54 (-6.21 to -2.86)
        Itch (score range: 0 to 15) (n=100, 95)
    -3.47 (-4.08 to -2.86)
    -2.89 (-3.50 to -2.28)
        Social (score range:8-50)(n=99, 95)
    -2.57 (-3.71 to -1.43)
    -2.42 (-3.56 to -1.29)
        Symptoms (score range:6-35)(n=100, 95)
    0.54 (-0.18 to 1.25)
    0.08 (-0.62 to 0.79)
    Statistical analysis title
    		 Statistical Analysis 1 (Cognitive)
    Statistical analysis description
    The mixed model repeated measures analysis includes Treatment Group, Visit, Visit*Treatment Group interaction, Baseline PBC-40 domain scores, Visit*Baseline PBC-40 domain scores interaction, Baseline Concomitant Itch Medication.
    Comparison groups
    Part A: Placebo v Part A: Linerixibat 40 milligrams (mg)
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.176 [6]
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.34
         upper limit
    		 1.86
    Notes
    [6] - Not adjusted for multiplicity; two-sided p- values <0.05 were considered to be nominally significant as per SAP.
    Statistical analysis title
    		 Statistical Analysis 2 (Emotional)
    Statistical analysis description
    The mixed model repeated measures analysis includes Treatment Group, Visit, Visit*Treatment Group interaction, Baseline PBC-40 domain scores, Visit*Baseline PBC-40 domain scores interaction, Baseline Concomitant Itch Medication.
    Comparison groups
    Part A: Placebo v Part A: Linerixibat 40 milligrams (mg)
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.403 [7]
    Method
    		 Mixed Model Repeated Measure Analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.36
         upper limit
    		 0.89
    Notes
    [7] - Not adjusted for multiplicity; two-sided p- values <0.05 were considered to be nominally significant as per SAP.
    Statistical analysis title
    		 Statistical Analysis 3 (Fatigue)
    Statistical analysis description
    The mixed model repeated measures analysis includes Treatment Group, Visit, Visit*Treatment Group interaction, Baseline PBC-40 domain scores, Visit*Baseline PBC-40 domain scores interaction, Baseline Concomitant Itch Medication.
    Comparison groups
    Part A: Placebo v Part A: Linerixibat 40 milligrams (mg)
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.132 [8]
    Method
    		 Mixed Model Repeated Measures
    Parameter type
    		 Mean difference (net)
    Point estimate
    1.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.48
         upper limit
    		 3.67
    Notes
    [8] - Not adjusted for multiplicity; two-sided p- values <0.05 were considered to be nominally significant as per SAP.
    Statistical analysis title
    		 Statistical Analysis 4 (Itch)
    Statistical analysis description
    The mixed model repeated measures analysis includes Treatment Group, Visit, Visit*Treatment Group interaction, Baseline PBC-40 domain scores, Visit*Baseline PBC-40 domain scores interaction, Baseline Concomitant Itch Medication.
    Comparison groups
    Part A: Placebo v Part A: Linerixibat 40 milligrams (mg)
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.132 [9]
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.34
         upper limit
    		 0.18
    Notes
    [9] - Not adjusted for multiplicity; two-sided p- values <0.05 were considered to be nominally significant as per SAP.
    Statistical analysis title
    		 Statistical Analysis 5 (Social)
    Statistical analysis description
    The mixed model repeated measures analysis includes Treatment Group, Visit, Visit*Treatment Group interaction, Baseline PBC-40 domain scores, Visit*Baseline PBC-40 domain scores interaction, Baseline Concomitant Itch Medication.
    Comparison groups
    Part A: Placebo v Part A: Linerixibat 40 milligrams (mg)
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.836 [10]
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.57
         upper limit
    		 1.27
    Notes
    [10] - Not adjusted for multiplicity; two-sided p- values <0.05 were considered to be nominally significant as per SAP.
    Statistical analysis title
    		 Statistical Analysis 6 (Symptoms)
    Statistical analysis description
    The mixed model repeated measures analysis includes Treatment Group, Visit, Visit*Treatment Group interaction, Baseline PBC-40 domain scores, Visit*Baseline PBC-40 domain scores interaction, Baseline Concomitant Itch Medication.
    Comparison groups
    Part A: Placebo v Part A: Linerixibat 40 milligrams (mg)
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.318 [11]
    Method
    		 Mixed Model Repeated Measure Analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.44
         upper limit
    		 1.34
    Notes
    [11] - Not adjusted for multiplicity; two-sided p- values <0.05 were considered to be nominally significant as per SAP.

    Secondary: Part A: Mean Change from Baseline in Patient's Global Impression of Severity (PGI-S) over 24 weeks

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    End point title
    		 Part A: Mean Change from Baseline in Patient's Global Impression of Severity (PGI-S) over 24 weeks
    End point description
    The PGI-S is a patient-reported outcome measure used to assess the severity of symptoms from the participant's perspective. The PGI-S asks participant to rate the severity of their itch in the past 7 days on a single item, using a scale ranging from 0 (absent) to 5 (very severe). Higher score indicates higher severity. Baseline is the last assessment prior to the first dose of randomized treatment for Part A (Day 1). Change from Baseline is defined as the post dose value minus baseline value. LS means and the corresponding 95% confidence intervals are reported by taking average of LS means of change from baseline in PGI-S obtained over 24 weeks using equal weighting for all time points, analyzed using MMRM method. The analysis was performed on the ITT set that included all randomized participants. Only participants with data at baseline and at least one post-baseline time point were included.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 24
    End point values
    		 Part A: Linerixibat 40 milligrams (mg) Part A: Placebo
    Number of subjects analysed
    114
    111
    Units: Scores on a scale
        least squares mean (confidence interval 95%)
    -1.22 (-1.36 to -1.07)
    -0.84 (-0.99 to -0.70)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    The mixed model repeated measures analysis includes Treatment Group, Visit, Visit*Treatment Group interaction, Baseline PGI-S score, Visit*Baseline PGI-S score interaction, Baseline Concomitant Itch Medication.
    Comparison groups
    Part A: Placebo v Part A: Linerixibat 40 milligrams (mg)
    Number of subjects included in analysis
    225
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [12]
    Method
    		 Mixed Model Repeated Measure Analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.55
         upper limit
    		 -0.2
    Notes
    [12] - Not adjusted for multiplicity; two-sided p- values <0.05 were considered to be nominally significant as per SAP.

    Secondary: Part A: Patient's Global Impression of Change (PGI-C) scores over 24 weeks

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    End point title
    		 Part A: Patient's Global Impression of Change (PGI-C) scores over 24 weeks
    End point description
    Patient’s Global Impression of Change (PGI-C) was assessed using a 7-level response scale, ranging from 1 (very much improved) to 7 (very much worse). Higher score indicates higher level of change. LS means and the corresponding 95% confidence intervals are reported by taking average of LS means of PGI-C obtained over 24 weeks using equal weighting for all timepoints, analyzed using Mixed Model Repeated Measures (MMRM) method. The analysis was performed on the ITT set that included all randomized participants. Participants in the ITT Population were classified according to the treatment as randomized. Only participants with data for at least one time point were included.
    End point type
    Secondary
    End point timeframe
    Week 4 up to 24 weeks
    End point values
    		 Part A: Linerixibat 40 milligrams (mg) Part A: Placebo
    Number of subjects analysed
    117
    116
    Units: Scores on a scale
        least squares mean (confidence interval 95%)
    1.97 (1.74 to 2.20)
    2.46 (2.23 to 2.69)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    The mixed model repeated measures analysis includes Treatment Group, Visit, Visit*Treatment Group interaction, Baseline Concomitant Itch Medication.
    Comparison groups
    Part A: Placebo v Part A: Linerixibat 40 milligrams (mg)
    Number of subjects included in analysis
    233
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [13]
    Method
    		 Mixed Model Repeated Measure Analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.76
         upper limit
    		 -0.21
    Notes
    [13] - Not adjusted for multiplicity; two-sided p- values <0.05 were considered to be nominally significant as per SAP.

    Secondary: Part A: Mean Change from Baseline in Alkaline Phosphatase (ALP) at Week 24

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    End point title
    		 Part A: Mean Change from Baseline in Alkaline Phosphatase (ALP) at Week 24
    End point description
    Blood samples were collected at indicated time points for evaluation of ALP. Change from Baseline in ALP at Week 24 was evaluated. Baseline was established using an average of two sets of laboratory values obtained at least 4 weeks apart within 56 days prior to randomization (Day 1). Change from Baseline was calculated as Week 24 value minus Baseline value. The analysis was performed on the ITT set that included all randomized participants. Participants in the ITT Population were classified according to the treatment as randomized. Only participants with data at baseline and at least one post-baseline time point were included.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    		 Part A: Linerixibat 40 milligrams (mg) Part A: Placebo
    Number of subjects analysed
    102
    107
    Units: International units per Liter (IU/L)
        least squares mean (confidence interval 95%)
    10.61 (-8.53 to 29.74)
    -8.03 (-26.79 to 10.74)
    No statistical analyses for this end point

    Secondary: Part A: Mean change from baseline in Bilirubin at Week 24

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    End point title
    		 Part A: Mean change from baseline in Bilirubin at Week 24
    End point description
    Blood samples were collected at indicated time points for evaluation of Bilirubin. Change from Baseline in total bilirubin at Week 24 was evaluated. Baseline was established using an average of two sets of laboratory values obtained at least 4 weeks apart within 56 days prior to randomization (Day 1). Change from Baseline was calculated as Week 24 value minus Baseline value. The analysis was performed on the ITT set that included all randomized participants. Participants in the ITT Population were classified according to the treatment as randomized. Only participants with data at baseline and at least one post-baseline time point were included.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    		 Part A: Linerixibat 40 milligrams (mg) Part A: Placebo
    Number of subjects analysed
    102
    107
    Units: Micromoles per Liter (mmol/L)
        least squares mean (confidence interval 95%)
    1.77 (0.84 to 2.71)
    -0.31 (-1.24 to 0.62)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    SAEs were collected from the signing of informed consent until last visit (Week 32) or follow up phone call. AEs were collected from start of treatment until last visit (Week 32) or follow up phone call.
    Adverse event reporting additional description
    All randomized participants from ITT population (N=238) were included in Part A. One participant in Part A was not included in Safety population (N=237) and 15 participants from ITT Population (N=211) in Part B were not included in Safety population (N=196) as they did not receive study intervention.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    27.1
    Reporting groups
    Reporting group title
    Part A: Placebo
    Reporting group description
    		 Participants were randomized to receive Placebo in Part A (up to Week 24).

    Reporting group title
    Part A: Linerixibat 40 milligrams (mg)
    Reporting group description
    		 Participants were randomized to receive Linerixibat 40 mg orally twice a day (BID) in Part A (up to Week 24).

    Reporting group title
    Part B: Placebo in Part A and Part B
    Reporting group description
    		 Participants who were randomized to receive Placebo (up to Week 24) in Part A, continued to receive Placebo (from Week 24 to Week 32) in Part B.

    Reporting group title
    Part B: Placebo in Part A and Linerixibat 40 mg in Part B
    Reporting group description
    		 Participants who were randomized to receive Placebo (up to Week 24) in Part A, switched to receive Linerixibat 40 mg BID (from Week 24 to Week 32) in Part B.

    Reporting group title
    Part B: Linerixibat 40 mg in Part A and Placebo in Part B
    Reporting group description
    		 Participants who were randomized to receive Linerixibat 40 mg BID (up to Week 24) in Part A, switched to receive Placebo (from Week 24 to Week 32) in Part B.

    Reporting group title
    Part B: Linerixibat 40 mg in Part A and Part B
    Reporting group description
    		 Participants who were randomized to receive Linerixibat 40 mg BID (up to Week 24) in Part A, continued to receive Linerixibat 40 mg BID (from Week 24 to Week 32) in Part B.

    Serious adverse events
    		 Part A: Placebo Part A: Linerixibat 40 milligrams (mg) Part B: Placebo in Part A and Part B Part B: Placebo in Part A and Linerixibat 40 mg in Part B Part B: Linerixibat 40 mg in Part A and Placebo in Part B Part B: Linerixibat 40 mg in Part A and Part B
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 118 (3.39%)
    14 / 119 (11.76%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    2 / 46 (4.35%)
    0 / 45 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Investigations
    Blood pressure increased
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 119 (0.84%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    0 / 46 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant melanoma
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 119 (0.84%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    0 / 46 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal cell carcinoma
         subjects affected / exposed
    0 / 118 (0.00%)
    0 / 119 (0.00%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    1 / 46 (2.17%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Sinus arrest
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 119 (0.00%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    0 / 46 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral infarction
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 119 (0.84%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    0 / 46 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 119 (0.84%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    0 / 46 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 119 (0.00%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    0 / 46 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 119 (0.00%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    0 / 46 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 119 (0.84%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    0 / 46 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic disorder
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 119 (0.84%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    0 / 46 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytosis
         subjects affected / exposed
    0 / 118 (0.00%)
    0 / 119 (0.00%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    1 / 46 (2.17%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Ascites
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 119 (0.84%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    0 / 46 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 119 (0.84%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    0 / 46 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric mucosal lesion
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 119 (0.84%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    0 / 46 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Intermenstrual bleeding
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 119 (0.00%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    0 / 46 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 119 (0.84%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    0 / 46 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 119 (0.84%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    0 / 46 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 119 (0.84%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    0 / 46 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 119 (0.84%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    0 / 46 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 119 (0.84%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    0 / 46 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 119 (0.00%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    0 / 46 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 119 (0.00%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    0 / 46 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Part A: Placebo Part A: Linerixibat 40 milligrams (mg) Part B: Placebo in Part A and Part B Part B: Placebo in Part A and Linerixibat 40 mg in Part B Part B: Linerixibat 40 mg in Part A and Placebo in Part B Part B: Linerixibat 40 mg in Part A and Part B
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    54 / 118 (45.76%)
    96 / 119 (80.67%)
    5 / 53 (9.43%)
    16 / 52 (30.77%)
    3 / 46 (6.52%)
    7 / 45 (15.56%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    4 / 118 (3.39%)
    11 / 119 (9.24%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    0 / 46 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    4
    12
    0
    0
    0
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 118 (0.85%)
    10 / 119 (8.40%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    0 / 46 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    1
    11
    0
    0
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    3 / 118 (2.54%)
    7 / 119 (5.88%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    0 / 46 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    4
    7
    0
    0
    0
    0
    Headache
         subjects affected / exposed
    4 / 118 (3.39%)
    10 / 119 (8.40%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    0 / 46 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    5
    10
    0
    0
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    7 / 118 (5.93%)
    2 / 119 (1.68%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    0 / 46 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    8
    2
    0
    0
    0
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 118 (0.00%)
    0 / 119 (0.00%)
    2 / 53 (3.77%)
    3 / 52 (5.77%)
    0 / 46 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    0
    2
    3
    0
    1
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    6 / 118 (5.08%)
    8 / 119 (6.72%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    0 / 46 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    6
    10
    0
    0
    0
    0
    Abdominal pain
         subjects affected / exposed
    4 / 118 (3.39%)
    22 / 119 (18.49%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    0 / 46 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    4
    27
    0
    0
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    5 / 118 (4.24%)
    8 / 119 (6.72%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    0 / 46 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    6
    14
    0
    0
    0
    0
    Constipation
         subjects affected / exposed
    11 / 118 (9.32%)
    9 / 119 (7.56%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    0 / 46 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    11
    9
    0
    0
    0
    0
    Diarrhoea
         subjects affected / exposed
    21 / 118 (17.80%)
    72 / 119 (60.50%)
    3 / 53 (5.66%)
    14 / 52 (26.92%)
    0 / 46 (0.00%)
    6 / 45 (13.33%)
         occurrences all number
    28
    112
    3
    18
    0
    12
    Dyspepsia
         subjects affected / exposed
    1 / 118 (0.85%)
    9 / 119 (7.56%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    0 / 46 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    1
    9
    0
    0
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    5 / 118 (4.24%)
    8 / 119 (6.72%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    0 / 46 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    9
    13
    0
    0
    0
    0
    Nausea
         subjects affected / exposed
    11 / 118 (9.32%)
    12 / 119 (10.08%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    0 / 46 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    13
    17
    0
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Cholestatic pruritus
         subjects affected / exposed
    0 / 118 (0.00%)
    0 / 119 (0.00%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    3 / 46 (6.52%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    0
    3
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    6 / 118 (5.08%)
    7 / 119 (5.88%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    0 / 46 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    9
    8
    0
    0
    0
    0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    3 / 118 (2.54%)
    8 / 119 (6.72%)
    0 / 53 (0.00%)
    0 / 52 (0.00%)
    0 / 46 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    3
    9
    0
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Jan 2021
    Originial Protocol
    01 Mar 2021
    Amendment 1
    12 Jul 2021
    Amendment 2
    02 Sep 2021
    Amendment 3
    20 Nov 2023
    Amendment 4

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

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

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